Luminescent Measurements: Techniques used for determining the values of photometric parameters of light resulting from LUMINESCENCE.Intercalating Agents: Agents that are capable of inserting themselves between the successive bases in DNA, thus kinking, uncoiling or otherwise deforming it and therefore preventing its proper functioning. They are used in the study of DNA.Melphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - MELPHALAN, the racemic mixture - MERPHALAN, and the dextro isomer - MEDPHALAN; toxic to bone marrow, but little vesicant action; potential carcinogen.DNA Damage: Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.DNA Repair: The reconstruction of a continuous two-stranded DNA molecule without mismatch from a molecule which contained damaged regions. The major repair mechanisms are excision repair, in which defective regions in one strand are excised and resynthesized using the complementary base pairing information in the intact strand; photoreactivation repair, in which the lethal and mutagenic effects of ultraviolet light are eliminated; and post-replication repair, in which the primary lesions are not repaired, but the gaps in one daughter duplex are filled in by incorporation of portions of the other (undamaged) daughter duplex. Excision repair and post-replication repair are sometimes referred to as "dark repair" because they do not require light.DNA Breaks, Double-Stranded: Interruptions in the sugar-phosphate backbone of DNA, across both strands adjacently.Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Circadian Rhythm: The regular recurrence, in cycles of about 24 hours, of biological processes or activities, such as sensitivity to drugs and stimuli, hormone secretion, sleeping, and feeding.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Chemotherapy, Cancer, Regional Perfusion: Neoplasm drug therapy involving an extracorporeal circuit with temporary exclusion of the tumor-bearing area from the general circulation during which high concentrations of the drug are perfused to the isolated part.Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals.Veterinary Drugs: Drugs used by veterinarians in the treatment of animal diseases. The veterinarian's pharmacological armamentarium is the counterpart of drugs treating human diseases, with dosage and administration adjusted to the size, weight, disease, and idiosyncrasies of the species. In the United States most drugs are subject to federal regulations with special reference to the safety of drugs and residues in edible animal products.Education, Veterinary: Use for general articles concerning veterinary medical education.Antineoplastic Agents, Alkylating: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)Surgery, Veterinary: A board-certified specialty of VETERINARY MEDICINE, requiring at least four years of special education, training, and practice of veterinary surgery after graduation from veterinary school. In the written, oral, and practical examinations candidates may choose either large or small animal surgery. (From AVMA Directory, 43d ed, p278)Schools, Veterinary: Educational institutions for individuals specializing in the field of veterinary medicine.Pathology, Veterinary: The field of veterinary medicine concerned with the causes of and changes produced in the body by disease.Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group.Veterinarians: Individuals with a degree in veterinary medicine that provides them with training and qualifications to treat diseases and injuries of animals.Wegener Granulomatosis: A multisystemic disease of a complex genetic background. It is characterized by inflammation of the blood vessels (VASCULITIS) leading to damage in any number of organs. The common features include granulomatous inflammation of the RESPIRATORY TRACT and kidneys. Most patients have measurable autoantibodies (ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES) against neutrophil proteinase-3 (WEGENER AUTOANTIGEN).Polyarteritis Nodosa: A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized ARTERIES, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called CHURG-STRAUSS SYNDROME.Focal InfectionAntibodies, Antineutrophil Cytoplasmic: Autoantibodies directed against cytoplasmic constituents of POLYMORPHONUCLEAR LEUKOCYTES and/or MONOCYTES. They are used as specific markers for GRANULOMATOSIS WITH POLYANGIITIS and other diseases, though their pathophysiological role is not clear. ANCA are routinely detected by indirect immunofluorescence with three different patterns: c-ANCA (cytoplasmic), p-ANCA (perinuclear), and atypical ANCA.Myeloblastin: A polymorphonuclear leukocyte-derived serine protease that degrades proteins such as ELASTIN; FIBRONECTIN; LAMININ; VITRONECTIN; and COLLAGEN. It is named for its ability to control myeloid cell growth and differentiation.Lymphomatoid Granulomatosis: An angiocentric and angiodestructive lymphoproliferative disorder primarily involving the lungs. It is caused by an Epstein-Barr virus-induced transformation of the B-cells, in a T-cell rich environment. Clinically and pathologically it resembles EXTRANODAL NK-T-CELL LYMPHOMA.Vasculitis: Inflammation of any one of the blood vessels, including the ARTERIES; VEINS; and rest of the vasculature system in the body.Arteritis: INFLAMMATION of any ARTERIES.Glomerulonephritis: Inflammation of the renal glomeruli (KIDNEY GLOMERULUS) that can be classified by the type of glomerular injuries including antibody deposition, complement activation, cellular proliferation, and glomerulosclerosis. These structural and functional abnormalities usually lead to HEMATURIA; PROTEINURIA; HYPERTENSION; and RENAL INSUFFICIENCY.Churg-Strauss Syndrome: Widespread necrotizing angiitis with granulomas. Pulmonary involvement is frequent. Asthma or other respiratory infection may precede evidence of vasculitis. Eosinophilia and lung involvement differentiate this disease from POLYARTERITIS NODOSA.Mechlorethamine: A biologic alkylating agent that exerts its cytotoxic effects by forming DNA ADDUCTS and DNA interstrand crosslinks, thereby inhibiting rapidly proliferating cells. The hydrochloride is an antineoplastic agent used to treat HODGKIN DISEASE and LYMPHOMA.Thiosulfates: Inorganic salts of thiosulfuric acid possessing the general formula R2S2O3.Nitrogen Mustard Compounds: A group of alkylating agents derived from mustard gas, with the sulfur replaced by nitrogen. They were formerly used as toxicants and vesicants, but now function as antineoplastic agents. These compounds are also powerful mutagens, teratogens, immunosuppressants, and carcinogens.Amphotericin B: Macrolide antifungal antibiotic produced by Streptomyces nodosus obtained from soil of the Orinoco river region of Venezuela.Vasopressins: Antidiuretic hormones released by the NEUROHYPOPHYSIS of all vertebrates (structure varies with species) to regulate water balance and OSMOLARITY. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a CYSTINE. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the KIDNEY COLLECTING DUCTS to increase water reabsorption, increase blood volume and blood pressure.Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Urinary Bladder: A musculomembranous sac along the URINARY TRACT. URINE flows from the KIDNEYS into the bladder via the ureters (URETER), and is held there until URINATION.Inappropriate ADH Syndrome: A condition of HYPONATREMIA and renal salt loss attributed to overexpansion of BODY FLUIDS resulting from sustained release of ANTIDIURETIC HORMONES which stimulates renal resorption of water. It is characterized by normal KIDNEY function, high urine OSMOLALITY, low serum osmolality, and neurological dysfunction. Etiologies include ADH-producing neoplasms, injuries or diseases involving the HYPOTHALAMUS, the PITUITARY GLAND, and the LUNG. This syndrome can also be drug-induced.Nystatin: Macrolide antifungal antibiotic complex produced by Streptomyces noursei, S. aureus, and other Streptomyces species. The biologically active components of the complex are nystatin A1, A2, and A3.Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed).Mechlorethamine: A biologic alkylating agent that exerts its cytotoxic effects by forming DNA ADDUCTS and DNA interstrand crosslinks, thereby inhibiting rapidly proliferating cells. The hydrochloride is an antineoplastic agent used to treat HODGKIN DISEASE and LYMPHOMA.Nitrogen Mustard Compounds: A group of alkylating agents derived from mustard gas, with the sulfur replaced by nitrogen. They were formerly used as toxicants and vesicants, but now function as antineoplastic agents. These compounds are also powerful mutagens, teratogens, immunosuppressants, and carcinogens.Rats, Inbred LewSpecies Specificity: The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species.Lung: Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood.Rats, Inbred Strains: Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding.Rats, Inbred BNMelphalan: An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - MELPHALAN, the racemic mixture - MERPHALAN, and the dextro isomer - MEDPHALAN; toxic to bone marrow, but little vesicant action; potential carcinogen.Rats, Inbred F344Mustard Gas: Severe irritant and vesicant of skin, eyes, and lungs. It may cause blindness and lethal lung edema and was formerly used as a war gas. The substance has been proposed as a cytostatic and for treatment of psoriasis. It has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP-85-002, 1985) (Merck, 11th ed).Consent Forms: Documents describing a medical treatment or research project, including proposed procedures, risks, and alternatives, that are to be signed by an individual, or the individual's proxy, to indicate his/her understanding of the document and a willingness to undergo the treatment or to participate in the research.Fanconi Anemia: Congenital disorder affecting all bone marrow elements, resulting in ANEMIA; LEUKOPENIA; and THROMBOPENIA, and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes. Spontaneous CHROMOSOME BREAKAGE is a feature of this disease along with predisposition to LEUKEMIA. There are at least 7 complementation groups in Fanconi anemia: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL. (from Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227650, August 20, 2004)Informed Consent: Voluntary authorization, by a patient or research subject, with full comprehension of the risks involved, for diagnostic or investigative procedures, and for medical and surgical treatment.ArchivesAmniocentesis: Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions.Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Fanconi Anemia Complementation Group Proteins: A diverse group of proteins whose genetic MUTATIONS have been associated with the chromosomal instability syndrome FANCONI ANEMIA. Many of these proteins play important roles in protecting CELLS against OXIDATIVE STRESS.Confidentiality: The privacy of information and its protection against unauthorized disclosure.Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing.Terminology as Topic: The terms, expressions, designations, or symbols used in a particular science, discipline, or specialized subject area.Postal Service: The functions and activities carried out by the U.S. Postal Service, foreign postal services, and private postal services such as Federal Express.Correspondence as Topic: Communication between persons or between institutions or organizations by an exchange of letters. Its use in indexing and cataloging will generally figure in historical and biographical material.Endocrine Surgical Procedures: Surgery performed on any endocrine gland.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Prognosis: A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations.Glioma: Benign and malignant central nervous system neoplasms derived from glial cells (i.e., astrocytes, oligodendrocytes, and ependymocytes). Astrocytes may give rise to astrocytomas (ASTROCYTOMA) or glioblastoma multiforme (see GLIOBLASTOMA). Oligodendrocytes give rise to oligodendrogliomas (OLIGODENDROGLIOMA) and ependymocytes may undergo transformation to become EPENDYMOMA; CHOROID PLEXUS NEOPLASMS; or colloid cysts of the third ventricle. (From Escourolle et al., Manual of Basic Neuropathology, 2nd ed, p21)Retrospective Studies: Studies used to test etiologic hypotheses in which inferences about an exposure to putative causal factors are derived from data relating to characteristics of persons under study or to events or experiences in their past. The essential feature is that some of the persons under study have the disease or outcome of interest and their characteristics are compared with those of unaffected persons.Chemotherapy, Adjuvant: Drug therapy given to augment or stimulate some other form of treatment such as surgery or radiation therapy. Adjuvant chemotherapy is commonly used in the therapy of cancer and can be administered before or after the primary treatment.Antineoplastic Agents, Alkylating: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Antineoplastic Agents, Alkylating: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Drug Evaluation: Any process by which toxicity, metabolism, absorption, elimination, preferred route of administration, safe dosage range, etc., for a drug or group of drugs is determined through clinical assessment in humans or veterinary animals.Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.Orphan Drug Production: Production of drugs or biologicals which are unlikely to be manufactured by private industry unless special incentives are provided by others.Drug Approval: Process that is gone through in order for a drug to receive approval by a government regulatory agency. This includes any required pre-clinical or clinical testing, review, submission, and evaluation of the applications and test results, and post-marketing surveillance of the drug.Cell Line, Tumor: A cell line derived from cultured tumor cells.Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.Alkylating Agents: Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Mechlorethamine: A biologic alkylating agent that exerts its cytotoxic effects by forming DNA ADDUCTS and DNA interstrand crosslinks, thereby inhibiting rapidly proliferating cells. The hydrochloride is an antineoplastic agent used to treat HODGKIN DISEASE and LYMPHOMA.Nitrogen Mustard Compounds: A group of alkylating agents derived from mustard gas, with the sulfur replaced by nitrogen. They were formerly used as toxicants and vesicants, but now function as antineoplastic agents. These compounds are also powerful mutagens, teratogens, immunosuppressants, and carcinogens.Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms.Alkylation: The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group.Microscopy, Ultraviolet: Microscopy in which the image is formed by ultraviolet radiation and is displayed and recorded by means of photographic film.Antineoplastic Agents, Alkylating: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)Nitrosourea CompoundsCarmustine: A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)

Activation of c-Jun N-terminal kinase 1 by UV irradiation is inhibited by wortmannin without affecting c-iun expression. (1/1003)

Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases is an early response of cells upon exposure to DNA-damaging agents. JNK-mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulation of JNK1 activity is not a general early response of cells exposed to genotoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as with methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs such as mafosfamide, mitomycin C, N-hydroxyethyl-N-chloroethylnitrosourea, and treosulfan did not elicit this response. The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2). To investigate the significance of JNK1 for transactivation of c-jun, we analyzed the effect of UV irradiation on c-jun expression under conditions of wortmannin-mediated inhibition of UV-induced stimulation of JNK1. Neither the UV-induced increase in c-jun mRNA, c-Jun protein, and AP-1 binding nor the activation of the collagenase and c-jun promoters was affected by wortmannin. In contrast, the mitogen-activated protein kinase/ERK kinase inhibitor PD98056, which blocked ERK2 but not JNK1 activation by UV irradiation, impaired UV-driven c-Jun protein induction and AP-1 binding. Based on the data, we suggest that JNK1 stimulation is not essential for transactivation of c-jun after UV exposure, whereas activation of ERK2 is required for UV-induced signaling leading to elevated c-jun expression.  (+info)

The Saccharomyces cerevisiae ETH1 gene, an inducible homolog of exonuclease III that provides resistance to DNA-damaging agents and limits spontaneous mutagenesis. (2/1003)

The recently sequenced Saccharomyces cerevisiae genome was searched for a gene with homology to the gene encoding the major human AP endonuclease, a component of the highly conserved DNA base excision repair pathway. An open reading frame was found to encode a putative protein (34% identical to the Schizosaccharomyces pombe eth1(+) [open reading frame SPBC3D6.10] gene product) with a 347-residue segment homologous to the exonuclease III family of AP endonucleases. Synthesis of mRNA from ETH1 in wild-type cells was induced sixfold relative to that in untreated cells after exposure to the alkylating agent methyl methanesulfonate (MMS). To investigate the function of ETH1, deletions of the open reading frame were made in a wild-type strain and a strain deficient in the known yeast AP endonuclease encoded by APN1. eth1 strains were not more sensitive to killing by MMS, hydrogen peroxide, or phleomycin D1, whereas apn1 strains were approximately 3-fold more sensitive to MMS and approximately 10-fold more sensitive to hydrogen peroxide than was the wild type. Double-mutant strains (apn1 eth1) were approximately 15-fold more sensitive to MMS and approximately 2- to 3-fold more sensitive to hydrogen peroxide and phleomycin D1 than were apn1 strains. Elimination of ETH1 in apn1 strains also increased spontaneous mutation rates 9- or 31-fold compared to the wild type as determined by reversion to adenine or lysine prototrophy, respectively. Transformation of apn1 eth1 cells with an expression vector containing ETH1 reversed the hypersensitivity to MMS and limited the rate of spontaneous mutagenesis. Expression of ETH1 in a dut-1 xthA3 Escherichia coli strain demonstrated that the gene product functionally complements the missing AP endonuclease activity. Thus, in apn1 cells where the major AP endonuclease activity is missing, ETH1 offers an alternate capacity for repair of spontaneous or induced damage to DNA that is normally repaired by Apn1 protein.  (+info)

Mismatch repair and differential sensitivity of mouse and human cells to methylating agents. (3/1003)

The long-patch mismatch repair pathway contributes to the cytotoxic effect of methylating agents and loss of this pathway confers tolerance to DNA methylation damage. Two methylation-tolerant mouse cell lines were identified and were shown to be defective in the MSH2 protein by in vitro mismatch repair assay. A normal copy of the human MSH2 gene, introduced by transfer of human chromosome 2, reversed the methylation tolerance. These mismatch repair defective mouse cells together with a fibroblast cell line derived from an MSH2-/- mouse, were all as resistant to N-methyl-N-nitrosourea as repair-defective human cells. Although long-patch mismatch repair-defective human cells were 50- to 100-fold more resistant to methylating agents than repair-proficient cells, loss of the same pathway from mouse cells conferred only a 3-fold increase. This discrepancy was accounted for by the intrinsic N-methyl-N-nitrosourea resistance of normal or transformed mouse cells compared with human cells. The >20-fold differential resistance between mouse and human cells could not be explained by the levels of either DNA methylation damage or the repair enzyme O6-methylguanine-DNA methyltransferase. The resistance of mouse cells to N-methyl-N-nitrosourea was selective and no cross-resistance to unrelated DNA damaging agents was observed. Pathways of apoptosis were apparently intact and functional after exposure to either N-methyl-N-nitrosourea or ultraviolet light. Extracts of mouse cells were found to perform 2-fold less long-patch mismatch repair. The reduced level of mismatch repair may contribute to their lack of sensitivity to DNA methylation damage.  (+info)

Tightly regulated and inducible expression of rabbit CYP2E1 using a tetracycline-controlled expression system. (4/1003)

A tetracycline (Tc)-controlled gene expression system that quantitatively controls gene expression in eukaryotic cells () was used to express cytochrome P-450 2E1 (CYP2E1) in HeLa cells in culture. The rabbit CYP2E1 cDNA was subcloned into the Tc-controlled expression vector (pUHD10-3) and transfected into a HeLa cell line constitutively expressing the Tc-controlled transactivator, a positive regulator of expression in the absence of Tc. The expression of CYP2E1 was tightly regulated. There was a time-dependent induction of CYP2E1 after removal of Tc. In the absence of Tc, the enzyme was induced more than 100-fold and expressed about 18 pmol of CYP2E1/mg microsomal protein. At maximal levels of expression the enzyme catalyzed the formation of 158 pmol 6-hydroxychlorzoxazone/min/mg total cellular protein. In addition, the level of the enzyme could be modulated by the concentration of Tc in the media. In the absence of Tc, exposure of cells to N-nitrosodimethylamine caused a significant dose-dependent decrease in cell viability. In contrast, menadione, a redox cycling toxicant, was less toxic to the cells after induction of CYP2E1 when compared with noninduced cells. Pulse-chase studies conducted 72 h after removal of Tc indicated a rapid turnover of CYP2E1 with a half-life of 3.9 h. Addition of the ligand, 4-methylpyrazole, and the suicide substrate, 1-aminobenzotrizole, decreased the degradation of CYP2E1. This cell line offers a useful system to examine the role of CYP2E1 in the cytotoxicity of xenobiotics and to investigate post-translational regulation of the enzyme.  (+info)

Cells deficient in DNA polymerase beta are hypersensitive to alkylating agent-induced apoptosis and chromosomal breakage. (5/1003)

DNA polymerase beta (beta-pol), which is involved in base excision repair, was investigated for its role in protection of cells against various genotoxic agents and cytostatic drugs using beta-pol knockout mouse fibroblasts. We show that cells lacking beta-pol are highly sensitive to induction of apoptosis and chromosomal breakage by methylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine and methyl methanesulfonate and the cross-linking antineoplastic drugs mitomycin C and mafosfamide. The cross-sensitivity between the agents observed suggests that beta-pol is involved in repair not only of DNA methylation lesions but also of other kinds of DNA damage induced by various cytostatic drugs. Cells deficient in beta-pol were not hypersensitive to cisplatin, melphalan, benzo(a)pyrene diol epoxide, chloroethylnitrosourea, or UV light. Because both established and primary beta-pol knockout fibroblasts displayed the hypersensitive phenotype, which, moreover, was complemented by transfection with a beta-pol expression vector, the alkylating agent hypersensitivity can clearly be attributed to the beta-pol deficiency. The results demonstrate that beta-pol-driven base excision repair is highly important for protection of cells against cell killing due to apoptosis and induced chromosomal breakage and suggest that incompletely repaired DNA damage causes chromosomal changes and may act as a trigger of DNA damage-induced apoptosis.  (+info)

Molecular analysis of mutants obtained by treatment with alkylating agents in a quadruplicated white-ivory strain of Drosophila melanogaster. (6/1003)

The use of a white-ivory (wi) strain of Drosophila melanogaster carrying four copies of this allele, (wi)4, has proved to be useful in detecting somatic mutation in genotoxicity testing. Nevertheless, until now very little information exists about the nature of the genetic effects detected in such a strain. This work presents molecular data on the changes that have taken place in different germinal mutants obtained after treatment with alkylating agents. Three different phenotypes were obtained: wild-type red eyes, dark red eyes and eyes lighter than (wi)4. Our results show that, in at least one of the four copies of the allele, the wild-type red eye phenotypes are due to a precise excision of the 2.96 kb duplicated region characteristic of the wi allele. These data agree with previous results obtained in a strain carrying only a single copy of the wi allele. The dark red eye mutants analysed seemed to be generated as a cluster and all proved to be caused by deletions at the 3'-end of the duplicated wi region in two of the copies of the (wi)4 genome. Finally, the light eye mutants (obtained at high frequencies) failed to show alterations at the molecular level, although we cannot discard the possibility that they might have originated by the loss of some of the wi copies of the (wi)4 strain.  (+info)

Alterations in Bacillus subtilis transforming DNA induced by beta-propiolactone and 1,3-propane sultone, two mutagenic and carcinogenic alkylating agents. (7/1003)

Transforming DNA was exposed to either beta-propiolactone or 1,3-propane sultone and then used for transformation of competent bacteria to nutritional independence from tyrosine and tryptophan (linked markers) and leucine (an unlinked marker). The ability to transform was progressively lost by the DNA during incubation with either of these two chemicals. For all three markers the inactivation curve was biphasic, with a short period of rapid inactivation followed by one characterized by a much slower rate. The overall rate of inactivation was different for all three markers and presumably was related to the size of the marker. The decrease in the transforming activity was in part due to the slower rate of penetration of alkylated DNA through the cellular membrane and its inability to enter the recipient bacteria. This decrease in the rate of cellular uptake, even for DNA eventually destined to enter the cell, began almost immediately after its exposure to the chemical and ended up with an almost complete lack of recognition of the heavily alkylated DNA by the specific surface receptors of competent cells. Such DNA attached to sites on the surface of competent bacteria which were different from receptors specific for the untreated nucleic acid. This attachment was not followed by uptake of the altered DNA. Presence of albumin during the incubation with a carcinogen further increased the degree of inactivation, indicating that the artificial nucleoproteins produced under such conditions were less efficient in the transformation assay than was the naked DNA. Cotransfomration of close markers progressively decreased, beginning immediately after the start of incubation of DNA with the chemicals. Extensively alkylated DNA fractionated by sedimentation through sucrose density gradients showed a peculiar distribution of cotransforming activity for such markers; namely, molecules larger than the bulk of DNA ("megamolecules") showed less ability to transform the second marker than did some of the apparently smaller molecules which sedimented more slowly through the gradient. An increase in cotransformation of distant markers was evident in DNA molecules after a short exposure to an alkylating agent, but cotransformation of such markers was absent in DNA treated for longer periods. The observed changes in the transforming and cotransforming activities of the alkylated DNA can be explained by what is known about the physicochemistry of such DNA and in particular about the propensity of the alkylated and broken molecules to form complexes with themselves and with other macromolecules.  (+info)

The role of thiotepa in allogeneic bone marrow transplantation for genetic diseases. (8/1003)

Graft-versus-host disease (GVHD), graft rejection, disease recurrence and long-term toxicity remain significant obstacles to successful allogeneic bone marrow transplantation (BMT) in children with genetic diseases. In an attempt to improve results, we used a preparative regimen consisting of three alkylating agents, busulfan (BU), thiotepa (TTP) and cyclophosphamide (CY), for T cell-depleted allogeneic bone marrow transplantation instead of the conventional BU-CY protocol. The effect of this intensified regimen was investigated in 26 consecutive children with genetic diseases who underwent T cell-depleted BMT from HLA-identical siblings. Sixteen patients were males and 10 females, of median age 5 (0.2-14) years. The diseases included beta-thalassemia major, osteopetrosis, severe combined immunodeficiency, Wiskott-Aldrich syndrome, familial agranulocytosis, congenital idiopathic hemolytic anemia (CIHA), Gaucher's disease, Niemann-Pick disease, Hurler's syndrome, and adrenoleukodystrophy. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was as expected, with WBC >1.0 x 10(9)/l at day +19 (10-33), ANC >0.5 x 10(9)/l at day +22 (10-56) and platelets >25 x 10(9)/l at day +32 (18-131). Transplant-related mortality was 19%. Overall survival and disease-free survival (DFS) at 60 months follow-up were both 77%. Our results with the BU-TTP-CY regimen followed by T cell-depleted BMT in genetic diseases may provide a basis for prospective comparison with the standard conditioning regimen of BU-CY in the management of children suffering from these conditions.  (+info)

*Melphalan

... is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents. An alkylating agent adds an alkyl group ( ... The agent was first investigated as a possible drug for use in melanoma, it was not found to be effective. On March 15, 2016 it ... The rationale behind incorporating an alkylating function in a molecule resembling a primary cellular metabolite was to get a ... due to melphalan not being withdrawn early enough Cardiac arrest Another amino acid-like drug is the antineoplastic agent ...

*Alkylating antineoplastic agent

... alkylating agents are classified under L01A. Many of the agents are known as "Classical alkylating agents". These include true ... An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to ... List of hormonal alkylating antineoplastic agents "Alkylating Agents". US National Library of Medicine. Retrieved 2 August 2014 ... University of Nebraska page on alkylating agent drugs Alkylating antineoplastic agents at the US National Library of Medicine ...

*List of hormonal alkylating antineoplastic agents

This is a list of dual hormonal and alkylating antineoplastic agents. Estramustine phosphate (Emcyt, Estracyt; Leo 299, NSC- ...

*Triethyloxonium tetrafluoroborate

They are strong alkylating agents. Aside from the BF− 4 salt, many related derivatives are available. Triethyloxonium ... Triethyloxonium tetrafluoroborate is a strong alkylating agent, although the hazards are diminished because it is non-volatile ...

*2-Bromopropane

Alkylating agents are often carcinogenic. M G. Gergel "Excuse Me Sir, Would You Like to Buy a Kilo of Isopropyl Bromide?" ...

*Chemotherapy

Siddik ZH (2005). Mechanisms of Action of Cancer Chemotherapeutic Agents: DNA-Interactive Alkylating Agents and Antitumour ... there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, ... Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason ... Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of ...

*Mutation

Alkylating agents (e.g., N-ethyl-N-nitrosourea (ENU)). These agents can mutate both replicating and non-replicating DNA. In ... Agents that form DNA adducts (e.g., ochratoxin A) DNA intercalating agents (e.g., ethidium bromide) DNA crosslinkers Oxidative ...

*Menshutkin reaction

Typical alkylating agents and benzylic halides. Even though alkyl chlorides are poor alkylating agents, the Menshutkin reaction ... Alkyl iodides are superior alkylating agents relative to the bromides, which in turn are superior to chlorides. ... In addition to solvent and alkylating agent, other factors strongly influence the reaction. One particular macrocycle system ...

*Triaziquone

It is an alkylating agent. It can react with DNA to form intrastrand crosslinks.[citation needed]. ...

*Sodium tetrasulfide

Treatment with alkylating agents gives organic polysulfides. In one commercial application, it is used to produce the cross- ... linking agent bis(triethoxysilylpropyl)tetrasulfide: Na2S4 + 2 ClC3H6Si(OEt)3 → S4[C3H6Si(OEt)3]2 + 2 NaCl Sometimes as a ...

*Organosulfate

These compounds are potentially dangerous alkylating agents. The reduction of sulfate in nature involves the formation of one ...

*Oxonium ion

... they are extensively used as alkylating agents. For example, triethyloxonium tetrafluoroborate (Et 3O+ )(BF− 4) is a white ... It is a powerful ethylating agent. It can be used, for example, to produce ethyl esters when the conditions of traditional ...

*Ritter reaction

The original reaction formed the alkylating agent using an alkene in the presence of a strong acid: The reaction has been the ... Fernholz, H.; Schmidt, H. J. (1969). "Tert-Butyl Acetate as Alkylating Agent". Angewandte Chemie International Edition in ... Ritter reaction is a chemical reaction that transforms a nitrile into an N-alkyl amide using various electrophilic alkylating ...

*Benzyl chloride

... is an alkylating agent. Indicative of its high reactivity (relative to alkyl chlorides), benzyl chloride reacts ...

*Ethylene oxide

... is an alkylating agent; it has irritating, sensitizing and narcotic effects. Chronic exposure to ethylene oxide ... Ethylene oxide is used as a sterilizing agent, disinfecting agent and fumigant as a mixture with carbon dioxide (8.5-80% of ... the reducing agent is actually titanium dichloride, formed by the reaction between LiAlH4 and TiCl3) and of iron(III) chloride ...

*Methyl 2-bromoacetate

It is incompatible with acids, bases, oxidizing agents, and reducing agents. Methyl bromoacetate is an alkylating agent. It has ... It reacts with conjugated base and produce alkylated carbene complexes. Methyl bromoacetate can be toxic by ingestion and ... been used to alkylate phenol and amino groups. Moreover, it can be used to make vitamins and pharmaceutical drugs. It is ...

*HN1 (nitrogen mustard)

Because HN1 is an alkylating agent, it damages DNA, causes immunosuppression, and causes injury to areas that come into contact ... HN1 is also an alkylating agent. Nitrogen mustards react via an initial cyclization to the corresponding aziridinium salt. The ... HN1 was developed in the 1920s and 1930s to remove warts and later as a military agent. Because of the latter use, it is a ... If HN1 has been ingested, emetics (agents that induce vomiting) and gastric lavage are contraindicated, and nothing should be ...

*Mutagenesis

Some alkylating agents such as N-Nitrosamines may require the catalytic reaction of cytochrome-P450 for the formation of a ... Alkylating agents like mustard gas may also cause breakages in the DNA backbone. Oxidative stress may also generate highly ... Some alkylating agents may produce crosslinking of DNA. Some natural occurring chemicals may also promote crosslinking, such as ... DNA may be modified, either naturally or artificially, by a number of physical, chemical and biological agents, resulting in ...

*Trofosfamide

... (INN) is a nitrogen mustard alkylating agent. It is sometimes abbreviated "TRO". Jahnke K, Thiel E, Bechrakis NE, ...

*S-Adenosyl methionine

SAM is a weak DNA-alkylating agent. Another reported side effect of SAM is insomnia; therefore, the supplement is often taken ...

*Butyl iodide

It is used as an alkylating agent. Merck Index, 13th Edition, 1572. "1-iodobutane - Compound Summary". PubChem Compound. USA: ...

*Chronic lymphocytic leukemia

Alkylating agents approved for CLL include bendamustine and cyclophosphamide. Targeted therapy attacks cancer cells at a ... Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression- ... Exposure to Agent Orange and certain insecticides might also be a risk. CLL results in the build up of B cell lymphocytes in ... Exposure to Agent Orange increases the risk of CLL, and exposure to certain insecticides may increase the risk. Exposure to ...

*Procarbazine

... is in the alkylating agents family of medication. How it works is not clearly known. Procarbazine was approved for ...

*Dimethyl sulfate

Like all strong alkylating agents, Me2SO4 is extremely toxic. Its use as a laboratory reagent has been superseded to some ... Compared to other methylating agents, dimethyl sulfate is preferred by the industry because of its low cost and high reactivity ... Me2SO4 is mainly used as a methylating agent in organic synthesis. Under standard conditions, Me2SO4 is a colourless oily ... In general, the toxicity of methylating agents is correlated with their efficiency as methyl transfer reagents.[citation needed ...

*Tetramethoxymethane

In addition to the use as a solvent, tetramethoxymethane is used as a fuel in polymer fuel cells, as an alkylating agent at ... M. Selva et al., Esters and Orthoesters as Alkylating Agents at High Temperature. Applications to Continuous-flow Processes, J ... For example, trichloromethanesulfenyl chloride (also used as a chemical warfare agent and easily accessible from carbon ...

*Pyrrolobenzodiazepine

... are sequence selective DNA alkylating compounds. As a class of DNA-crosslinking agents they are significantly more potent than ... The company has been developing its PBD technology for more than ten years, including a standalone PBD agent in a Phase II ... As DNA minor groove binding agents, pyrrolobenzodiazepines bind and cross-link specific sites of DNA of the cancer cell. This ... The development of pyrrolobenzodiazepines as antitumour agents. Hartley, JA; (2011) Pyrrolobenzodiazepine (PBD); ADC Review / ...

*Ames test

"Do dose response thresholds exist for genotoxic alkylating agents?". Mutagenesis. 20 (6): 389-98. doi:10.1093/mutage/gei054. ...
Title:A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents. VOLUME: 15 ISSUE: 5. Author(s):Pravin C. Patil, Vijay Satam and Moses Lee. Affiliation:Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.. Keywords:Antitumor-antibiotics, apoptosis, centanamycin, duocarmycins, tafuramycin A.. Abstract:The duocarmycins and CC-1065 are members of a class of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity none of the analogs have passed clinical evaluation. As a result, ...
Alkylating Antineoplastic Agents: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)
The major alkylating agents are the nitrogen mustards and the nitrosoureas. These drugs covalently alkylate various cellular constituents. Most importantly for
... definition, any of various potentially cytotoxic, carcinogenic, and mutagenic substances: used therapeutically to destroy cells, especially proliferating cancer cells. See more.
1.Polyfunctional alkylating agents 2.Other Alkylating Drugs 3.Antimetabolites 4.Purine antagonists 5.Pyrimidine antagonists 6.Plant alkaloids 7.Antibiotics 8.Monoclonal Antibodies, 9.Hormonal agents, 10.Miscellaneous anticancer drugs
Read "The effect of the Primary Structure of DNA on Induction of Mutations by Alkylating Agents, Russian Journal of Genetics" on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
alkylating agent: Any highly reactive drug that binds to certain chemical groups (phosphate, amino, sulfhydryl, hydroxyl, and imidazole groups) commonly found in nucleic acids and other macromolecules,...
Learn about the veterinary topic of Alkylating Agents. Find specific details on this topic and related topics from the Merck Vet Manual.
Alkylating agents are among the most potent cytotoxic drugs used in the clinic for the therapy of many solid tumors including breast and lung carcinomas (Trudeau et al., 2005). However, the potency of these compounds is often mitigated by resistance associated with DNA repair proteins. Furthermore, their lack of selectivity for tumor tissues has become a major deterrent in their use for the therapy of solid tumors. This study was designed to analyze the selective potency of a novel class of combi-molecules carrying a methylating species. In this model, EGFR and ErbB2 transfection significantly reduced cell sensitivity to TEM, which is not targeted to the aforementioned receptors. Inversely, EGFR and ErbB2 transfection enhanced the potency of RB24, a methylating triazene of the same class as TEM. Thus, we hypothesized that selective and enhanced potency of RB24 against the transfectants is based upon mechanisms related to receptor targeting and cell signaling.. The first significant observation ...
Leukemia is not an important factor in the natural history of breast cancer, though its association with breast cancer therapy has frequently been reported. There are reports of therapy related hematological malignancies in breast cancer dated as early as 1980s describing the incidence as 1.68 ± .33% at 10 years with chemotherapy vis a vis 0.06% to 0.27% with surgery alone [1]. In 1992, a large case-control study of 82,700 women with breast cancer demonstrated a relative risk of developing AML as 2.4 for radiotherapy, 10 for therapy with alkylating agents and 17.4 when the two were used in combination [2] The chemotherapy regimens employed during these studies used mainly melphalan as alkylating agent and that for long durations (12 to 24 months) [1, 2]. Though over the last decade anthracyclines along with safer alkylating agents have formed the main core of the breast cancer therapy; the modern chemotherapy is not entirely safe. The more recent reports in the background of anthracycline and ...
Cisplatin is similar to the bifunctional alkylating agents. It covalently binds to DNA and disrupts DNA function. After cisplatin enters the cells, the chloride ligands are replaced by water molecules. This reaction results in the formation of positively charged platinum complexes that react with the nucleophilic sites on (...). ...
Melphalan is a DNA alkylating agent; induces cytotoxicity through the formation of stable interstrand and intrastrand crosslinks within DNA which inhibits growth of PC-3 cells (IC50 values are 0.074 and 0.77 μM for sequential dosing and single dosing respectively). Learn More ...
Reporting biases in published trials were first identified in 1986.1 Published randomized studies of combination chemotherapy compared with treatment with an alkylating agent as first line treatment for ovarian cancer showed a significant survival advantage for combination chemotherapy. Unpublished cancer trial registry data from the same studies, however, showed no such advantage.2 Similarly, in the treatment of multiple myeloma, registry data suggested a smaller survival advantage for combination chemotherapy (over prednisone and an alkylating agent) than the results of published studies. The author who reported the discrepancy concluded that his findings "demonstrate the value and importance of an international registry of all clinical trials."1Subsequent evidence for biased and selective reporting included prompt or delayed publication depending on whether trial results were positive or negative3 and more favorable results and conclusions in published studies funded by industry than in those ...
Reporting biases in published trials were first identified in 1986.1 Published randomized studies of combination chemotherapy compared with treatment with an alkylating agent as first line treatment for ovarian cancer showed a significant survival advantage for combination chemotherapy. Unpublished cancer trial registry data from the same studies, however, showed no such advantage.2 Similarly, in the treatment of multiple myeloma, registry data suggested a smaller survival advantage for combination chemotherapy (over prednisone and an alkylating agent) than the results of published studies. The author who reported the discrepancy concluded that his findings "demonstrate the value and importance of an international registry of all clinical trials."1Subsequent evidence for biased and selective reporting included prompt or delayed publication depending on whether trial results were positive or negative3 and more favorable results and conclusions in published studies funded by industry than in those ...
S. B. J. Kan, H. Maruyama, M. Akakura, T. Kano, K. Maruoka, Angew. Chem. Int. Ed., 56, 9487-9491 (2017). (Highlighted in SYNFACTS, 2017, 985). Alkylsilyl Peroxides as Alkylating Agents in the Copper-Catalyzed Selective Mono-N-Alkylation of Primary Amides and Arylamines ...
Phthalmustine is an alkylating agent containing the N-mustard (N,N-bis-2-chloroethylamino) group attached to a phthalimido ethyl chain. It was undergoing
O6-methylguanine-DNA methyltransferase plays vital roles in preventing induction of mutations and cancer as well as cell death related to alkylating agents. Mice defective in the Mgmt gene, encoding the methyltransferase, were used to evaluate cell death-inducing and tumorigenic activities of therapeutic agents which have alkylation potential. Mgmt-/- mice were considerably more sensitive to dacarbazine, a monofunctional triazene, than were wild-type mice, in terms of survival. When dacarbazine was administered i.p. to 6-week-old mice and survival at 30 days was enumerated, LD50 values of Mgmt-/- and Mgmt+/+ mice were 20 and 450 mg/kg body wt, respectively. Increased sensitivity of Mgmt-/- mice to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), a bifunctional nitrosourea, was also noted. On the other hand, there was no difference in survival of Mgmt+/+ and Mgmt-/- mice exposed to cyclophosphamide, a bifunctional nitrogen mustard. It appears that dacarbazine and ...
Bendamustine has demonstrated clinical efficacy in the treatment of haematological malignancies and distinguish itself from other alkylating agents. The mechanistic and clinical differences associated with Bendamustine may be related to its structural features including a benzimidazole ring, although the mechanism of action is poorly understood. Understanding the molecular mechanism of Bendamustine could explain the therapeutic efficacy and identify potential biomarkers for response. The Bendamustine-DNA interaction in naked DNA, cytotoxicity, and ICL formation and repair (unhooking) in naked DNA or in cell lines and patient multiple myeloma cells by the single cell gel electrophoresis (comet) assay, were analyzed. DNA damage response (DDR) and potential mechanisms of acquired resistance to Bendamustine were also evaluated. Bendamustine alkylated DNA at guanine-N7 positions, produced ICLs in naked DNA and in cells, and demonstrated a cytotoxic effect comparable to conventional ICL drugs ...
Attempts to administer personalized standard cytotoxic chemotherapy based on individual patient characteristics have been disappointing. Alkylating agents are one of the oldest classes of anticancer medicine with a wide variety of molecular actions and thus the potential for broad utility. Bendamustine hydrochloride, a new addition to this class, was previously developed in the 1960s and has now been trialled in hematological malignancies and many solid tumor types as monotherapy or in combination with the known standard of care. It appears to occupy a particular role in resistant or refractory hematological disease and it was approved by the US FDA for the treatment of chronic lymphocytic leukemia in March 2008. Further trials will reveal whether it is likely to become incorporated into front-line regimens in non-Hodgkins lymphoma and other malignancies.. ...
The great diversity in sarcoma phenotypes and genotypes make this disease family exceptionally challenging. Phenotypically diverse human adult and pediatric sarcoma lines were screened with a defined set of drugs and compounds (22). Sarcoma genomics have been explored using cell lines and clinical specimens (12, 23). This study presents gene-expression data derived from exon array data as well as microRNA data, which are available in GEO.. One study goal was to identify small-molecule drugs for further examination in sarcoma. The constellation relational map provides visualization of the sarcoma screen for compounds with a dynamic range of at least one log in IC50 across the panel (Fig. 1). The clusters are compounds with similar patterns of response. Aurora kinase inhibitors form a distinct cluster adjacent to bifunctional alkylating agents, topoisomerase I and II inhibitors. Taxanes and microtubule fragmenters form a cluster adjacent to topoisomerase I and II inhibitors. The results are ...
Consistent results from three case-control studies and a pooled analysis, totaling 555 head and neck cancer cases and 792 controls, suggest that genetic variations in MGMT84, MGMT143, and XRCC1399 influence susceptibility to head and neck cancer. Moreover, the MGMT143 variant may modify alcohol-related risk.. MGMT encodes O6-alkylguanine DNA alkyltransferase, which preferentially removes O6-guanine alkyl adducts caused by carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone found in tobacco smoke (40), and the Val143 allele has previously been related to increased lung cancer risk in two small studies (each with ∼130 cases; refs. 28, 41). In our study, Val143 was associated with reduced head and neck cancer risk, particularly among heavy drinkers. In vivo and in vitro experiments show that MGMT-mediated repair of alkylated DNA is reduced by treatment with ethanol or its primary metabolite, acetaldehyde (42, 43), possibly due to MGMT inhibition (44). Although the functional ...
5622 Pancreatic cancer is refractive to treatment with DNA alkylating agents due to its high levels of the DNA repair proteinO6-methylguanine-DNA methyltransferase (MGMT). An impressive improvement in the efficacy of carmustine (BCNU) and temozolomide (TMZ) has been demonstrated following the inactivation of MGMT with O6-benzylguanine (BG) (Kokkinakis et al., Clin. Cancer Res. 2003). Here we report that mutant-p53 cell lines are markedly more resistant than isogenic wt-p53 lines to treatment with TMZ and BG and that the induction of a protracted cell cycle arrest in response to DNA damage induced by TMZ plus BG treatment correlates with a greater incidence of apoptosis in cell cultures of pancreatic tumor cells. This is in accordance with the hypothesis that p53 controlled cell cycle arrest in either G1/S or G2/M is linked to a pro-apoptotic response. Further investigation into the mechanism by which functional p53 contributes to the toxicity of unrepaired O6-methylguanine adducts demonstrated ...
Failure to Diagnose Antituberculous agent-induced liver damage including overlooked symptoms and complications for under-diagnosed medical conditions.
Principal Investigator:SUGIYAMA Hiroshi, Project Period (FY):1997 - 1998, Research Category:Grant-in-Aid for Scientific Research (B), Section:展開研究, Research Field:Synthetic chemistry
Carmustine belongs to the group of alkylating agents. It interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by carmustine, other effects may occur. Some of these may be serious and must be reported to your doctor. Other effects (e.g., hair loss), may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used. Before you begin treatment with carmustine, you and your doctor should talk about the benefits this medicine will do as well as the risks. This medicine is to be administered only by or under the immediate supervision of your doctor. This product is available in the following dosage forms:. ...
At left, photoreceptor cells of the retina have undergone severe damage after treatment with an alkylating agent. This damage is exacerbated by the DNA repair
In this article you will know all of the Main drugs used in cancer treatment. Know about Mitotic Inhibitors, Antibiotics, Antimetabolites and Alkylating
Diazomethane is toxic by inhalation or by contact with the skin or eyes (TLV 0.2ppm). Symptoms include chest discomfort, headache, weakness and, in severe cases, collapse.[14] Symptoms may be delayed. Deaths from diazomethane poisoning have been reported. In one instance a laboratory worker consumed a hamburger near a fumehood where he was generating a large quantity of diazomethane, and died four days later from fulminating pneumonia.[15] Like any other alkylating agent it is expected to be carcinogenic, but such concerns are overshadowed by its serious acute toxicity. CH2N2 may explode in contact with sharp edges, such as ground-glass joints, even scratches in glassware.[16] Glassware should be inspected before use and preparation should take place behind a blast shield. Specialized kits to prepare diazomethane with flame-polished joints are commercially available. The compound explodes when heated beyond 100 °C, exposed to intense light, alkali metals, or calcium sulfate. Use of a blast ...
Introduction. High dose melphalan 200mg/m2 (MEL200) followed by autologous stem cell transplantation (ASCT) is the standard of care for fit patients with Multiple Myeloma (MM). Bendamustine has been shown to induce responses in MM resistant to other alkylating agents. Our prior Phase I trial, adding bendamustine to MEL200, demonstrated no additional toxicity above that expected with MEL200 alone (Mark et. al. BBMT 2013). A phase 2 trial of bendamustine/MEL200 conditioning was conducted to evaluate treatment efficacy. Objective and Methods. This single arm, open-label, phase II study was designed to establish the efficacy of Bendamustine (225 mg/m2) in combination with MEL200 in patients undergoing first ASCT for MM. Patients 18 to 75 years with confirmed MM, prior induction therapy, adequate mobilization (at least 2x106 of CD34+ hematopoietic stem cells), Karnofsky performance status ,70% and life expectancy ,12 weeks were eligible for screening. Major exclusion criteria included ...
After relapse or after early progression on first-line treatment, the prognosis of multiple myeloma (MM) patients is unfavourable, and the search for new treatment regimens, including drugs with novel mechanisms of action is essential.. Bendamustine and bortezomib have shown high activity boch in first-line regimens and pre-treated patients. The novel mechanism of action of the proteasome inhibitor and the non-cross resistance of bendamustine to other alkylating agents established in the first-line treatment of multiple myeloma seem to recommend a combination of the two drugs for salvage therapy (second-line regimen). Finally, the promising response data in a series of relapsing MM patients treated with bendamustine, bortezomib and prednisone support this assumption, as well as the feasibility and tolerability of the combination.. In summary, there is some evidence for a favorable risk/benefit ratio for the combination of bendamustine, bortezomib and a corticoid drug, warranting the exploration ...
Treg-cell function is compromised in rheumatoid arthritis (RA). As the master regulator of Treg cells, FOXP3 controls development and suppressive function. Stable Treg-cell FOXP3 expression is epigenetically regulated; constitutive expression requires a demethylated Treg-specific demethylated region. Here, we hypothesised that methylation of the FOXP3 locus is altered in Treg cells of established RA patients. Methylation analysis of key regulatory regions in the FOXP3 locus was performed on Treg cells from RA patients and healthy controls. The FOXP3 Treg-specific demethylated region and proximal promoter displayed comparable methylation profiles in RA and healthy-donor Treg cells. We identified a novel differentially methylated region (DMR) upstream of the FOXP3 promoter, with enhancer activity sensitive to methylation-induced silencing. In RA Treg cells we observed significantly reduced DMR methylation and lower DNA methyltransferase (DNMT1/3A) expression compared with healthy Treg cells. Furthermore,
A vesicant and necrotizing irritant destructive to mucous membranes, mechlorethamine is an alkylating drug. It was formerly used as a war gas. The hydrochloride is used as an antineoplastic in Hodgkins disease and lymphomas. It causes severe gastrointestinal and bone marrow damage. [PubChem] The FDA granted marketing approval for the orphan drug Valchlor (mechlorethamine) gel on August 23, 2013 for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL) in patients who have received prior skin-directed therapy. Each tube of Valchlor contains 0.016% of mechlorethamine which is equivalent to 0.02% mechlorethamine HCL.
Epichlorohydrin (ECH) is a DNA bifunctional alkylating agent that has been shown to form DNA inter-strand cross-links in vitro at the N7 position of guanines at the 5-GNC and 5-GC consensus sequences. We used the quantitative polymerase chain reaction (QPCR) to monitor the formation of in vivo ECH lesions in 6C2 chicken erythroid progerutor cells. Three distinct loci were investigated in order to determine the effect of ECH reactivity in different levels of chromatin condensation. The sites consisted of an open locus of the nuclear genome, a closed locus of the nuclear genome, and a naked locus of the mitochondrial genome. We found that ECH alkylation was preferentially targeted towards the nuclear sites and that chromatin structure had no effect upon ECH reactivity. Repair assays of the three sites revealed that there appears to be no repair of ECH lesions in the nuclear genome.
The drug shows high potency and activity in various experimental models including P-gp- and MRP1-expressing multidrug resistant tumors as well as tumors resistant to platinum derivatives, alkylating agents and topoisomerase I and II inhibitors. Nemorubicin has a peculiar mechanism of action requiring NER activity for its full cytotoxicity. Cell lines defective in NER, which show an increased sensitivity to classical alkylating agents, display a three-four fold resistance to nemorubicin. Interestingly, L1210 murine leukemia cells selected for resistance to nemorubicin (L1210/MMDX) show a collateral sensitivity to both platinum derivatives and alkylating agents and are more sensitive (about 4-5 times) to UV light. In addition, these cells are not able to repair UV-induced damage on transfected DNA (host -cell reactivation assay), suggesting that the NER system might be involved in mediating the cytotoxic activity of nemorubicin. The aim of the present study was to evaluate the possible presence of ...
Consistent results from three case-control studies and a pooled analysis, totaling 555 head and neck cancer cases and 792 controls, suggest that genetic variations in MGMT84, MGMT143, and XRCC1399 influence susceptibility to head and neck cancer. Moreover, the MGMT143 variant may modify alcohol-related risk.. MGMT encodes O6-alkylguanine DNA alkyltransferase, which preferentially removes O6-guanine alkyl adducts caused by carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone found in tobacco smoke (40), and the Val143 allele has previously been related to increased lung cancer risk in two small studies (each with ∼130 cases; refs. 28, 41). In our study, Val143 was associated with reduced head and neck cancer risk, particularly among heavy drinkers. In vivo and in vitro experiments show that MGMT-mediated repair of alkylated DNA is reduced by treatment with ethanol or its primary metabolite, acetaldehyde (42, 43), possibly due to MGMT inhibition (44). Although the functional ...
... is used to treat the symptoms of several types of cancer. Mechlorethamine treats only the symptoms of cancer but does not treat the cancer itself. Mechlorethamine is also sometimes injected into body spaces around the heart, lungs, or stomach to treat fluid retention in these areas caused by cancer...
4.1 Polymorphisms and mutations are both variations in DNA sequence and can arise through the same mechanisms. We use the term polymorphism to refer to DNA variants that are relatively common in populations. Mutations affect the phenotype.. 4.2 Misreading of bases during replication can lead to substitution and can be caused by things like tautomerism, DNA alkylating agents, and irradiation.. 4.3 Looping out of DNA on the template strand during replication; strand breakage, due to radiation and other mutagens; and (discussed in earlier chapters) chromosomal aberrations such as deletions and translocations.. 4.4 Looping out of DNA on the growing strand during replication; transposition; and (discussed in earlier chapters) chromosomal aberrations such as duplications, insertions, and translocation.. 4.5 Benzopyrene is one of many hazardous compounds present in smoke. Benzopyrene is an intercalating agent, which slides between the bases of the DNA molecule, distorting the shape of the double helix, ...
Fanconi anemia (FA) patients are hypersensitive to DNA alkylating agents and require lower doses than non-FA patients to minimize serious toxicity. The
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In a phase II study reported in the Journal of Clinical Oncology, Chawla et al found that the combination of a hypoxia-activated alkylating prodrug (TH-302) and doxorubicin was active in first-line treatment of advanced soft-tissue sarcoma. TH-302 is a prodrug of the cytotoxic alkylating agent.... ...
Professional guide for Mechlorethamine (Systemic). Includes: pharmacology, pharmacokinetics, contraindications, interactions, adverse reactions and more.
Function: Corrects defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents ...
Alkeran: Melphalan belongs to the group of cancer-fighting medications known as antineoplastics, and specifically to the group of antineoplastics known as alkylating agents.
In the present thesis, the feasibility of an esterase-triggered prodrug strategy for 2-5A trimer has been evaluated by synthesizing two different 2-5A prodrug candidates and studying the release of 2-5A by carboxyesterase. The protecting group scheme was based on esterase-labile 2,2-disubstituted acyloxypropyl groups for the phosphate protection and acyloxymethyl groups for the 3´- hydroxyl protection. The results demonstrated that deprotection of 2-5A, bearing esterase-labile protecting groups, became significantly slower upon accumulation of negative charge. Additionally, decomposition of the protecting groups produced electrophilic alkylating agents, which have been associated with potential toxicity. For these reasons, six different 2,2-disubstituted 4-acylthio-3-oxobutyl groups were developed as protecting groups for phosphodiesters. These groups are cleaved by esterases, but in addition they exhibit a novel feature being removed thermally, which is an advantage when the affinity of the ...
Were found to alkylate all oxygens and nitrogens in nucleic acids , whereas a host of more moderately reactive electrophilic agents typically target nitrogens
AA-CW236 is a novel non-pseudosubstrate inhibitor of human O(6)-alkylguanine DNA methyltransferase (MGMT) by targeting MGMT active site Cys145 for covalent modification.
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In response to replication stress, a phospho-signaling cascade is activated and required for coordination of DNA repair and replication of damaged templates (intra-S phase checkpoint). How phospho-signaling coordinates the DNA replication stress response is largely unknown. We employed state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) approaches to generate high-coverage and quantitative proteomic and phospho-proteomic profiles during replication stress in yeast, induced by continuous exposure to the DNA alkylating agent methyl methanesulfonate (MMS). We identified 32,057 unique peptides representing the products of 4,296 genes, and 22,061 unique phosphopeptides representing the products of 3,183 genes. 542 phosphopeptides (mapping to 339 genes) demonstrated an abundance change of ≥ 2-fold in response to MMS. The screen enabled detection of nearly all of the proteins known to be involved in the DNA damage response, as well as many novel MMS-induced phosphorylations. We ...
The alkylating agents are a group of strong disinfecting chemicals that act by replacing a hydrogen atom within a molecule with an alkyl group (CnH2n+1), thereby inactivating enzymes and nucleic acids ([link]). The alkylating agent formaldehyde (CH2OH) is commonly used in solution at a concentration of 37% (known as formalin) or as a gaseous disinfectant and biocide. It is a strong, broad-spectrum disinfectant and biocide that has the ability to kill bacteria, viruses, fungi, and endospores, leading to sterilization at low temperatures, which is sometimes a convenient alternative to the more labor-intensive heat sterilization methods. It also cross-links proteins and has been widely used as a chemical fixative. Because of this, it is used for the storage of tissue specimens and as an embalming fluid. It also has been used to inactivate infectious agents in vaccine preparation. Formaldehyde is very irritating to living tissues and is also carcinogenic; therefore, it is not used as an ...
In human cancer, the MGMT gene is not commonly inactivated by mutation; loss of MGMT function is most frequently caused by promoter region hypermethylation (21, 22). Preclinical studies have shown that methylation of discrete regions of the MGMT promoter is associated with epigenetic silencing of the gene, loss of MGMT expression (23, 24), and diminished DNA repair activity. Tumors with methylated MGMT promoters are more sensitive to alkylating agents, whereas tumors with unmethylated MGMT promoters express high levels of the enzyme and are more resistant to alkylating agents (10). From a clinical standpoint, MGMT promoter methylation is associated with improved response to alkylating agents, as evidenced by improved survival in patients with high-grade gliomas who are treated with BCNU or temozolomide (25-27). Therefore, MGMT promoter methylation may predict the therapeutic response to alkylating agents (10). Several ongoing studies are investigating the correlation between MGMT methylation ...
Here, we demonstrate that OTUD4 may serve as a master regulator of alkylation damage resistance through stabilization of the human AlkB homologues. A number of distinct lines of evidence support this role for OTUD4. First, OTUD4 interacts specifically with ALKBH2 and ALKBH3 and encodes a K48‐specific DUB (Fig 1). Consistently, ALKBH3 is subjected to K48‐linked ubiquitination and proteasomal degradation (Fig 2A-D). OTUD4 antagonizes ALKBH3 ubiquitination and stabilizes both ALKBH2 and ALKBH3 in vivo (Fig 2E-H). ALKBH3 protein levels do not correlate well with ALKBH3 mRNA levels in various tumor cell lines but do correlate with OTUD4 levels (Supplementary Fig S2). Finally, overexpression of ALKBH3 in PC‐3 cells, which depend primarily on ALKBH3 instead of ALKBH2 for alkylation damage resistance, is sufficient to rescue alkylation damage sensitivity upon loss of OTUD4 (Fig 7G).. What is most striking is that we find OTUD4 catalytic activity to be apparently dispensable for its stabilization ...
Looking for online definition of alkylate in the Medical Dictionary? alkylate explanation free. What is alkylate? Meaning of alkylate medical term. What does alkylate mean?
Solid neoplasms may contain deficient or poorly functional vascular beds, a property that leads to the formation of hypoxic tumor cells, which form a therapeutically resistant cell population within the tumor that is difficult to eradicate by ionizing irradiation and most existing chemotherapeutic agents. As an approach to the therapeutic attack of hypoxic cells, we have measured the cytotoxicity and DNA lesions produced by the bioreductive alkylating agents mitomycin C and porfiromycin, two structurally similar antibiotics, in oxygen-deficient and aerobic cells. Mitomycin C and porfiromycin were preferentially cytotoxic to hypoxic EMT6 cells in culture, with porfiromycin producing a greater differential kill of hypoxic EMT6 cells relative to their oxygenated counterparts than did mitomycin C. Chinese hamster ovary cells were more resistant to these quinone antibiotics; although in this cell line, porfiromycin was significantly more cytotoxic to hypoxic cells than to aerobic cells, and the ...
Home » Busulfan. Busulfan (Science: chemical) An alkylating agent having a selective immunosuppressive effect on bone marrow. It has been used in the palliative treatment of chronic myeloid leukaemia, but although symptomatic relief is provided, no permanent remission is brought about. According to the fourth annual report on carcinogens (ntp 85-002, 1985), busulfan is listed as a known carcinogen. Pharmacological action: alkylating agents, antineoplastic agent, alkylating, carcinogens, immunosuppressive agents. chemical name: 1,4-Butanediol, dimethanesulfonate ...
Therapeutic radiation increases AML risk, particularly if given concomitantly with alkylating agents. Two categories of therapy-related AML have been described. Patients exposed to alkylating agents (eg, cyclophosphamide, melphalan, nitrogen mustard) can develop AML after a latency period of 4 to 8 years, which is often associated with abnormalities of chromosomes 5 and/or 7. Exposure to agents that inhibit the DNA repair enzyme topoisomerase II (eg, etoposide) is also associated with secondary AML with a shorter latency period, usually 1 to 3 years (4). Benzene, smoking, dyes, herbicides, and pesticides have been implicated as potential risk factors for development of AML (5). ...
The 7-bromoacetyl-7-desacetyl (BrAcFsk) and 7-chloroacetyl-7-desacetyl (CIAcFsk) analogs of forskolin were synthesized as alkylating agents to study the high affinity binding sites for forskolin. BrAcFsk and CIAcFsk activated adenylate cyclase in human platelet membranes with EC50 values of about 20 and 12 microM, respectively. Both analogs increased cyclic AMP in human platelets; however, they were less potent that forskolin. Forskolin inhibited [3H]forskolin binding to human platelet membranes with an IC50 of 20 nM, whereas BrAcFsk and CIAcFsk inhibited [3H] forskolin binding with IC50 values of 0.1 microM. Pretreatment of intact platelets with 10 microM BrAcFsk caused a 90% irreversible loss in [3H]forskolin binding sites, whereas pretreatment with 10 microM CIAcFsk led to a loss of 55% of the binding sites. The loss of binding sites occurred within 5 min for BrAcFsk and within 30 min for CIAcFsk. The time required for the loss of binding sites produced by either alkylating agent was ...
The appearance of electrophoretically separable isozyme patterns is specific both to type of tissue and to its stage of development (Markert & Møller, 1959). In abnormally developing embryonic systems there are alterations in the time of initial appearance and the persistence of isozymes from a variety of metabolic areas (Johnson & Spinuzzi, 1966, 1968). In malformed embryos from folic-aciddeficient rats the altered zymogram patterns of esterases from abnormal limbs were different from those of abnormal kidneys, yet differentiation of zymograms from the normal hearts of these embryos was unaltered. This implies a correlation between altered tissue-specific zymogram patterns and abnormally developing systems, though no causal relationship has as yet been shown (Johnson, 1968). Moreover, when tibial hemimelia in the rat was elicited by two different teratogens-a folic acid antagonist, 9-methylpteryol-glutamic acid (PGA), and the alkylating agent N-nitroso-N-methylurea (NNMU)-there were similar ...
Alkylation reactions represent an important organic transformation to form C-C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various
Introduction: After lymphoma the risk of secondary cancer namely lung cancer increases. Treatment (alkylating agents, radiotherapy) and smoking are known risk factors. Aims: To report on patients with lung cancer (LC) after lymphoma (LY), focusing on disease characteristics, detection methods and clinical outcomes. Methods: Retrospective study of patients diagnosed in a single institution with LC and previous LY from 1992 to 2012. Data regarding LY characteristics and treatment, smoking history and LC stage, histology and survival were obtained from medical records. Results: Of the 44 patients 43% had Hodgkin and 57% non Hodgkin lymphoma. All had known risk factors: 13 (30%) thoracic radiotherapy, 21 (48%) alkylating chemotherapy, 34 (75%) smoking habits. Median time between diagnoses was 9,5 years (±9.3).Thirteen were female (30%). Median age at LC diagnosis was 60 years (±13). Stage distribution was: 21(48%) IV, 10(23%) III; 13(30%) I/II. PS was 0/1 in 36(81%) patients. Diagnosis was ...
Mitomycin is one of the older chemotherapy drugs, which has been around and in use for decades. It is an antibiotic which has been shown to have antitumor activity. Mitomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Mitomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2 ...
Mitomycin is one of the older chemotherapy drugs, which has been around and in use for decades. It is an antibiotic which has been shown to have antitumor activity. Mitomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Mitomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2 ...
The nitrosoureas are alkylating agents that are highly lipid soluble and share similar pharmacological and clinical properties. Carmustine (BCNU), lomustine
165 medications are known to interact with mechlorethamine. Includes Adriamycin (doxorubicin), Adrucil (fluorouracil), Ascriptin Enteric (aspirin).
During the annual meeting, new preclinical data on ImmunoGens novel ADCs, IMGN632 and IMGN779 will be presented. IMGN632, is a CD123-targeting ADC while IMGN779, targets CD33. Both investigational agents use ImmunoGens new family of indolino-benzodiazepine cancer-killing agents called IGNs. Scientists at ImmunoGen designed IGN payloads to alkylate DNA without crosslinking it. The data being presented in both oral as well as poster presentations demonstrates that DNA-alkylating IGNs are ultra-potent, yet provide increased tolerability compared with DNA crosslinking versions.. "Accelerating our earlier-stage portfolio with an emphasis on our IGN ADCs is one of [our] strategic priorities, and we believe the IMGN632 and IMGN779 preclinical … further demonstrates why we are excited about the potential of these programs," explained Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.. The preclinical data to be presented shows activity of IMGN632 in multiple ...
Hydrogen, Lead, Ability, Alkaline Comet Assay, Alkylation, Alkylators, Blood, Cancer, Cell, Cells, Chromatography, Comet Assay, Concentration, Concentrations, DNA, DNA Damage, Epithelial Cells, Ethylene Oxide, Gas Chromatography, Human
Mechanism of Action Prodrug; pharmacologically active free thiol metabolite can reduce the toxic effects of cisplatin (is available to bind to , and detoxify, reactive metabolites of cisplatin). It can also act as a scavenger of free radicals that may be generated in tissues exposed to cisplatin. It also protects against cell damage from radiation and other alkylators. Other mechanisms may be responsible for protection against paclitaxel toxicity and for therapeutic effect in MDS.. ...
Alkylating Agents, Breast, Cancers, Cholesterol, Drugs, Epoxide Hydrolase, Epoxides, Metabolism, Report, Styrene, Tamoxifen, Treatment
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The O(6)-alkylguanine-DNA alkyltransferase inactivator O(6)-benzylguanine was administered to BALB/c mice either alone or before exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea to study the role of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase in the protection of the testis against anti-cancer O(6)-alkylating agents. Exposure of the mice to 1, 3-bis(2-chloroethyl)-1-nitrosourea or O(6)-benzylguanine alone did not produce any marked testicular toxicity at the times studied. Testicular O(6)-alkylguanine-DNA alkyltransferase concentrations were assayed between 0 and 240 min after O(6)-benzylguanine treatment and were shown to be , 95% depleted 15 min after treatment with O(6)-benzylguanine and remained at , 95% at all the times assayed. Histological examination, the reduction in testicular mass and the induction of spermatogenic cell apoptosis showed that this depletion significantly potentiated 1, 3-bis(2-chloroethyl)-1-nitrosourea-induced testicular damage after treatment. Major ...
Another amino acid-like drug is the antineoplastic agent melphalan. Tumor cells spend less time in resting phases than normal cells so at any given time, they are more likely to be metabolically active than most normal host cells. The rationale behind incorporating an alkylating function in a molecule resembling a primary cellular metabolite was to get a greater safety margin by fooling tumor cells into taking up the toxin preferentially. ...
Accepted name: DNA-3-methyladenine glycosylase II. Reaction: Hydrolysis of alkylated DNA, releasing 3-methyladenine, 3-methylguanine, 7-methylguanine and 7-methyladenine. Other name(s): deoxyribonucleate 3-methyladenine glycosidase II; 3-methyladenine DNA glycosylase II; DNA-3-methyladenine glycosidase II; AlkA. Systematic name: alkylated-DNA glycohydrolase (releasing methyladenine and methylguanine). Comments: Involved in the removal of alkylated bases from DNA in Escherichia coli (cf. EC 2.1.1.63 methylated-DNA [protein]-cysteine S-methyltransferase).. Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 89287-38-7. References:. 1. Evensen, G. and Seeberg, E. Adaptation to alkylation resistance involves the induction of a DNA glycosylase. Nature 296 (1982) 773-775. [PMID: 7040984]. 2. Karran, P., Hjelmgren, T. and Lindahl, T. Induction of a DNA glycosylase for N-methylated purines is part of the adaptive response to alkylating agents. Nature 296 (1982) 770-773. ...
DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N -nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O 6 -alkylguanine DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made ...
The nitrosourea drugs, a class of DNA alkylating agents related to nitrogen mustards, include(BCNU),(CCNU), semustine (methyl CCNU), and chloroethylnitrosourea (Sar-CNU). Nitrosourea drugs are used to treat lymphoma, brain tumors, melanoma, and other
EMEA (Europe, Middle East and Africa) Mitomycin C Market 2017 Forecast to 2022. This report studies the Mitomycin C market, Mitomycin C is an antibiotic which acts as a double-stranded DNA alkylating agent. It covalently crosslinks DNA, inhibiting DNA synthesis and cell proliferation It acts by way of reductive activation either through low pH or NAD(P)H:quinone oxidoreductase (DT-diaphorase) or NADH cytochrome c reductase .... January 2018 , $4480 ,View Details>> ...
EMEA (Europe, Middle East and Africa) Mitomycin C Market 2017 Forecast to 2022. This report studies the Mitomycin C market, Mitomycin C is an antibiotic which acts as a double-stranded DNA alkylating agent. It covalently crosslinks DNA, inhibiting DNA synthesis and cell proliferation It acts by way of reductive activation either through low pH or NAD(P)H:quinone oxidoreductase (DT-diaphorase) or NADH cytochrome c reductase .... January 2018 , $4480 ,View Details>> ...
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, and is universally fatal. The DNA alkylating agent temzolomide (TMZ) is part of the standard-of-care for GBM. However, these tumors eventually develop therapy-driven resistance and inevitably recur. While loss of mismatch repair (MMR) and re-expression of MGMT have been shown to underlie chemoresistance in a fraction of GBMs, resistance mechanisms operating in the remaining GBMs are not well understood. In order to better understand the molecular basis for therapy-driven TMZ resistance, mice bearing orthotopic GBM xenografts were subjected to protracted TMZ treatment, and cell lines were generated from the primary (untreated) and recurrent (TMZ-treated) tumors. As expected, the cells derived from primary tumors were sensitive to TMZ while the cells from the recurrent tumors were significantly resistant to the drug. Importantly, the acquired resistance to TMZ in the recurrent lines was not driven by ...
Chemoresistance represents a major obstacle to successful treatment for malignant glioma with temozolomide. N (7)-methyl-G and N (3)-methyl-A adducts comprise more than 80 % of DNA lesions induced by temozolomide and are processed by the base excisi
Alkylating agents constitute a large class of DNA‐damaging agents that generate both mutagenic and cytotoxic DNA lesions. Much of our understanding of alkylation damage repair is from studies on Escherichia coli, in particular on the adaptive (Ada) response, which involves the upregulation of four genes: ada, aidB, alkA and alkB (Sedgwick et al, 2007). The Ada protein is a multifunctional DNA methyltransferase that also acts as a transcriptional activator of the response. The exact function of AidB, a flavin‐binding protein, remains to be explained and AlkA is a DNA glycosylase with a broad specificity. AlkB catalyses the demethylation of 1‐methyladenine and 3‐methylcytosine in DNA and RNA, coupled to the decarboxylation of 2‐oxoglutarate (2OG) to succinate and CO2 (Falnes et al, 2002; Trewick et al, 2002). Homologues of AlkB have been identified in species ranging from bacteria to humans; eight human homologues (ABH) have been described, but only two, ABH2 and ABH3, are known to ...
Oral alkylating drugs, alone and in combination therapy with steroids, have been extensively evaluated in the upfront treatment of WM. The greatest experience with oral alkylator therapy has been with chlorambucil, which has been administered on both a continuous (i.e. daily dose schedule) as well as an intermittent schedule. Patients receiving chlorambucil on a continuous schedule typically receive 0.1 mg/kg per day, whilst on the intermittent schedule patients will typically receive 0.3 mg/kg for 7 days, every 6 weeks. In a prospective randomized study, Kyle et al.109 reported no significant difference in the overall response rate between these schedules, although interestingly the median response duration was greater for patients receiving intermittent versus continuously dosed chlorambucil (46 vs. 26 months). Despite the favorable median response duration in this study for use of the intermittent schedule, no difference in the median overall survival was observed. Moreover, an increased ...
The tissue and cellular distribution of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase) is an important question in relation to the response of tumour and normal tissues to chemotherapeutic regimes employing alkylating agents such as methyltriazenes and nitrosoureas. In order to examine this issue by immunostaining, we have raised a rabbit antiserum to apparently pure recombinant human enzyme. The antiserum is highly specific and sensitive, detecting a band at 24 kDa on western blots of crude extracts of ATase-expressing human lymphoblastoid cells, liver and melanoma. Adjacent sections of acetone or formalin fixed normal human liver and subcutaneous malignant melanoma were reacted with preimmune serum or antiserum and an immunoperoxidase detection system with silver enhancement was used to locate binding of the primary antibody to the antigen. In sections reacted with preimmune serum or with antigen-preadsorbed antiserum, only faint cytoplasmic and little or no nuclear ...
Alkylating agents exert a wide range of biological effects in both pro- and eukaryotes and there is ever increasing evidence that these effects are mediated via alkylation at the O6position of...
D4337 - 89(2017) Standard Test Methods for Analysis of Linear Detergent Alkylates , linear alkylbenzenes, linear detergent alkylates ,,
Despite advances in surgery and intensive investigation into novel therapies, the overall 2-year survival rate for malignant gliomas (i.e., grades III and IV) remains ,20% (1 , 14) . For the most common diagnostic types, adjuvant therapy with radiation and alkylating agent-based chemotherapy modestly increases response rates and survival times (5 , 11) . However, adjuvant therapy provides no benefit to a sizeable fraction of patients and seldom produces long term remission. In addition, the modest benefit conferred depends greatly on patient and clinical variables, including age, neurological status, and histology (1 , 2 , 34) . Intrinsic and acquired resistance to alkylators and radiation are major factors affecting outcome. Hence, characterization of mechanisms underlying resistance is essential to identify potential targets for antiresistance therapies and to develop potential prognostic markers to guide adjuvant therapies. Our results suggest that Ap endo activity promotes resistance to ...
Non-toxic DAlCs, especially lighter dimethyl- and diethyl-carbonate, are regarded as very green alkylating reagents, particularly when coupled with metal-exchanged Y- and X-faujasites as catalysts. These reactions are selective, free from wastes or byproducts, and often require no additional solvent other th
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Definition of busulfan - A drug which is an alkylating agent with a destructive effect on bone marrow, used especially in the treatment of chronic myeloid
3804 Introduction: Inadequate tumor vascularization and/or anti-vascular effects of cancer chemotherapy contribute to anticancer drugs failure. We pursued physiological drug resistance of cancer chemotherapy in mouse breast cancer models using magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI). Methods: All animal experiments were conducted according to the institutional guidelines. Anesthetized SCID mice with orthotopic MCF-7 breast cancer were immobilized in the probe and maintained under gas anesthesia (Isoflurane 0.5%, 1 l/min). 13C-Labeled-temozolomide ([13C]TMZ) or temozolomide (TMZ: Temodar® capsule), alkylating agent, was used as a model drug. Two hundred microliter of [13C]TMZ (50 mM)/dimethyl-β-cyclodextrin (100 mM) inclusion complex was infused into the mouse via an i.p. catheter. Three-dimensional indirect 1H/13C MRSI was performed with an 8x8x8 matrix for a 16 mm isotropic field of view. During 3D map acquisition, a total of 400 μl of inclusion complex was ...
Cancer drugs can be divided into two general classes: CELL CYCLE SPECIFIC DRUGS (CCS; esp. plant alkaloids and antimetabolites), and CELL CYCLE NON-SPECIFIC DRUGS (CCNS; esp. alkylating agents and some natural products). Antineoplastic agents can also be organized according to their chemical class, mechanism of action, therapeutic use or their toxicities ...
1P7M: Solution structure and base perturbation studies reveal a novel mode of alkylated base recognition by 3-methyladenine DNA glycosylase I
Subjects may not have had , 3 prior regimens and must not have had a platinum or taxane agent within the past 6 months. Last chemotherapy must have been , 4 weeks prior to enrollment. Subjects may not have had prior whole abdomen or pelvic radiation. Patients may not have had , 6 cycles of an alkylating agent or , 450 mg/m2 of doxorubicin ...
Submission of the final clinical study report for study 101-09, A Phase 2 Study to Assess the Efficacy and Safety of Idelalisib in Subjects with Indolent B-Cell Non-Hodgkin Lymphomas Refractory to Rituximab and Alkylating Agents. This submission was an Annex II post-authorisation measure (ANX 002) and a category I commitment in the Zydelig Risk Management Plan (RMP).. The SmPC was updated to include the safety and efficacy data from Study 101-09 and the SmPC and PIL were updated to remove the inverted black triangle and requirement for additional monitoring as this submission fulfilled the last outstanding commitment in the Product Information Annex II.. We also took the opportunity to remove ofatumumab from the SmPC and PIL indication statement following the withdrawal of the Arzerra (ofatutumumab) licence in the EU. ...
The present invention pertains to a method for manufacturing alkylate oil using a composite ionic liquid as catalyst. A mixture of isobutane and C4 olefins is used as the raw material, and a composite
Two Chinese hamster ovary (CHO) cell variants differ substantially in their sensitivity to N-methyl-N -nitro-N-nitrosoguanidine (MNNG). The resistant clone (Cl 3) was isolated from the sensitive...
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Recently, the overproduction of Mycobacterium tuberculosis diaminopimelic acid (DAP) epimerase MtDapF in Escherichia coli using a novel codon alteration cloning strategy and the characterization of the purified enzyme was reported. In the present study, the effect of sulphydryl alkylating agents on the in vitro activity of M. tuberculosis DapF was tested. The complete inhibition of the enzyme by 2-nitro-5-thiocyanatobenzoate, 5,5-dithio-bis(2-nitrobenzoic acid) and 1,2-benzisothiazolidine-3-one at nanomolar concentrations suggested that these sulphydryl alkylating agents modify functionally significant cysteine residues at or near the active site of the epimerase. Consequently, the authors extended the characterization of MtDapF by studying the role of the two strictly conserved cysteine residues. The putative catalytic residues Cys87 and Cys226 of MtDapF were replaced individually with both serine and alanine. Residual epimerase activity was detected for both the serine replacement mutants ...
Classical approaches to immunotherapy that show promise in some malignancies have generally been disappointing when applied to high-grade brain tumors such as glioblastoma multiforme (GBM). We recently showed that ex vivo expanded/activated cd T cells recognize NKG2D ligands expressed on malignant glioma and are cytotoxic to glioma cell lines and primary GBM explants. In addition, cd T cells extend survival and slow tumor progression when administered to immunodeficient mice with intracranial human glioma xenografts. We now show that temozolomide (TMZ), a principal chemotherapeutic agent used to treat GBM, increases the expression of stress-associated NKG2D ligands on TMZ-resistant glioma cells, potentially rendering them vulnerable to cd T cell recognition and lysis. TMZ is also highly toxic to cd T cells, however, and to overcome this cytotoxic effect cd T cells were genetically modified using a lentiviral vector encoding the DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) from ...
Trade Name: Mustargen®. How is this drug used? Mechlorethamine is FDA approved for the treatment of advanced Hodgkins disease, lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, bronchogenic carcinoma, and metastatic cancer resulting in effusion. It is important for patients to remember that physicians have the ability to prescribe medication for conditions other than those for which the drug has been approved by the FDA. Patients who have received a prescription of this drug for a condition other than which it is approved may wish to discuss this issue with their physician.. What is the mechanism of action? Mechlorethamine belongs to a group of drugs called alkylating agents. Alkylating agents produce their anti-cancer effects by causing a chemical reaction that damages the DNA in a cell. The chemical reaction, called interstrand cross-linking, inhibits the cancer cell to grow or replicate and/or ultimately causes cellular death.. How is ...
The alkylation of bromobenzene and toluene on zeolite H-USY (Si/Al 15) was studied using a high-throughput frontal analysis experimental setup. Adsorption properties of the involved components were determined using the batch technique. Reactions were performed using allyl alcohol, allyl acetate, 1-octen-3-ol, and allyl chloride as alkylating agents at 200 degrees C in the liquid phase. The reaction products could be divided into 3 fractions: (1) light components formed in side reactions of the alkylating agent; (2) primary alkylation products resulting from the alkylation of bromobenzene or toluene and subsequent rearrangement reactions; and (3) a heavy fraction consisting of secondary alkylation products and polyaromatics. Whereas the use of allyl chloride and 1-octen-3-ol as alkylating agents resulted mainly in the formation of undesired side products, bromobenzene was efficiently alkylated with allyl alcohol and allyl acetate, resulting in the formation of allyl bromobenzene, cis-2-propenyl ...
During my first ten years on the Yale faculty, I participated in clinical trials evaluating the efficacy of bioreductive alkylating agents as an adjunct to radiotherapy in cervix cancer. A Phase III study comparing radiotherapy alone with radiotherapy plus Mitomycin C for cervix cancer has been completed in Venezuela with results showing a significant improvement in disease-free survival with the addition of Mitomycin C, which is a hypoxic cell cytotoxin. For several years, I had been collaborating with Interventional Cardiology and Medical Physics in a clinical program utilizing coronary brachytherapy to manage in-stent restenosis. Some current or upcoming clinical research projects include: 1) modifying radiation dose and volume in advanced stage Hodgkins disease based on response to initial chemotherapy (a cooperative group trial); 2) the effects of prostate edema during brachytherapy on modulating radiation dose delivery; 3) the changes in second malignancies seen after Hodgkins Lymphoma ...
Using in situ solid-state NMR spectroscopy we show that CO can act as an alkylating reagent and react with benzene to produce toluene over a Zn/H-ZSM-5 zeolite. In the alkylation reaction, CO provides the methyl group of toluene via a methoxy intermediate.

alkylating agent (CHEBI:22333)alkylating agent (CHEBI:22333)

mitomycin C (CHEBI:27504) has role alkylating agent (CHEBI:22333). MTIC (CHEBI:72568) has role alkylating agent (CHEBI:22333). ... dimethylmyleran (CHEBI:67107) has role alkylating agent (CHEBI:22333). esperamicin A1 (CHEBI:53273) has role alkylating agent ( ... busulfan (CHEBI:28901) has role alkylating agent (CHEBI:22333). carmustine (CHEBI:3423) has role alkylating agent (CHEBI:22333) ... iodoacetic acid (CHEBI:74571) has role alkylating agent (CHEBI:22333). lomustine (CHEBI:6520) has role alkylating agent (CHEBI: ...
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Alkylating agents - definition of Alkylating agents by The Free DictionaryAlkylating agents - definition of Alkylating agents by The Free Dictionary

Alkylating agents synonyms, Alkylating agents pronunciation, Alkylating agents translation, English dictionary definition of ... Alkylating agents. tr.v. al·kyl·at·ed , al·kyl·at·ing , al·kyl·ates To add one or more alkyl groups to . al′kyl·a′tion n. n 1. ... Alkylating agents - definition of Alkylating agents by The Free Dictionary https://www.thefreedictionary.com/Alkylating+agents ... redirected from Alkylating agents). Also found in: Medical, Encyclopedia.. Related to Alkylating agents: Antimetabolites ...
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alkylating agents Protocols and Video...'alkylating agents' Protocols and Video...

Ex Vivo Red Blood Cell Hemolysis Assay for the Evaluation of pH-responsive Endosomolytic Agents for Cytosolic Delivery of ... Busulfan as a Myelosuppressive Agent for Generating Stable High-level Bone Marrow Chimerism in Mice, Percutaneous Hepatic ... Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel, Adapting Human Videofluoroscopic ... Preparation and In Vitro Characterization of Dendrimer-based Contrast Agents for Magnetic Resonance Imaging, Whole Genome ...
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Alkylating Agents - Pharmacology - Merck Veterinary ManualAlkylating Agents - Pharmacology - Merck Veterinary Manual

Learn about the veterinary topic of Alkylating Agents. Find specific details on this topic and related topics from the Merck ... Other Alkylating Agents:. Of the other subgroups of alkylating agents, several have limited but specific uses. ... Alkylating Agents By Lisa G. Barber, DVM, Assistant Professor, Cummings School of Veterinary Medicine, Tufts University ... Resistance to one alkylating agent often implies resistance to other drugs in the same class and can be caused by increased ...
more infohttp://www.merckvetmanual.com/en-pr/pharmacology/antineoplastic-agents/alkylating-agents

Global response of Saccharomyces cerevisiae to an alkylating agent | PNASGlobal response of Saccharomyces cerevisiae to an alkylating agent | PNAS

Global response of Saccharomyces cerevisiae to an alkylating agent Message Subject (Your Name) has sent you a message from PNAS ... Global response of Saccharomyces cerevisiae to an alkylating agent. Scott A. Jelinsky and Leona D. Samson ... By using chips bearing oligonucleotide arrays, we show that, after exposure to the alkylating agent methyl methanesulfonate, ≈ ... Of the 21 genes that already were known to be induced by a DNA-damaging agent, 18 can be scored as inducible in this data set, ...
more infohttp://www.pnas.org/content/96/4/1486.short

Molecules | Free Full-Text | PM00104 (Zalypsis®): A Marine Derived Alkylating AgentMolecules | Free Full-Text | PM00104 (Zalypsis®): A Marine Derived Alkylating Agent

PM00104 is a DNA binding agent, causing inhibition of the cell cycle and transcription, which can lead to double stranded DNA ... The compound has been proposed as a potential chemotherapeutic agent in the treatment of solid human tumors and hematological ... Petek, B.J.; Jones, R.L. PM00104 (Zalypsis®): A Marine Derived Alkylating Agent. Molecules 2014, 19, 12328-12335. ... "PM00104 (Zalypsis®): A Marine Derived Alkylating Agent." Molecules 19, no. 8: 12328-12335. ...
more infohttp://www.mdpi.com/1420-3049/19/8/12328

Investigation of alpha 1-adrenoceptor subtypes in canine aorta, using alkylating agents.  - PubMed - NCBIInvestigation of alpha 1-adrenoceptor subtypes in canine aorta, using alkylating agents. - PubMed - NCBI

Investigation of alpha 1-adrenoceptor subtypes in canine aorta, using alkylating agents.. Hoo KH1, Kwan CY, Daniel EE. ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/7912162?dopt=Abstract

Ethylene imines | Alkylating agents | Antineoplastic agentsEthylene imines | Alkylating agents | Antineoplastic agents

Antineoplastic agents Brokerage service for pharmaceutical and parapharmaceutical products active ingredients and precursors.. ... Agents acting on the renin-angiot.. Ace inhibitors, plain Ace inhibitors, plain ... Beta blocking agents Beta blocking agents Beta blocking agents, non-selecti.. Beta blocking agents, selective ...
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Alkylating agent - Apoptosis inducer - Assorted Products - ProductsAlkylating agent - Apoptosis inducer - Assorted Products - Products

Alkylating agent. Alkylating agents are a ubiquitous family of reactive chemicals that transfer alkyl carbon groups onto a ... alkylating agents pose considerable threats to human health. In spite of this, certain toxic alkylating agents are commonly ... Internally, alkylating agents can arise as byproducts of oxidative damage or from cellular methyl donors such as S- ... Alkylating agents are generally unavoidable owing to their abundant presence in the environment and within living cells. ...
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The Use of Alkylating Agents in the Treatment of Wegeners Granulomatosis | Annals of Internal Medicine | American College of...The Use of Alkylating Agents in the Treatment of Wegener's Granulomatosis | Annals of Internal Medicine | American College of...

The Use of Alkylating Agents in the Treatment of Wegeners Granulomatosis DANIEL HOLLANDER, M.D.; ROBERT T. MANNING, M.D., F.A. ... The Use of Alkylating Agents in the Treatment of Wegeners Granulomatosis. Ann Intern Med. 1967;67:393-398. doi: 10.7326/0003- ...
more infohttps://annals.org/aim/article-abstract/681671/use-alkylating-agents-treatment-wegener-s-granulomatosis

ALKYLATING AGENTS AND THE EFFECTS OF ANTIDIURETIC HORMONE IN THE TOAD BLADDER | Journal of Pharmacology and Experimental...ALKYLATING AGENTS AND THE EFFECTS OF ANTIDIURETIC HORMONE IN THE TOAD BLADDER | Journal of Pharmacology and Experimental...

ALKYLATING AGENTS AND THE EFFECTS OF ANTIDIURETIC HORMONE IN THE TOAD BLADDER. Robert Z. Gussin, Ulrike Miksche and Alfred ... ALKYLATING AGENTS AND THE EFFECTS OF ANTIDIURETIC HORMONE IN THE TOAD BLADDER. Robert Z. Gussin, Ulrike Miksche and Alfred ... ALKYLATING AGENTS AND THE EFFECTS OF ANTIDIURETIC HORMONE IN THE TOAD BLADDER. Robert Z. Gussin, Ulrike Miksche and Alfred ... Mechlorethamine, a potent alkylating agent of the nitrogen mustard class, can interfere with the ability of antidiuretic ...
more infohttp://jpet.aspetjournals.org/content/156/3/606

Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma...Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma...

Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma ... We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final ... Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/9372546?dopt=Abstract

Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal...Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal...

... timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in ...
more infohttp://onlinelibrary.wiley.com/doi/10.1002/jat.2878/abstract?globalMessage=0

VAL-083 | bi-functional alkylating agent | Buy VAL-083 from Supplier AdooQ®VAL-083 | bi-functional alkylating agent | Buy VAL-083 from Supplier AdooQ®

VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer better than TMZ and caused ... bi-functional alkylating agent VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer ... VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer better than TMZ and caused ... VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer better than TMZ and caused ...
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Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide | Clinical Cancer...Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide | Clinical Cancer...

... and bases that have been alkylated either from endogenous or exogenous alkylating agents, including some chemotherapeutic ... Temozolomide is an alkylating agent that creates DNA lesions, including N7-methylguanine and N3-methyladenine, which are ... Temozolomide is an alkylating agent that creates DNA lesions that are repaired by the BER pathway (14). Once administered, ... Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide. Melissa L. Fishel, ...
more infohttp://clincancerres.aacrjournals.org/content/13/1/260

735 Contribution of Alkylating Agents in the Cytogenetic Diagnosis of Fanconi Anemia | Archives of Disease in Childhood735 Contribution of Alkylating Agents in the Cytogenetic Diagnosis of Fanconi Anemia | Archives of Disease in Childhood

735 Contribution of Alkylating Agents in the Cytogenetic Diagnosis of Fanconi Anemia ... 735 Contribution of Alkylating Agents in the Cytogenetic Diagnosis of Fanconi Anemia ...
more infohttp://adc.bmj.com/content/97/Suppl_2/A212.2.responses

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance...Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance...

Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or ... as an antiadhesive agent, which also caused sensitization to alkylating agents (8, 9). Thus, some forms of both acquired and ... Generation of Alkylating Agent-Resistant Cell Lines. In vitro selected drug-resistant variants of murine EMT-6 and human H69 ... EMT-6 alkylating agent-resistant model (5) to be the result of an enrichment of a subpopulation with increased cell-cell ...
more infohttps://mct.aacrjournals.org/content/4/10/1484

Screening of natural products and alkylating agents for antineoplastic activityScreening of natural products and alkylating agents for antineoplastic activity

On the other hand, alkylating agents such as cisplatin, cis- [PtCl2 (NH3) 2] have been widely used as antineoplastic agents for ... Screening of natural products and alkylating agents for antineoplastic activity. dc.contributor.advisor. Rees, Jasper. ... Screening of natural products and alkylating agents for antineoplastic activity. en_US. ... However, the use of cisplatin as an anticancer agent is limited due to toxicity and resistance problems. The aim of this ...
more infohttp://etd.uwc.ac.za/xmlui/handle/11394/3162?show=full

Quasi-adaptive response to alkylating agents and Ada-protein functions in Escherichia coli, Russian Journal of Genetics | 10...Quasi-adaptive response to alkylating agents and Ada-protein functions in Escherichia coli, Russian Journal of Genetics | 10...

"Quasi-adaptive response to alkylating agents and Ada-protein functions in Escherichia coli, Russian Journal of Genetics" on ... Quasi-adaptive response to alkylating agents and Ada-protein functions in Escherichia coli. Vasilieva, S.; Moshkovskaya, E.; ... Quasi-adaptive response to alkylating agents and Ada-protein functions in Escherichia coli. Quasi-adaptive response to ... lp/springer_journal/quasi-adaptive-response-to-alkylating-agents-and-ada-protein-functions-18qO5fx0qg ...
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A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents | Bentham ScienceA Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents | Bentham Science

"A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents", Anti-Cancer Agents ... A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents. Author(s): Pravin C ... Title:A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents ... Anti-Cancer Agents in Medicinal Chemistry. *Enhanced Oral Bioavailability of The Hydrophobic Chemopreventive Agent (Sr13668) in ...
more infohttp://www.eurekaselect.com/126969/article?tracking-code=4

The effect of the Primary Structure of DNA on Induction of Mutations by Alkylating Agents, Russian Journal of Genetics | 10...The effect of the Primary Structure of DNA on Induction of Mutations by Alkylating Agents, Russian Journal of Genetics | 10...

"The effect of the Primary Structure of DNA on Induction of Mutations by Alkylating Agents, Russian Journal of Genetics" on ... The effect of the Primary Structure of DNA on Induction of Mutations by Alkylating Agents. Rogozin, I.; Berikov, V.; Vasunina, ... The effect of the Primary Structure of DNA on Induction of Mutations by Alkylating Agents. The effect of the Primary Structure ... The spectra of mutations induced by various alkylating agents were studied. The nucleotide bases at positions -2, -1, +1 and +2 ...
more infohttps://www.deepdyve.com/lp/springer_journal/the-effect-of-the-primary-structure-of-dna-on-induction-of-mutations-MgUnBPgSTq

Apurinic Endonuclease Activity in Adult Gliomas and Time to Tumor Progression after Alkylating Agent-Based Chemotherapy and...Apurinic Endonuclease Activity in Adult Gliomas and Time to Tumor Progression after Alkylating Agent-Based Chemotherapy and...

Alkylating Agent-Based Chemotherapy.. The association of Ap endo activity with TTP after alkylating agent-based chemotherapy ... The role of alkylating agents in the treatment of grade II gliomas is under active investigation. Although early studies ... All received prior RT (54-62 Gy). Alkylating agent regimens were as follows: BCNU (200 mg/m2 every 6-8 weeks for up to 6 cycles ... Sixty-four gliomas were included in the analysis of alkylating agent therapy and 70 in the analysis of RT that we undertook ...
more infohttp://clincancerres.aacrjournals.org/content/10/23/7875

A Pilot Trial of Sequential Chemotherapy With Antimetabolite Induction, High-Dose Alkylating Agent Consolidation With...A Pilot Trial of Sequential Chemotherapy With Antimetabolite Induction, High-Dose Alkylating Agent Consolidation With...

three cycles of high-dose alkylating agents. First, patients will receive one cycle of. high-dose cyclophosphamide administered ... with antimetabolites, followed with consolidation using high-dose single alkylating agent. therapy and finally intensification ... agent doxorubicin.. This protocol combines several highly active chemotherapeutic agents in an attempt to. improve upon ... A Pilot Trial of Sequential Chemotherapy With Antimetabolite Induction, High-Dose Alkylating Agent Consolidation With ...
more infohttp://www.knowcancer.com/cancer-trials/NCT00001498/

Alkylating Antineoplastic Agents
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A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to ... Alkylating; Antineoplastics, Alkylating; Antineoplastic Alkylating Drugs; Drugs, Antineoplastic Alkylating; Alkylating Agents, ... Antineoplastic Agents, Alkylating; Alkylating Antineoplastic Drugs; Alkylating Antineoplastics; Alkylating Drugs, ... Alkylating Antineoplastic Agents. Subscribe to New Research on Alkylating Antineoplastic Agents A class of drugs that differs ...
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  • Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT, are warranted. (nih.gov)
  • One- and two-electron reduction of 2-methyl-1,4-naphthoquinone bioreductive alkylating agents: kinetic studies, free-radical production, thiol oxidation and DNA-strand-break formation. (semanticscholar.org)
  • The one- and two-electron enzymic reduction of the bioreductive alkylating agents 2-methylmethoxynaphthoquinone (quinone I) and 2-chloromethylnaphthoquinone (quinone II) was studied with purified NADPH-cytochrome P-450 reductase and DT-diaphorase respectively, and characterized in terms of kinetic constants, oxyradical production, thiol oxidation and DNA-strand-break formation. (semanticscholar.org)
  • Our results show that MPG-overexpressing IGROV-1 and IGROV-1mp53 cells are significantly more sensitive to the clinical chemotherapeutic temozolomide in combination with methoxyamine as assayed by cytotoxicity, apoptosis, and levels of DNA damage than either agent alone. (aacrjournals.org)
  • Alkylating agents are a ubiquitous family of reactive chemicals that transfer alkyl carbon groups onto a broad range of biological molecules, thereby altering their structure and potentially disrupting their function. (axonmedchem.com)
  • Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. (eurekaselect.com)
  • The Measles vaccine is not recommended (contraindicated) for persons with congenital immunodeficiency, HIV infection, leukaemia, lymphoma or generalised malignancy or those who are currently receiving alkylating agents , antimetabolites, radiation or large doses of corticosteroids, in addition to pregnant women. (thefreedictionary.com)
  • Immunosuppressant drugs include antimetabolites, alkylating agents , some antibiotics and specific adjuvants. (thefreedictionary.com)
  • Besides corticosteroids, long-term treatment options for the treatment of JIA-associated uveitis include antimetabolites, alkylating agents and biologic agents. (thefreedictionary.com)
  • The compound has been proposed as a potential chemotherapeutic agent in the treatment of solid human tumors and hematological malignancies. (mdpi.com)
  • Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors. (aacrjournals.org)
  • These studies show that although clinical trials in ovarian cancer to determine temozolomide single-agent efficacy are in development, through manipulation of the BER pathway, an increase in response to temozolomide is achieved. (aacrjournals.org)
  • Phenotypic expression of "quasi-Ada" is similar to the true Ada response, however in contrast it develops in the course of pretreatment of the cells by sublethal dose of non-alkylating agent, an NO-containing dinitrosyl iron complex with glutathione (DNICglu). (deepdyve.com)
  • Using clinically relevant and experimental agents this review will describe many of these mechanisms. (openrepository.com)
  • To improve the treatment of women with ovarian cancer, we are investigating the modulation of a prominent DNA-damaging agent, temozolomide, by manipulating the DNA base excision repair (BER) pathway via BER inhibitor, methoxyamine, and overexpression of N -methylpurine DNA glycosylase (MPG). (aacrjournals.org)
  • Our data show that we can effectively modulate the activity of the chemotherapeutic agent, temozolomide, via modulator methoxyamine, in three ovarian cancer cell lines, SKOV-3x, Ovcar-3, and IGROV-1. (aacrjournals.org)
  • We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. (nih.gov)
  • Dialkylating agents can react with two different 7-N-guanine residues, and, if these are in different strands of DNA, the result is cross-linkage of the DNA strands, which prevents uncoiling of the DNA double helix. (wikipedia.org)
  • Monoalkylating agents can react only with one 7-N of guanine. (wikipedia.org)
  • Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. (pharmacycode.com)
  • Internally, alkylating agents can arise as byproducts of oxidative damage or from cellular methyl donors such as S-adenosylmethionine, which is a common cofactor in biochemical reactions. (axonmedchem.com)
  • Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles: structure-activity relationships for cytotoxicity and antitumor activity. (openrepository.com)
  • Patients will then receive consolidation therapy with three cycles of high-dose alkylating agents. (knowcancer.com)
  • The main indication for the nervous system is treatment of central nervous system lymphoma and as an immunosuppressive agent in immune-mediated diseases. (cynologist.com)
  • Four of the SPM patients received either alkylating agents and/or immunomodulators during MM treatment, but the other two patients received only bortezomib plus dexamethasone (BD) therapy before SPM was diagnosed. (thefreedictionary.com)
  • The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. (aacrjournals.org)
  • The role of alkylating agents in the treatment of grade II gliomas is under active investigation. (aacrjournals.org)
  • These publications spurred rapid advancement in the previously non-existent field of cancer chemotherapy, and a wealth of new alkylating agents with therapeutic effect were discovered over the following two decades. (wikipedia.org)
  • In addition, another novel class of biologically active duocarmycin SA analogs that contained the seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco-cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) DNA alkylating submit was also designed and synthesized. (eurekaselect.com)
  • Patients will receive induction therapy with antimetabolite agents (methotrexate, leucovorin and 5-fluorouracil) for four cycles. (knowcancer.com)
  • O 6 -methylguanine-DNA methyltransferase plays vital roles in preventing induction of mutations and cancer as well as cell death related to alkylating agents. (oup.com)
  • Evidence for the induction of a program to eliminate and replace alkylated proteins is presented. (pnas.org)
  • Simple glycosylases, including N -methylpurine DNA glycosylase (MPG), remove the alkylated DNA base, creating an apurinic/apyrimidinic (AP) site but not nicking the DNA backbone. (aacrjournals.org)