TY - JOUR. T1 - A phase I study of DMS612, a novel bifunctional alkylating agent. AU - Appleman, Leonard J.. AU - Balasubramaniam, Sanjeeve. AU - Parise, Robert A.. AU - Bryla, Christine. AU - Redon, Christophe E.. AU - Nakamura, Asako J.. AU - Bonner, William M.. AU - Wright, John J.. AU - Piekarz, Richard. AU - Kohler, David R.. AU - Jiang, Yixing. AU - Belani, Chandra P.. AU - Eiseman, Julie. AU - Chu, Edward. AU - Beumer, Jan H.. AU - Bates, Susan E.. PY - 2015/2/15. Y1 - 2015/2/15. N2 - Purpose: DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-minute intravenous infusion on days 1, 8, and 15 of an every-28-day schedule. Experimental Design: Patients with advanced solid malignancies ...
Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially ...
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)
Melflufen is designed for targeted delivery of alkylating moieties to tumor cells. In contrast to other alkylating agents that are hydrophilic, the lipophilicity of melflufen leads to rapid and extensive distribution into tissues and cells. Inside cells, melflufen may directly bind DNA or is readily metabolized by intracellular peptidases into the well-known antitumor compound melphalan, or by esterases into des-ethylmelflufen, which also has alkylating properties. Due to the high activity of peptidases and esterases in human tumor cells, the formation of melflufens metabolites is rapid in these cells with subsequent inflow of more melflufen. Since des-ethylmelflufen and melphalan are relatively hydrophilic, there is a possibility for intracellular trapping of these alkylators ...
The major alkylating agents are the nitrogen mustards and the nitrosoureas. These drugs covalently alkylate various cellular constituents. Most importantly for
Alkylating drug definition, any of various potentially cytotoxic, carcinogenic, and mutagenic substances: used therapeutically to destroy cells, especially proliferating cancer cells. See more.
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.
Fingerprint Dive into the research topics of Mechanisms of chemoresistance to alkylating agents in malignant glioma. Together they form a unique fingerprint. ...
Learn about the veterinary topic of Alkylating Agents. Find specific details on this topic and related topics from the Merck Vet Manual.
The relationships between DNA damage from UV radiation, alkylating drugs and the methylated xanthines (MX) have been studied in normal and malignant rodent and human cells. A comparison of the level of DNA excision repair (repair replication and unscheduled DNA synthesis) confirms that some forms of alkylating-agent damage (probably mono-filar DNA adducts) are less completely removed by both normal and malignant rodent cells than by their human counterparts, rendering rodent cells more susceptible to the toxic potential of unexcised lesions. The toxicity of alkylating agents can be increased by the presence of several MXs during the period of DNA replication which follows infliction of the damage. Human cells appear capable of excising more DNA damage, rendering them somewhat less susceptible to enhancement of cytotoxicity by MX. This resistance of human cells is only quantitative, however, since 2 human cancer cell lines (HeLa and HT-29) could be sensitized to a variety of alkylating agents by ...
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 ...
The preferred site of alkylation of diazine N-oxides by representative hard and soft alkylating agents was established conclusively using the 1H-15N HMBC NMR technique in combination with other NMR spectroscopic methods. Alkylation of pyrazine N-oxides (1 and 2) occurs preferentially on nitrogen regardless of the alkylating agent employed, while O-methylation of pyrimidine N-oxide (3) is favoured in its reaction with MeOTf. As these outcomes cannot be explained in the context of the hard/soft acid/base (HSAB) principle, we have instead turned to Marcus theory to rationalise these results. Marcus intrinsic barriers (∆G0‡) and ∆rG° values were calculated at the DLPNO-CCSD(T)/def2-TZVPPD/SMD//M06-2X-D3/6-311+G(d,p)/SMD level of theory for methylation reactions of 1 and 3 by MeI and MeOTf, and used to derive Gibbs energies of activation (∆G‡) for the processes of N- and O-methylation, respectively. These values, as well as those derived directly from the DFT calculations, closely reprod... ...
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 ...
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 ...
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 ...
Many chemotherapeutic agents have been associated with pulmonary toxicities. Busulfan was the first chemotherapeutic drug with evidence of drug-induced lung disease 6. Other alkylating agents, such as cyclophophamide and chlorambucil have been clearly associated with pulmonary toxicity as well 7. Dacarbazine, which is closely related to temozolomide has been associated with pulmonary adverse effects only when used in combination with fotemustine, a nitrosourea agent 8.. Temozolomide is an imidazotetrazine compound and a derivative of the alkylating agent dacarbazine (second-generation oral alkylating agent). Temozolomide has proven activity against recurrent glioma 9. In a recent randomised trial, concomitant and adjuvant temozolomide chemotherapy with radiation significantly improved progression free survival and overall survival in glioblastoma multiforme patients 2.. Various adverse reactions have been reported, but they are usually mild to moderate and in the majority of cases do not require ...
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 ...
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene (or their equivalents).[1] An alkyl group is a piece of a molecule with the general formula CnH2n+1, where n is the integer depicting the number of carbons linked together. For example, a methyl group (n = 1, CH3) is a fragment of a methane molecule (CH4). Alkylating agents use selective alkylation by adding the desired aliphatic carbon chain to the previously chosen starting molecule. This is one of many known chemical syntheses. Alkyl groups can also be removed in a process known as dealkylation. Alkylating agents are often classified according to their nucleophilic or electrophilic character. In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. For upgrading of petroleum, alkylation produces a premium blending stock for gasoline.[2]. In medicine, alkylation of DNA is used in ...
DNA damaging alkylating agents are present abundantly in the environment and also produced endogenously.The majority of the DNA adducts caused by such alkylating agents would be in double-stranded DNA. However, single-strand- specific lesions canarise when DNA double helix is temporarily unwound during replication or recombination. The N1 position of purines and the N3 of pyrimidines, which are normally protected from alkylation by base pairing in duplex DNA, can be alkylated in single-stranded DNA. The Escherichia coliAlkB protein is an oxidative demethylase that repairs such alkylatedbases present in single stranded DNA. Although AlkB function was known in great detail, its regulation was poorly characterized. I hypothesized that some proteins might directly interact with AlkB to regulate its function.. ...
This trial is investigating the tolerability of irinotecan, temozolomide and bevacizumab in combination with existing high dose alkylator based chemotherapy for
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 ...
Anesthetic agent-induced liver damage information including symptoms, diagnosis, misdiagnosis, treatment, causes, patient stories, videos, forums, prevention, and prognosis.
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
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
Generic name Melphalan hydrochloride Pronunciation MEL-fa-lan HIGH-droe-KLOR-ide Brand name(s), other common name(s) EvomelaTM Drug type Alkylating agent How the drug is given
Alkeran tablets and injection contain the active ingredient melphalan, which is a type of chemotherapy medicine to treat cancer called an alkylating agent.
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 ...
Lomustine (INN), abbreviated as CCNU (original brand name (formerly available) is CeeNU, now marketed as Gleostine), is an alkylating nitrosourea compound used in chemotherapy. It is closely related to semustine and is in the same family as streptozotocin. It is a highly lipid-soluble drug,[2] thus it crosses the blood-brain barrier. This property makes it ideal for treating brain tumors, which is its primary use, although it is also used to treat Hodgkin lymphoma as a second-line option.[3] Lomustine has a long time to nadir (the time when white blood cells reach their lowest number). Unlike carmustine, lomustine is administered orally. It is a monofunctional alkylating agent, alkylates both DNA and RNA, has the ability to cross-link DNA.[4] As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.[5] Lomustine is cell-cycle nonspecific. It has also been used in veterinary practice as a treatment for mast cell tumors in ...
TY - JOUR. T1 - Unraveling innate immunity using large scale N-ethyl-N-nitrosourea mutagenesis. AU - Hoebe, Kasper. AU - Beutler, B.. PY - 2005/5. Y1 - 2005/5. N2 - With the mouse genome almost entirely sequenced and readily accessible to all who wish to examine it, the challenge across most biological disciplines now lies in the decipherment of gene and protein function rather than in the realm of gene identification per se. In the field of innate immunity, forward genetic methods have repeatedly been applied to identify key sensors, adapters, and effector molecules. However, most spontaneous mutations that affect innate immune function have been mapped and cloned, and the need for new monogenic phenotypes has been felt evermore keenly. N-Ethyl-N-nitrosourea (ENU) mutagenesis is an efficient tool for the creation of aberrant monogenic innate immune response phenotypes. In this review, we will discuss the potential of the forward genetic approach and ENU mutagenesis to identify new genes and new ...
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 ...
TY - JOUR. T1 - Prevention of N-methyl-N-nitrosourea-induced breast cancer by α-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP. AU - Parikh, Rahul R.. AU - Gildener-Leapman, Neil. AU - Narendran, Amithi. AU - Lin, Hung Yun. AU - Lemanski, Nicole. AU - Bennett, James A.. AU - Jacobson, Herbert I.. AU - Andersen, Thomas T.. PY - 2005/12/1. Y1 - 2005/12/1. N2 - Purpose: α-Fetoprotein (AFP) is a protein of pregnancy associated with a decrease in lifetime risk of breast cancer in parous women. A synthetic, cyclic nonapeptide has been developed that mimics the antioncogenic active site of AFP. To test the hypothesis that the AFP-derived peptide (AFPep) can prevent breast cancer, the N-methyl-N-nitrosourea-induced breast cancer model was used in rats. Experimental Design: AFPep was given daily by injection beginning 10 days after N-methyl-N-nitrosourea treatment and continued for 23 days (a time designed to mimic pregnancy) or for other times to assess efficacy as a ...
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.
Mechanism: Valchlor is a gel formulation of mechlorethamine, an alkylating agent which inhibits rapidly proliferating cells. Valchlor is specifically indicated for the topical treatment of Stage IA and IB mycosisfungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy. Valchlor is supplied as a gel for topical administration. The recommendation is to apply a thin film of Valchlor gel once daily to affected areas of the skin. Upon improvement, treatment with Valchlor can be restarted at a reduced frequency of once every 3 days. If reintroduction of treatment is tolerated for at least one week, the frequency of application can be increased to every other day for at least one week and then to once daily application if tolerated. Valchlor is a gel formulation of mechlorethamine, also known as nitrogen mustard, an alkylating agent which inhibits rapidly proliferating cells. ...
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 ...
When paternally transmitted, two independent ENU-induced mutations showed reduced whole body wet weight soon after birth. The mutations were mapped to Chromosome 9 (Chr 9) between the markers D9Mit208 and D9Mit215. Their map position and imprinted status suggested that they might alter RAS protein-specific guanine nucleotide releasing factor 1 expression. Both mutations introduced premature chain termination codons into the coding sequence of Rasgrf1, and no Ras-GRF1 protein was detected in the brain. The GENA53 line had a C to T transition at nucleotide 2137, and the line GENA37 had a T to A transversion at nucleotide 3552 of the cDNA sequence. Mutant mice had near normal body weight at birth, but their weight started to lag behind that of wild-type littermates during the first week, and they were about 15% lighter as adults.. ...
Mechlorethamine 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...
Medscape - Indication-specific dosing for Mustargen, mechlorethamine hcl (mechlorethamine), frequency-based adverse effects, comprehensive interactions, contraindications, pregnancy & lactation schedules, and cost information.
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, ...
Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells tre …
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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.... ...
Function: Corrects defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents ...
A catalyst composition that is the combination of or the reaction product of ingredients comprising (a) a nickel-containing compound, (b) an alkylating agent, (c) a fluorine-containing compound, and (d) a chlorine-containing compound.
Novel Heat shock 70 kDa protein 5 (HSPA5) inhibitor and ERCC1-XPF protein-protein interaction inhibitor, synergizing alkylating agents in cancer cells.; High Quality Biochemicals for Research Uses
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.
An antineoplastic agent with alkylating properties. It also acts as a mutagen by damaging DNA and is used experimentally for that effect. . ...