Camptothecin: An alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata. This compound selectively inhibits the nuclear enzyme DNA TOPOISOMERASES, TYPE I. Several semisynthetic analogs of camptothecin have demonstrated antitumor activity.Topoisomerase I Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASE I.DNA Topoisomerases, Type I: DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.Antineoplastic Agents, Phytogenic: Agents obtained from higher plants that have demonstrable cytostatic or antineoplastic activity.Topotecan: An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA TOPOISOMERASES, TYPE I.Topoisomerase Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASES.Camptotheca: A plant genus of the family NYSSACEAE (sometimes classified in the CORNACEAE family). It is a source of CAMPTOTHECIN.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.Teniposide: A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle.Topoisomerase II Inhibitors: Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II.Organosilicon Compounds: Organic compounds that contain silicon as an integral part of the molecule.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Rubiaceae: The Madder plant family of the order Rubiales, subclass Asteridae, class Magnoliopsida includes important medicinal plants that provide QUININE; IPECAC; and COFFEE. They have opposite leaves and interpetiolar stipules.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Aphidicolin: An antiviral antibiotic produced by Cephalosporium aphidicola and other fungi. It inhibits the growth of eukaryotic cells and certain animal viruses by selectively inhibiting the cellular replication of DNA polymerase II or the viral-induced DNA polymerases. The drug may be useful for controlling excessive cell proliferation in patients with cancer, psoriasis or other dermatitis with little or no adverse effect upon non-multiplying cells.Organic Chemistry Phenomena: The conformation, properties, reaction processes, and the properties of the reactions of carbon compounds.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Drug Screening Assays, Antitumor: Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.Etoposide: A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.KB Cells: This line KB is now known to be a subline of the ubiquitous KERATIN-forming tumor cell line HeLa. It was originally thought to be derived from an epidermal carcinoma of the mouth, but was subsequently found, based on isoenzyme analysis, HeLa marker chromosomes, and DNA fingerprinting, to have been established via contamination by HELA CELLS. The cells are positive for keratin by immunoperoxidase staining. KB cells have been reported to contain human papillomavirus18 (HPV-18) sequences.DNA Topoisomerases, Type II: DNA TOPOISOMERASES that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex.Cell Line, Tumor: A cell line derived from cultured tumor cells.DNA, Superhelical: Circular duplex DNA isolated from viruses, bacteria and mitochondria in supercoiled or supertwisted form. This superhelical DNA is endowed with free energy. During transcription, the magnitude of RNA initiation is proportional to the DNA superhelicity.Amsacrine: An aminoacridine derivative that intercalates into DNA and is used as an antineoplastic agent.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).Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.DNA Cleavage: A reaction that severs one of the covalent sugar-phosphate linkages between NUCLEOTIDES that compose the sugar phosphate backbone of DNA. It is catalyzed enzymatically, chemically or by radiation. Cleavage may be exonucleolytic - removing the end nucleotide, or endonucleolytic - splitting the strand in two.DNA Replication: The process by which a DNA molecule is duplicated.Iridoid Glucosides: A subclass of iridoid compounds that include a glucoside moiety, usually found at the C-1 position.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.Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.Leukemia L1210Drug Resistance, Neoplasm: Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.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.Cell Cycle: The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.Ellipticines: Pyrido-CARBAZOLES originally discovered in the bark of OCHROSIA ELLIPTICA. They inhibit DNA and RNA synthesis and have immunosuppressive properties.Secondary Metabolism: A physiochemical process which occurs in a wide range of organisms which unlike BASAL METABOLISM is not required for or essential to short-term survivability but to long-term general well-being of the organism.Lactones: Cyclic esters of hydroxy carboxylic acids, containing a 1-oxacycloalkan-2-one structure. Large cyclic lactones of over a dozen atoms are MACROLIDES.Leukemia P388: An experimental lymphocytic leukemia originally induced in DBA/2 mice by painting with methylcholanthrene.Chemistry, Organic: The study of the structure, preparation, properties, and reactions of carbon compounds. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)DNA, Neoplasm: DNA present in neoplastic tissue.Tumor Suppressor Protein p53: Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.Poly(ADP-ribose) Polymerases: Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE.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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Indenes: A family of fused-ring hydrocarbons isolated from coal tar that act as intermediates in various chemical reactions and are used in the production of coumarone-indene resins.Naphthoquinones: Naphthalene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups.S Phase: Phase of the CELL CYCLE following G1 and preceding G2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Iridoids: A type of MONOTERPENES, derived from geraniol. They have the general form of cyclopentanopyran, but in some cases, one of the rings is broken as in the case of secoiridoid. They are different from the similarly named iridals (TRITERPENES).Prodrugs: A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug.Alkaloids: Organic nitrogenous bases. Many alkaloids of medical importance occur in the animal and vegetable kingdoms, and some have been synthesized. (Grant & Hackh's Chemical Dictionary, 5th ed)Nucleic Acid Synthesis Inhibitors: Compounds that inhibit cell production of DNA or RNA.HeLa Cells: The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.Leishmania donovani: A parasitic hemoflagellate of the subgenus Leishmania leishmania that infects man and animals and causes visceral leishmaniasis (LEISHMANIASIS, VISCERAL). The sandfly genera Phlebotomus and Lutzomyia are the vectors.Acrylamides: Colorless, odorless crystals that are used extensively in research laboratories for the preparation of polyacrylamide gels for electrophoresis and in organic synthesis, and polymerization. Some of its polymers are used in sewage and wastewater treatment, permanent press fabrics, and as soil conditioning agents.HT29 Cells: Human colonic ADENOCARCINOMA cells that are able to express differentiation features characteristic of mature intestinal cells such as the GOBLET CELLS.Drug Synergism: The action of a drug in promoting or enhancing the effectiveness of another drug.DNA Fragmentation: Splitting the DNA into shorter pieces by endonucleolytic DNA CLEAVAGE at multiple sites. It includes the internucleosomal DNA fragmentation, which along with chromatin condensation, are considered to be the hallmarks of APOPTOSIS.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Catha: A plant genus of the family CELASTRACEAE. The leafy stems of khat are chewed by some individuals for stimulating effect. Members contain ((+)-norpseudoephedrine), cathionine, cathedulin, cathinine & cathidine.Drug Carriers: Forms to which substances are incorporated to improve the delivery and the effectiveness of drugs. Drug carriers are used in drug-delivery systems such as the controlled-release technology to prolong in vivo drug actions, decrease drug metabolism, and reduce drug toxicity. Carriers are also used in designs to increase the effectiveness of drug delivery to the target sites of pharmacological actions. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Diterpenes: Twenty-carbon compounds derived from MEVALONIC ACID or deoxyxylulose phosphate.HL-60 Cells: A promyelocytic cell line derived from a patient with ACUTE PROMYELOCYTIC LEUKEMIA. HL-60 cells lack specific markers for LYMPHOID CELLS but express surface receptors for FC FRAGMENTS and COMPLEMENT SYSTEM PROTEINS. They also exhibit phagocytic activity and responsiveness to chemotactic stimuli. (From Hay et al., American Type Culture Collection, 7th ed, pp127-8)DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.Colonic Neoplasms: Tumors or cancer of the COLON.Caspases: A family of intracellular CYSTEINE ENDOPEPTIDASES that play a role in regulating INFLAMMATION and APOPTOSIS. They specifically cleave peptides at a CYSTEINE amino acid that follows an ASPARTIC ACID residue. Caspases are activated by proteolytic cleavage of a precursor form to yield large and small subunits that form the enzyme. Since the cleavage site within precursors matches the specificity of caspases, sequential activation of precursors by activated caspases can occur.Dichlororibofuranosylbenzimidazole: An RNA polymerase II transcriptional inhibitor. This compound terminates transcription prematurely by selective inhibition of RNA synthesis. It is used in research to study underlying mechanisms of cellular regulation.Mitoxantrone: An anthracenedione-derived antineoplastic agent.Flavanones: A group of FLAVONOIDS characterized with a 4-ketone.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Inhibitory Concentration 50: The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.RecQ Helicases: A family of structurally-related DNA helicases that play an essential role in the maintenance of genome integrity. RecQ helicases were originally discovered in E COLI and are highly conserved across both prokaryotic and eukaryotic organisms. Genetic mutations that result in loss of RecQ helicase activity gives rise to disorders that are associated with CANCER predisposition and premature aging.Granulocyte Precursor Cells: The cells in the granulocytic series that give rise to mature granulocytes (NEUTROPHILS; EOSINOPHILS; and BASOPHILS). These precursor cells include myeloblasts, promyelocytes, myelocytes and metamyelocytes.Staurosporine: An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Kinetics: The rate dynamics in chemical or physical systems.Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.Mice, Nude: Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses.Caspase 3: A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 9. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

Novel selective inhibitors for human topoisomerase I, BM2419-1 and -2 derived from saintopin. (1/2758)

Compounds BM2419-1 and -2 were isolated from a culture broth of a fungus Paecilomyces sp. BM2419. It was shown that these novel compounds were artifacts derived from saintopin, a dual inhibitor of topoisomerase I and II by independent processes. In the human topoisomerase I inhibition assay using the recombinant Saccharomyces cerevisiae, BM2419-1 and -2 inhibited selectively the yeast growth dependent on human topoisomerase I induction with IC50 values of 0.3 ng/ml and 6.0 ng/ml, respectively.  (+info)

Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes. (2/2758)

Replication protein A (RPA) is a DNA single-strand binding protein essential for DNA replication, recombination and repair. In human cells treated with the topoisomerase inhibitors camptothecin or etoposide (VP-16), we find that RPA2, the middle-sized subunit of RPA, becomes rapidly phosphorylated. This response appears to be due to DNA-dependent protein kinase (DNA-PK) and to be independent of p53 or the ataxia telangiectasia mutated (ATM) protein. RPA2 phosphorylation in response to camptothecin required ongoing DNA replication. Camptothecin itself partially inhibited DNA synthesis, and this inhibition followed the same kinetics as DNA-PK activation and RPA2 phosphorylation. DNA-PK activation and RPA2 phosphorylation were prevented by the cell-cycle checkpoint abrogator 7-hydroxystaurosporine (UCN-01), which markedly potentiates camptothecin cytotoxicity. The DNA-PK catalytic subunit (DNA-PKcs) was found to bind RPA which was replaced by the Ku autoantigen upon camptothecin treatment. DNA-PKcs interacted directly with RPA1 in vitro. We propose that the encounter of a replication fork with a topoisomerase-DNA cleavage complex could lead to a juxtaposition of replication fork-associated RPA and DNA double-strand end-associated DNA-PK, leading to RPA2 phosphorylation which may signal the presence of DNA damage to an S-phase checkpoint mechanism. KEYWORDS: camptothecin/DNA damage/DNA-dependent protein kinase/RPA2 phosphorylation  (+info)

The topoisomerase-related function gene TRF4 affects cellular sensitivity to the antitumor agent camptothecin. (3/2758)

Camptothecin is an antitumor agent that kills cells by converting DNA topoisomerase I into a DNA-damaging poison. Although camptothecin derivatives are now being used to treat tumors in a variety of clinical protocols, the cellular factors that influence sensitivity to the drug are only beginning to be understood. We report here that two genes required for sister chromatid cohesion, TRF4 and MCD1/SCC1, are also required to repair camptothecin-mediated damage to DNA. The hypersensitivity to camptothecin in the trf4 mutant does not result from elevated expression of DNA topoisomerase I. We show that Trf4 is a nuclear protein whose expression is cell cycle-regulated at a post-transcriptional level. Suppression of camptothecin hypersensitivity in the trf4 mutant by gene overexpression resulted in the isolation of three genes: another member of the TRF4 gene family, TRF5, and two genes that may influence higher order chromosome structure, ZDS1 and ZDS2. We have isolated and sequenced two human TRF4 family members, hTRF4-1 and hTRF4-2. The hTRF4-1 gene maps to chromosome 5p15, a region of frequent copy number alteration in several tumor types. The evolutionary conservation of TRF4 suggests that it may also influence mammalian cell sensitivity to camptothecin.  (+info)

Fractionated administration of irinotecan and cisplatin for treatment of lung cancer: a phase I study. (4/2758)

A combination chemotherapy of irinotecan (CPT-11) and cisplatin (CDDP) has been reported to be active for lung cancer. In the previous trial, however, diarrhoea and leucopenia became the major obstacle for sufficient dose escalation of CPT-11 to improve the treatment outcome. We conducted a phase I study to investigate whether the fractionated administration of CDDP and CPT-11 at escalated dose was feasible and could improve the treatment outcome. Twenty-four previously untreated patients with unresectable non-small-cell lung cancer (NSCLC) or extensive disease of small-cell lung cancer (SCLC) were eligible. Both CDDP and CPT-11 were given on days 1 and 8, and repeated every 4 weeks. The dose of CDDP was fixed at 60 mg m(-2) and given by 1-h infusion before CPT-11 administration. The starting dose of CPT-11 was 40 mg m(-2), and the dose was escalated by an increase of 10 mg m(-2). The maximally tolerated dose of CPT-11 was determined as 60 mg m(-2) because grade 4 haematological or grade 3 or 4 non-haematological toxicities developed in six patients out of 11 patients evaluated. Diarrhoea became a dose-limiting toxicity. The objective response rates were 76% for NSCLC and 100% for SCLC. The recommended dose of CPT-11 and CDDP in a phase II study will be 50 mg m(-2) and 60 mg m(-2) respectively.  (+info)

Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model. (5/2758)

6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with CPT-11 or 5FU. MGI-114 was administered at doses of 3.5 and 7 mg/kg i.p. daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i.p. on days 1, 12, and 19. In the single agent studies, MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights compared with vehicle-treated controls (P<0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P< or =0.001). Also, administration of the low-dose combination (MGI-114 at 35 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent. Moreover, the combination of MGI-114 and CPT-11 produced partial responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned.  (+info)

Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer. (6/2758)

PURPOSE: To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. RESULTS: The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION: Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.  (+info)

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer. (7/2758)

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.  (+info)

Cyclosporine inhibited calcium-mediated apoptosis of HL-60 cells. (8/2758)

AIM: To study the effects of cyclosporine (Cyc) on apoptosis of HL-60 cells. METHODS: Apoptotic cells induced by harringtonine (Har), camptothecin (Cam), or calcimycin (Cal), thapsigargin (Tha) were identified with DNA electrophoresis, morphology, and flow cytometry. Relative [Ca2+]i alteration of apoptotic HL-60 cells were determined with flow cytometry. RESULTS: Cal 1 mg.L-1 or Tha 0.5 mg.L-1 induced apoptosis of HL-60 cells. This effect was inhibited by nontoxic concentration of Cyc 1 mg.L-1. Cyc did not inhibit Har- or Cam-induced apoptosis of HL-60 cells. Both Cal and Tha increased intracellular calcium, whereas Har or Cam did not. CONCLUSION: Cyc inhibited apoptosis only induced by calcium increasement in HL-60 cells. The mechanism of apoptosis induced by Cal or Tha was different from that by Har or Cam.  (+info)

RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and ramucirumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab and ramucirumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet know whether giving cetuximab and irinotecan hydrochloride together is more effective with or without ramucirumab in treating colorectal cancer.. PURPOSE: This randomized phase II trial is studying the side effects and how well giving cetuximab and irinotecan hydrochloride with or without ramucirumab work in treating patients with advanced colorectal cancer with progressive disease after treatment with bevacizumab-containing chemotherapy. ...
RATIONALE: Drugs used in chemotherapy, such as capecitabine and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy, cetuximab, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.. PURPOSE: This phase I/II trial is studying the side effects of giving capecitabine and irinotecan hydrochloride together with cetuximab and radiation therapy and to see how well it works in treating patients undergoing surgery for locally advanced rectal cancer. ...
Camptothecin analogues showing more potent anti-tumor activity than a naturally occurring alkaloid camptothecin, which also exhibit an immunosuppressive activity, in which the 1-ethyl of camptothecin is replaced by various members of substitutents such as alkyls (except ethyl), alkenyls, alkynyls, aralkyls or aryloylalkyls; being produced from readily accessible starting materials on totally synthetic method newly developed by the present inventor.
Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[(dimethylamino)-methyl]-10-hydroxy-CPT), 9-amino-CPT (9AC), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109) in combination with PD0332991, CDK4I, roscovitine and olomoucine. SCLC cell lines employed are chemoresistant NCI-H417 and DMS153 and the chemosensitive SCLC26A line established at our institution. The CPT analogs exhibiting highest cytotoxicity towards the three SCLC lines tested were SN38 and 9AC, followed by rubitecan, HOCPT, TPT and CPT109. NCI-H417 and DMS153 revealed an approximately 25-fold and 7-fold higher resistance compared to
Irinotecan Hydrochloride Trihydrate for Injection by Sandoz Canada Inc.: Irinotecan belongs to the group of cancer-fighting medications known as antineoplastics. It kills cancer cells by interfering with the genetic material DNA, which is necessary for their growth and reproduction. Irinotecan is usually used in combination with other medications to treat colon or rectal cancer.
TY - JOUR. T1 - Design, synthesis and potent cytotoxic activity of novel 7-(N-[(substituted-sulfonyl)piperazinyl]-methyl)-camptothecin derivatives. AU - Zhu,Gao Xiang. AU - Cheng,Pi Le. AU - Goto,Masuo. AU - Zhang,Na. AU - Morris-Natschke,Susan L.. AU - Hsieh,Kan Yen. AU - Yang,Guan Zhou. AU - Yang,Qian Ru. AU - Liu,Ying Qian. AU - Chen,Hai Le. AU - Zhang,Xiao Shuai. AU - Lee,Kuo Hsiung. PY - 2017. Y1 - 2017. N2 - In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC50 values in the low μM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds 12l (IC50, 1.2 nM) and 12k (IC50, 20.2 nM) displayed the ...
Find a comprehensive guide to possible side effects including common and rare side effects when taking Camptosar Injection (Irinotecan Hydrochloride) for healthcare professionals and consumers.
Background The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan. Methods Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine- containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m 2 (or 300 mg/m 2 if age | 70 or performance status (PS) = 2) or 3-weekly irinotecan at 140 mg/m 2 (120 mg/m 2 if age | 70 or PS = 2) with ciclosporin 3 mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end
In the intent-to-treat analysis of the pooled data across all three studies, 193 of the 304 patients began therapy at the recommended starting dose of 125 mg/m2. Among these 193 patients, 2 complete and 27 partial responses were observed, for an overall response rate of 15.0% (95% Confidence Interval [CI], 10.0% to 20.1%) at this starting dose. A considerably lower response rate was seen with a starting dose of 100 mg/m2. The majority of responses were observed within the first two cycles of therapy, but responses did occur in later cycles of treatment (one response was observed after the eighth cycle). The median response duration for patients beginning therapy at 125 mg/m2 was 5.8 months (range, 2.6 to 15.1 months). Of the 304 patients treated in the three studies, response rates to Irinotecan were similar in males and females and among patients older and younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum and in patients with single and ...
Camptothecin analogues have become mainstays of chemotherapy for numerous malignancies (11). The mechanisms of action and resistance to camptothecins have extensively been investigated (12-14). The parent camptothecin molecule has several disadvantages: it is highly insoluble, and it is in the inactive carboxylate form at physiologic pH and, additionally, the inactive carboxylate form binds preferentially to human serum albumin, further shifting the equilibrium to this form (15, 16).. Clinical trials with the parent camptothecin (NSC 10880) in solid tumors, melanoma, and gastrointestinal malignancies (6, 7, 17, 18) were conducted by the National Cancer Institute more than 30 years ago. This compound was handicapped by dose limiting hemorrhagic cystitis (occurring in 5 of 15 patients) and severe bone marrow suppression (7, 18). Further investigation showed that a large fraction of camptothecin was excreted in urine where an acidic environment favors closing of the lactone and a reactivation of ...
The next step was: "The efficacy 5-FU/LV in combination with irinotecan or oxaliplatin in patients with metastatic CRC has been well documented in various phase II trials. To determine the most effective sequence of therapy, researchers randomized patients receive either a 2-hour infusion of leucovorin (200 mg/m2 or 400 mg/m2) on day 1 and irinotecan (180 mg/m2) followed by bolus 5-FU (400 mg/m2) and a 46-hour infusion of 5-FU (2400-3000 mg/m2) every 2 weeks (FOLFIRI) or the same regimen with oxaliplatin (100 mg/m2) replacing irinotecan on day 1 (FOLFOX6). Patients received the assigned therapeutic regimen until progression or unacceptable toxicity, at which time they crossed over and received the alternate regimen. Patients in the FOLFIRI group were crossed over to receive FOLFOX6 and those in the FOLFOX6 group were crossed over to the FOLFIRI arm. Of 109 patients randomized to FOLFIRI treatment, 81 (74%) were switched to FOLFOX6. Of 111 patients randomized to FOLFOX6, 69 (62%) switched to ...
Background: Poly (ADP-ribose) polymerase (PARP) is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitormediated DNA damage. This Phase I study determined the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) and pharmacodynamics (PD) of veliparib, an orally-bioavailable PARP 1/2 inhibitor, in combination with irinotecan. Methods: Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily (BID) oral dosing of veliparib (10-50 mg) occurred days 3- 14 (Cycle 1) and days -1-14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear gamma-H2AX and pNBS1). Results: Thirty-five patients were treated. DLTs included fatigue, ...
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The plant alkaloid camptothecin (CPT) has demonstrated the ability to inhibit replication of the equine anemia virus (E1AV) and the human immunodeficiency virus (HIV) in infected cells in culture....
The present study describes camptothecin resistance and the potential for drug glucuronidation in two cell lines overexpressing the ABC half-transporter, MXR. These sublines, S1-M1-80 and MCF-7 AdVp3000, show high levels of cross-resistance toward mitoxantrone, epirubicin, the CPT-11 metabolite SN-38, topotecan, and several other camptothecins (32) . This cross-resistance is associated with reduced drug accumulation and increased drug efflux. Using TLC, we investigated the ability of the sensitive and resistant cell lines to glucuronidate different compounds. Lysates from both S1-M1-80 resistant cells and S1 parental cells were able to glucuronidate 4-MU and epirubicin with no evidence of increased capacity in the resistant cells. In contrast, enzymatic assays indicated an up-regulation of glucuronidating capacity in the resistant breast cancer cells, and quantitative PCR demonstrated an increase in UGT1A mRNA. These results are consistent with a role for MXR in resistance to the camptothecins ...
... - Browse fuzing.com to find 7-Ethyl-10-HydroxyCamptothecin (SN-38) sellers, suppliers, wholesalers, companies, manufacturers, exporters, factories.
A crystalline form of 5(S)-(2-hydroxyethoxy)-20(S)-camptothecin diastereoisomer of 5(RS)-(2-hydroxyethoxy)-20(S)-camptothecin is described that is characterized by having an X-ray powder diffraction pattern comprising one or more peak intensities expressed in degrees 2.theta. that are selected from the group consisting of 7.2.+-.0.1, 9.4.+-.0.1, 11.02.+-.0.1, 12.00.+-.0.1, 14.54.+-.0.1, 15.2.+-.0.1, 18.92.+-.0.1, 21.86.+-.0.1, 22.74.+-.0.1 and 26.42.+-.0.1. Methods of making and using the compound are also described.
Guidchem offer qualified suppliers for 7-Ethyl-10-hydroxycamptothecin (CAS NO.86639-52-3) ,Find latest products of 7-Ethyl-10-hydroxycamptothecin manufacturers, suppliers, exporters and producers on guidechem.com.
Irinotecan liposomal is a cancer medicine that interferes with the growth and spread of cancer cells in the body. Irinotecan liposomal is used to treat pancreatic cancer that has spread to other parts of the body. Irinotecan liposomal is usually given in combination with other cancer medicines. Irinotecan liposomal may...
Differential involvement of the Mre11/Rad50/NBS (M/R/N) complex, BRCA1 and MLH1 in NF-kappaB activation by camptothecin and X- ...
Research Agreement for Camptothecin - Clayton Foundation for Research, Research Development Foundation and SuperGen Inc. and Other Business Contracts, Forms and Agreeements. Competitive Intelligence for Investors.
Drugs used in chemotherapy us different ways to stop tumor cells from dividing so they stop growing or die. Irinotecan may be effective in treating pat
Irinotecan is a chemotherapy drug that is given as a treatment for some types of cancer. It is most commonly used to treat bowel cancer...
Patient information for IRINOTECAN 20MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION Including dosage instructions and possible side effects.
We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro andin vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic ("phototheranostic").. ...
TY - JOUR. T1 - Determination of the glucuronide metabolites of the topoisomerase I inhibitors, 7-ethyl-10-hydroxy-camptothecin (SN-38) and NU-ICRF 505 by high performance liquid chromatography. AU - Cummings, J.. AU - Ethell, B T.. AU - Boyd, Gary. AU - Burchell, B.. AU - Smyth, J F.. AU - Jodrell, D I.. PY - 2002. Y1 - 2002. N2 - HPLC methods are presented for the determination of the topoisomerase I inhibitors 7-ethyl 10-hydroxycamptothecin (SN-38) and NU/ICRF 505, their chemical/enzymatic hydrolysis products and glucuronide metabolites in both aqueous media and biological specimens. Chromatographic conditions were optimised for baseline resolution of the water-soluble metabolites from their non-water soluble parent compounds while eetaining compatibility with both atmospheric pressure electrospray ionisation and electron impact ionisation mass spectrometric detection. Solid phase extraction sample preparation utilising a C2-bonded silica sorbent enabled simultaneous recovery of parent ...
Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)-camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)camptothecin (CMMDC). The greatest potentiation was observed with the alkylating camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the mechanism of action of camptothecin.
Cells maintain genomic stability by the coordination of DNA-damage repair and cell-cycle checkpoint control. In replicating cells, DNA damage usually activates intra-S-phase checkpoint controls, which are characterized by delayed S-phase progression and increased Rad53 phosphorylation. We show that in budding yeast, the intra-S-phase checkpoint controls, although functional, are not activated by the topoisomerase I inhibitor camptothecin (CPT). In a CPT-hypersensitive mutant strain that lacks the histone 2A (H2A) phosphatidylinositol-3-OH kinase (PI(3) K) motif at Ser 129 (h2a-s129a), the hypersensitivity was found to result from a failure to process full-length chromosomal DNA molecules during ongoing replication. H2A Ser 129 is not epistatic to the RAD24 and RAD9 checkpoint genes, suggesting a non-checkpoint role for the H2A PI(3) K site. These results suggest that H2A Ser 129 is an essential component for the efficient repair of DNA double-stranded breaks (DSBs) during replication in yeast, ...
BACKGROUND: The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Childrens Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma. METHODS: Patients with newly diagnosed metastatic hepatoblastoma or those with a serum alpha-fetoprotein (AFP) level /mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/m2 /day intravenously on days 1 and 8 and I at a dose of 50 mg/m2 /day intravenously on days 1 to 5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to Response Evaluation Criteria In Solid Tumors (RECIST) or a 90% ( | 1 log10 ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD)
A phase II study was conducted to assess the response rate and toxicity profile of the combination of irinotecan (CPT-11, Camptosar) and cisplatin (Platinol) administered weekly to patients with untreated advanced 1
In vivo neuroblastoma (NB) xenograft model, resistant to the DNA-topoisomerase I inhibitor irinotecan (CPT-11), has been established to study resistance mechanisms acquired in a therapeutic setting. Common mechanisms of resistance were not involved in this resistance. Thus, we compared the gene expression profiles of sensitive, resistant, and reverted tumors using cDNA expression arrays. Expression of selected transcripts was confirmed by quantitative real-time PCR. We found that pleiotrophin (PTN), a heparin-binding growth factor, was the only gene significantly affected: PTN gene expression was downregulated in all resistant tumors (8-14-fold) as compared to sensitive tumors, and was increased (2-4-fold) in all reverted tumors as compared to resistant tumors. PTN thus appeared to be a likely candidate gene associated with resistance to CPT-11 in this in vivo model. To investigate the direct implication of PTN in NB, we transfected two NB cell lines with RNA interferences in order to silence PTN. PTN
In southern China, where Camptotheca acuminata is native, people call these big-leafed trees "Happy Trees." Chinese herbalists have been prescribing medicine from the leaves for centuries to treat various ailments, including leukemia. In the 1950s, National Cancer Institute researchers in the U.S. isolated the alkaloid camptothecin from the leaves, and today, several drugs derived from camptothecin help treat ovarian and colon cancer.. (Podcast: The Plant Detective, 8/16/14). ...
MeSH-minor] Aged. Aged, 80 and over. Area Under Curve. Camptothecin / administration & dosage. Camptothecin / adverse effects. Camptothecin / analogs & derivatives. Camptothecin / pharmacokinetics. Carcinoma, Small Cell / drug therapy. Cholangiocarcinoma / drug therapy. Deoxycytidine / administration & dosage. Deoxycytidine / adverse effects. Deoxycytidine / analogs & derivatives. Deoxycytidine / pharmacokinetics. Diarrhea / chemically induced. Dose-Response Relationship, Drug. Drug Interactions. Female. Gastrointestinal Hemorrhage / chemically induced. Half-Life. Humans. Infusions, Intravenous. Lung Neoplasms / drug therapy. Male. Middle ...
The present invention provides generally a compound having the following general formula (1): wherein R1 and R2 are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, -OC(O)ORd, wherein Rd is an alkyl group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, -SRc, wherein, Rc is hydrogen, an acyl group, an alkyl group, or an aryl group, or R1 and R2 together form a group of the formula -O(CH2)nO- wherein n represents the integer 1 or 2; R3 is H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or R2 and R3 together form a group of the formula -O(CH2)nO- wherein n represents the integer 1 or 2; R4 is H, F, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, or a C1-3 alkoxyl group; R5 is a C1-10 alkyl group, or a propargyl
The objective of this study is to evaluate the safety and efficacy of Irinotecan Bead in the neoadjuvant treatment (i.e. the Irinotecan Bead is administ
Kessel, D, "Effects of camptothecin on rna synthesis in leukemia l1210 cells." (1971). Subject Strain Bibliography 1971. 891 ...
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Anwendungsgebiete Panitumumab Vectibix ist indiziert zur Behandlung von erwachsenen Patienten mit metastasiertem kolorektalem Karzinom (mCRC, metastatic colorectal cancer) mit RAS-Wildtyp in der Erstlinientherapie in Kombination mit FOLFOX oder FOLFIRI. in der Zweitlinientherapie in Kombination mit FOLFIRI bei Patienten, die in der Erstlinientherapie eine Fluoropyrimidin-haltige Chemotherapie erhalten haben (ausgenommen Irinotecan). als Monotherapie nach Versagen von Fluoropyrimidin-, Oxaliplatin- und Irinotecan-haltigen Chemotherapieregimen. Fachinformation Vectibix, Stand März 2015 Zulassungserweiterung März 2015
inproceedings{318597, author = {MONSAERT, ELS and De Vos, Martine and Peeters, Marc}, booktitle = {ACTA GASTRO-ENTEROLOGICA BELGICA}, issn = {0001-5644}, pages = {D59-D59}, title = {A retrospective analysis of the efficacy and toxicity of irinotecan and 5FU/FA in patients with advanced carcinoma of the stomach or oesophagogastric junction}, volume = {66}, year = {2003 ...
The U.S. Food and Drug Administration (FDA) has approved panitumumab (Vectibix) for use in combination with FOLFOX (fluorouracil, leucovorin, oxaliplatin) as first-line treatment in patients with wild-type KRAS (exon 2) metastatic colorectal cancer.. This approval converts the accelerated monotherapy approval granted in 2006 to a full approval. Panitumumab was previously approved by the FDA as a monotherapy for patients with EGFR-expressing metastatic colorectal cancer after disease progression and prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The agent is not indicated for the treatment of patients with KRAS-mutant metastatic colorectal cancer or for whom KRAS mutation status is unknown.. The FDA has also approved the therascreen KRAS test as a companion diagnostic to guide use of panitumumab in the treatment of metastatic colorectal cancer.. Phase III Studies. The approval is based on results from the phase III PRIME and -ASPECCT trials. The ...
Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA
Metastatic Colorectal Cancer - Pipeline Review, H1 2014SummaryGlobal Markets Directs, Metastatic Colorectal Cancer - Pipeline Review, H1 2014, provides an overview of the Metastatic Colorectal Cancers therapeutic pipeline.This report provides comprehensive information on the therapeutic development for Metastatic Colorectal Cancer, complete with comparative analysis at various stages, therapeutics
In the phase III RAISE trial reported in The Lancet Oncology, Josep Tabernero, MD, PhD, Head of Medical Oncology at Vall dHebron Institute of Oncology, Barcelona, and colleagues found that the addition of the antiangiogenic anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab (Cyramza) to second-line FOLFIRI (leucovorin, fluorouracil, irinotecan) improved overall survival in patients with metastatic colorectal cancer that had progressed on first-line bevacizumab, oxaliplatin, and fluoropyrimidine treatment.1. Study Details. In this double-blind trial, 1,072 patients from 24 countries were randomly assigned between December 2010 and August 2013 to receive ramucirumab at 8 mg/kg plus FOLFIRI (n = 536) or FOLFIRI plus placebo (n = 536) every 2 weeks until disease progression or unacceptable toxicity after progression on first-line therapy. Randomization was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. ...
This is an open-label, nonrandomized phase I trial to determine the safety and maximum tolerated dose of irinotecan with a fixed dose of UFT plus oral leucovorin in patients with advanced or metastatic colorectal cancer.
Effect of BSO on the Toxicity of the Camptothecins. To assess the contribution of GSH in the sensitivity to the camptothecins, cells were pretreated with BSO before the cytotoxicity assays. BSO is an inhibitor of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis (23). Treatment of MCF-7 and MDA-MB-231 cells for 24 h with 50 μm BSO led to a reduction in GSH levels of at least 75% in the cell lines tested (Table 1) without affecting cell growth. Pretreatment with BSO also resulted in lower IC50 values for each of the analogues tested in all of the cell lines (Table 1). GSH depletion had the greatest effect on CMMDC, the alkylating camptothecin analogue.. Effect of BSO on the Formation of topo I-DNA Complexes. To determine whether GSH depletion directly affected the stabilization of the camptothecin-topo I cleavage complex, the levels of camptothecin-induced DPCs were measured in control cells and in cells pretreated with BSO. These DPCs correspond to topo I cleavage ...
Mice and primary neuronal cultures. Hq, Apaf1-/-, and Bax-/- mice were maintained and genotyped as described previously (Fortin et al., 2001; Klein et al., 2002). Cortical neurons and cerebellar granule neurons (CGNs) were cultured from cortices of E15.5 mice and cerebellums of postnatal day 7 mice, respectively, as described previously (Fortin et al., 2001). Recombinant adenoviral vectors carrying human AIF or LacZ expression cassettes were prepared and used at 50 multiplicity of infection as described previously (Cregan et al., 2002).. Camptothecin treatment and cell viability assays. Neurons were treated with 10 μm camptothecin with or without 10 μm Boc-aspartyl (Ome)-fluoromethylketone (BAF) (Enzyme System Products, Livermore, CA) after 2 d in vitro (DIV). Cell survival was measured by the following: live/dead staining (Molecular Probes, Eugene, OR), Hoechst staining, MTT assay (Cell Titer kit; Promega, Madison, WI), terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end ...
This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canadas national genomics strategy with funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc. ...
Bevacizumab (B) and cetuximab (C) are both approved for use in the treatment of metastatic colorectal cancer (mCRC) in the second-line. We examined patient reported symptom burden during second-line treatment of mCRC. Adult mCRC patients treated in the second-line setting with a regimen that included B, C, or chemotherapy only (O) and who had completed ≥ 1 Patient Care Monitor (PCM) surveys as part of routine clinical care were drawn from the ACORN Data Warehouse. Primary endpoints were rash, dry skin, itching, nail changes, nausea, vomiting, fatigue, burning in hands/feet, and diarrhea. Linear mixed models examined change in PCM scores across B, C and O (B = reference). 182 patients were enrolled (B: n = 106, C: n = 38, O: n = 38). Patients were 51% female, 67% Caucasian, with mean age of 62.0 (SD = 12.6). Groups did not differ on demographic or clinical characteristics. The most common second-line regimens were FOLFIRI ± B or C (23.1%) and FOLFOX ± B or C (22.5%). Results showed baseline scores to
TY - JOUR. T1 - Therapeutic targeting of CPT-11 induced diarrhea. T2 - a case for prophylaxis.. AU - Swami, Umang. AU - Goel, Sanjay. AU - Mani, Sridhar. PY - 2013/6. Y1 - 2013/6. N2 - CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. ...
5-Fluorouracil (5-FU) is the most common chemotherapeutic agent used in the treatment of colorectal cancer, yet objective response rates are low. Recently, camptothecin (CPT) has emerged as an effective alternative therapy. Decisive means to determine treatment, based on the likelihood of response to each of these agents, could greatly enhance the management of this disease. Here, the ability of cDNA microarray-generated basal gene expression profiles to predict apoptotic response to 5-FU and CPT was determined in a panel of 30 colon carcinoma cell lines. Genes whose basal level of expression correlated significantly with 5-FU- and CPT-induced apoptosis were selected, and their predictive power was assessed using a "leave one out" jackknife cross-validation strategy. Selection of the 50 genes best correlated with 5-FU-induced apoptosis, but not 50 randomly selected genes, significantly predicted response to this agent. Importantly, this gene expression profiling approach predicted response more ...
A French team of investigators evaluated whether irinotecan and bevacizumab added to temozolomide-based chemoradiation would improve the prognosis of patients with unresectable glioblastoma. The study results show a trend towards improved progression-free survival and are presented by Dr B. Chauffert at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.. This phase II, randomized trial enrolled 120 patients, aged 18 to 70 years with de novo unresectable glioblastoma, Karnofsky performance status , 50 and recursive partitioning analysis (RPA) class 5. Patients were randomized, 60 patients per arm, to receive four cycles of neo-adjuvant bevacizumab plus irinotecan prior to radiotherapy with concurrent temozolomide and bevacizumab or to receive control treatment of concomitant temozolomide plus radiotherapy for 6 months.. Clinical factors were well balanced between arms and cross-over was allowed upon progression. An evaluation done at 16 months after the treatment ...
Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29.6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance,MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 2-[4-Diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 μM PAK-104P increased the ...
Clincally available camptothecin derivatives, though highly effective against a broad range tumors, are limited by their chemical instability, solubility, ABCG2-mediated efflux and reversibility of Top1-DNA complexes. Indenoisoquinolines were identified as topoisomerase I (Top1) inhibitors by the COMPARE analysis of the NCI drug screen database. Although structurally similar to camptothecin, idenoisoquinolines are chemically stable, able to overcome ABCG2 efflux while forming more persistent Top1-DNA complexes and maintaining potent antitumor activity. The potential for indenoisoquinoline derivatives as possible clinical agents is further aided by the synergistic effect observed between camptothecin and Chk1/2 inhibitors. Chk1/2 kinases regulate cell cycle, DNA damage response via ATM, ATR and DNA-PK, which are activated by genomic instability. Previous studies have shown Chk1/2 inhibitors, such as UCN-01, can potentiate camptothecin-mediated cytotoxicity in p53 mutant cells by eliminating the ...
Increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy or radiation therapy. ESAs are not indicated for this population. Patients receiving ESAs pre-operatively for reduction of allogeneic red blood cell transfusions: A higher incidence of deep venous thrombosis was documented in patients receiving Epoetin alfa who were not receiving prophylactic anticoagulation. Aranesp(R) is not approved for this indication.. Aranesp is contraindicated in patients with uncontrolled hypertension.. About Vectibix. Vectibix(TM) is indicated for the treatment of EGFr-expressing, metastatic colorectal cancer with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.. The effectiveness of Vectibix for the treatment of EGFr-expressing, metastatic colorectal cancer is based on progression-free survival. Currently no data are available that demonstrate an ...
In this case-based interview series, Tanios Bekaii-Saab, MD, FACP, discusses the treatment of a patient with metastatic colorectal cancer who progresses on upfront and second-line therapy.
The Report Metastatic Colorectal Cancer - Pipeline Review, H2 2015 provides information on pricing, market analysis, shares, forecast, and company profiles for key industry participants. - MarketResearchReports.biz
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BackgroundThis multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma.MethodsPatients received temozolomide 100-125 mg/m2/day (days 1-5) and irinotecan 10 mg/m2/day (days 1-5 and 8-12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful.ResultsSixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%-48.0%). Median duration of response was 27.0 weeks ...
Patients with mCRC and disease control after induction with standard 1st-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase 2 IMPACT trial. The trial was prematurely closed after randomization of 59 (43 MGN1703, 16 placebo) out of 129 planned patients due to slow recruitment. In the final analysis reported in 2013 a superior effect of MGN1703 compared to placebo was shown; the hazard ratio (HR) for the primary endpoint PFS on maintenance was 0.55 (p = 0.041) by local investigator assessment and 0.56 (p = 0.070) by independent radiological review. During the study 3 responses were observed in the MGN1703 arm, two of them appearing as late as 9 months after the start of treatment, showing a pattern similar to other immune active agents currently under investigation. At time of study closure 4 patients (3 responders to MGN1703 and one patient randomized with a CR after induction chemotherapy) were still free of progression and opted to continue MGN1703 ...
A facile synthetic method was developed for the novel acid-sensitive camptothecin norcantharidin acid ester derivatives 3in sealed tube. This method offers several advantages including high yield...
The aim of this project is the development of Tyrosyl DNA phosphodiesterase (Tdp1) inhibitors in order to enhance the activity of DNA topoisomerase I inhibitors ...
Camptothecin, an extract of the Chinese tree Camptotheca acuminata, is a potent inhibitor of topoisomerase I, a molecule required for DNA synthesis. Camptothecin has been shown to induce apoptosis in a dose-dependent manner in vitro. Camptothecin is routinely used as a general method for inducing apoptosis.. ...
Introduction. Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, affecting men and women equally.1 In 2017, there will be an estimated 135,430 new cases, with 50,260 deaths due to CRC.1 Approximately 20% of patients are diagnosed with advanced or metastatic disease on presentation, and 50% of all CRC patients will develop progressive disease and metastases over time. The prognosis for patients with advanced disease without treatment is poor, with a median overall survival of 6 months. However, advances in systemic therapy with combination chemotherapy using a fluoropyrimidine, irinotecan, and oxaliplatin have improved survival rates up to 20 months.2. The development of targeted agents aimed at blocking key pathways involved in CRC cell growth and invasion further improved survival through the latter part of the first decade of the 2000s. The VEGF pathway inhibitors-primarily bevacizumab, but more recently ziv-aflibercept and ramucirumab-increased ...
Wellona Pharma - Manufacturers, Exporters, Suppliers & Trader of API/Bulk drugs Irinotecan Powder at Cheap Price in India. Buy Irinotecan Online
Cancer, the irregular and uncontrolled cell division and abnormal growth of tissues is the cause of increasing number of deaths all over the world. The cause of death may be environmental factors, genetic mutations or prolonged infections or other abnormalities. The timely diagnosis and the treatment thereof is a major concern for the control. The various remedies and treatment factors have been in consideration since long. The various synthetic drugs like Abiraterone Acetate, Abitrexate (Methotrexate), Adcetris (Brentuximab Vedotin), Bavencio (Avelumab), BEACOPP, Becenum (Carmustine), Capecitabine, Cabazitaxel, Chlorambucil are in clinical use with good result in Phase-1 but still not effectively potent. The natural products obtained from medicinal plants, marine plants, blue-green algeae include vinblastine, vincristine, camptothecin derivatives, taxol, phyllotoxin derivatives, flabones, etoposides are found to have selective activity against cancer and related targets despite their toxicity and
Each of these structures contained unresolvable portions of the protein in the connector region (Pro635-Phe640). Moreover, the reconstituted enzyme has altered kinetics and is not sensitive to camptothecin in a plasmid relaxation assay (35). Hence, the structures reported here are the first structures of a fully active human TOP-I in covalent complex with DNA in the absence and presence of bound drug. (C) Comparison of the 22mer duplex oligonucleotides of the drug-bound (blue) and nondrug-bound (yellow). Arg364 makes a hydrogen bond contact with N3 of adenosine at position -1 of the uncleaved strand (-1A). Lys532 makes a hydrogen bond with the oxygen of thymidine at position -1 (-1T). Lys374 and the main chain nitrogens of 362 and 363 make hydrogen bond contacts Chapter 2 / Topoisomerase-DNA-Drug X-Ray Structure 27 with the nonbridging phosphodiester of the uncleaved strand (0P). Consistent with the observed drug-binding mode, mutations at position Arg364 (14) would be expected to destabilize ...
General : Outside of a well-designed clinical study, ZINOTECAN Injection should not be used in combination with the "Mayo Clinic" regimen of 5-FU/LV (administration for 4-5 consecutive days every 4 weeks) because of reports of increased toxicity, including toxic deaths. Irinotecan should be used as recommended (see In patients receiving either Irinotecan/5-FU/LV or 5-FU/LV in the clinical trials, higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance status of 0 or 1.. Diarrhea : Irinotecan can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Early diarrhea (occurring during or shortly after infusion of Irinotecan) is cholinergic in nature. It is usually transient and only infrequently is severe. It may be accompanied by symptoms of rhinitis, increased salivation, ...
To determine safety and effectiveness of temozolomide, irinotecan and bevacizumab. All three of these agents have shown effectiveness in pediatric brain tumors.
Purpose Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic...
... : Cell survival percentage obtained in MTT assay, expressed as survival percentage. (A) CAL27 cells cultured in 3D spherorids or in 2D monolayers when exposed to various concentrations of erlotinib, docetaxel, and bleomycin, for 72 h; and (B) DU145 cells in 3D spheroids or in 2D monolayer when exposed to various concentrations of rapamycin, docetaxel, and camptothecin for 72 h. Data is expressed as mean ± standard deviation based on three independent experiments with triplicate wells for each drug concentration ...
Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11), is a potent anticancer drug that is increasingly used in chemotherapy. A frequent limiting side effect involves gastrointestinal toxicity (diarrhea), which is thought to be related to the biliary excretion of CPT-11 and its metabolites. Accordingly, the biliary excretion mechanisms for both the lactone and carboxylate forms of CPT-11 and its metabolites, SN-38 and its glucuronide (SN38-Glu), were investigated using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR), with the latter being mutant rats with a genetic deficiency of the canalicular multispecific organic anion transporter. After i.v. administration of CPT-11, the biliary excretion clearance, defined as the biliary excretion rate normalized to the hepatic concentration, of both the lactone and carboxylate forms of SN38-Glu was much lower in EHBR. The biliary excretion clearance for the carboxylate form of both CPT-11 and SN-38 was ...
TY - JOUR. T1 - Phase II study of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer. AU - DeVore, Russell F.. AU - Johnson, David H.. AU - Crawford, Jeffrey. AU - Garst, Jennifer. AU - Dimery, Isaiah W.. AU - Eckardt, John. AU - Eckhardt, S. Gail. AU - Elfring, Gary L.. AU - Schaaf, Larry J.. AU - Hanover, Cristy K.. AU - Miller, Langdon L.. PY - 1999/9. Y1 - 1999/9. N2 - Purpose: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non-small- cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38. Patients and Methods: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m2) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m2) after CPT-11 administration on day 1. Results: Fifty-two patients were enrolled, including 33 men ...
FOLFIRI Combined with Bevacizumab as First-Line Treatment for Metastatic Colorectal Cancer Patients with Hyperbilirubinemia after UGT1A1 Genotyping. Yeh, Yung-Sung; Huang, Meng-Lin; Chang, Se-Fen; Chen, Chin-Fan; Hu, Huang-Ming; Wang, Jaw-Yuan // Medical Principles & Practice;Sep2014, Vol. 23 Issue 5, p478 Objective: To report a metastatic colorectal cancer patient with hyperbilirubinemia treated with a combination of bevacizumab and FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) using uridine diphosphate glucuronosyl transferase (UGT1A1) genotyping. Clinical Presentation and Intervention: A... ...
Metastatic Colorectal Cancer Pipeline Review, H2 2012 Global Markets Directs, \Metastatic Colorectal Cancer Pipeline Review, H2 2012\, provides an overview of the Metastatic Colorectal Cancer therapeutic pipeline. This report provides information on the therapeutic development for Metastatic Colorectal Cancer, complete with latest updates, and special features on late-stage and discontinued p
Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer; A JSMO - ESMO initiative. The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery.. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity.. These guidelines represent the ...
4. Biochemistry and molecular biology of alkaloid biosynthesis in plants. The enzymes involved in quinolizidine alkaloid formation in the Leguminosae plants were purified, and their enzymatic properties and distribution were investigated. We are currently studying to isolate cDNAs responsible for quinolizidine alkaloid biosynthesis from bitter and sweet varieties of Lupinus plants by differential screening between two varieties. The project for the production of anti-neoplastic camptothecin alkaloid in cell culture has been also conducted. We have established the hairy root culture that produced and excreted camptothecin, and isolated several genes involved in biosynthesis of camptothecin. We have isolated a set of genes which are specifically expressed only in the cells producing camptothecin and thus presumed to be involved in camptothecin formation by PCR-select subtraction. We are also investigating self-resistance mechanism of camptothecin-producing plants against toxicity of ...
CHICAGO -- Time off from chemotherapy early in oxaliplatin (Eloxatin)-based treatment for metastatic colorectal cancer may reduce toxicity but impair survival, researchers said.
Background. Metastatic colorectal cancer has a poor prognosis, and the majority of patients are left with palliative measures. The development seen using medical treatments are reviewed.. Material and methods. A systematic approach to the literature-based evidence of effects from palliative chemotherapy and targeted drugs was aimed at.. Results. The continuous improvements during the past 20-25 years have been documented in several large conclusive trials. At the end of the 1980s, the evidence that chemotherapy should be used at all was very limited, whereas presently most patients can be offered three lines of chemotherapy with or without a targeted drug based upon good scientific evidence. Median survival in trials has gradually improved from about 6 months to above 24 months in the most recent trials. Survival in the populations has, however, not improved to the same extent. Several important issues remain to be solved, such as the best sequence of treatments, what regimens to use in various ...
Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordicschedule as first-line therapy in advanced colorectal cancer. ...
Pro-Pharmaceuticals announced that the FDA has agreed to the design of its Phase 3 trial of Davanat co-administered with standard chemotherapy for second line treatment of patients with metastatic colorectal cancer.
Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma tumors in vivo, we took advantage of the fact that healthy lymphocytes can be programmed to phenocopy the biodistribution of the tumor cells. In a murine model of disseminated lymphoma, we expanded autologous polyclonal T cells ex vivo under conditions that retained homing receptors mirroring lymphoma cells, and functionalized these T cells to carry SN-38-loaded nanocapsules on their surfaces. Nanocapsule-functionalized T cells were resistant to SN-38 but mediated efficient killing of lymphoma cells in vitro. Upon adoptive transfer into tumor-bearing mice, these T cells served as active vectors to deliver the chemotherapeutic into tumor-bearing lymphoid organs. Cell-mediated delivery concentrated ...
The prognostic relevance of KRAS status, wild-type or mutant, is not significantly different in MCRC pts treated with BEV-containing chemotherapy. Reported median OS ranges from 29.9 to 38 months in KRAS wild-type and 19.9 to 21 months in KRAS mutant pts [4, 5, 8, 13]. The addition of anti-EGFR or anti-VEGF molecules to doublet chemotherapy predicts a favorable clinical outcome in KRAS wild-type pts [2, 5]. BEV addition to IFL compared to IFL significantly predicts prolonged PFS up to 9.3 months, but not increased OS and activity, in KRAS mutant pts [5, 14]. BEV addition to triplet chemotherapy, according to FIr-B/FOx or FOLFOXIRI/BEV schedules, resulted in high activity and efficacy in KRAS wild-type and mutant MCRC pts [8, 13]. In particular, KRAS mutant pts had an ORR of 67% and 71%, median PFS of 11 and 12.6 months, and median OS 20 months, respectively [8, 13]. We recently reported a significantly favorable prognosis (PFS and OS) in KRAS wild-type L-L compared to O/MM pts [11, 13]. ...
The goal of this clinical research study is to find the highest tolerable dose of lenalidomide combined with Camptosar (irinotecan) as well as to see if this drug combination can help control malignant gliomas. Researchers will also study if a special magnetic resonance imaging (MRI) technique (dynamic MRI scan) is useful in looking at the effect of treatment on the tumor. Another goal is to learn the effect of lenalidomide on tumor tissue in patients who need surgery for the disease.
LMP744 hydrochloride (MJ-III65 hydrochloride) is a DNA intercalator and Topoisomerase I (Top1) inhibitor with antitumor activity. - Mechanism of Action & Protocol.
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We systematically searched the Cochrane Database of Systematic Reviews, EMBASE and Medline for records published between January 2002 and May 2017, and cancer congress databases for records published between January 2014 and June 2017. Eligible studies evaluated the efficacy, safety and patient-reported outcomes of monotherapies or combination therapies at any dose and number of treatment cycles for use beyond the second line in patients with mCRC. Studies were assessed for design and quality, and a qualitative data synthesis was conducted to understand the impact of treatment on overall survival (OS) and other relevant cancer-related outcomes.. ...
Journal of Unexplored Medical Data is an online journal that encompasses reporting of pilot and unpublished clinical and biological medical studies.
The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumorss profile, publications, research topics, and co-authors
During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market. ...
Current drugs shortage notification for Irinotecan Injection including reason for shortage, estimated resupply dates, and alternative drug therapy if available.
Simplicity is enormously complex in the treatment of metastatic colorectal cancer. In terms of survival, life expectancy of patients with metastatic colorectal cancer improved substantially from 3 to 6 months in the 1980s when only 5-fluorouracil was available, to more than 20 months today with the availability of various new chemotherapeutic and targeted agents. The use of chemotherapeutic agents - including fluoropyrimidines, irinotecan, and oxaliplatin - has been refined through decades of clinical experience. Maximal exposure, irrespective of sequence, is simply the principle of treating patients through progression with chemotherapy. Targeted therapy has emerged in the past decade, and adds complexity to the treatment principle: survival benefit has been shown with both anti-vascular endothelial growth factor and anti-epidermal growth factor receptor antibodies in individual lines of treatment, but controversy exists as to the best sequence of application. Adding to this complexity, ...
TY - JOUR. T1 - Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil. T2 - N9841. AU - Kim, George P.. AU - Sargent, Daniel J.. AU - Mahoney, Michelle R.. AU - Rowland, Kendrith M.. AU - Philip, Philip A.. AU - Mitchell, Edith. AU - Mathews, Abraham P.. AU - Fitch, Tom R.. AU - Goldberg, Richard M.. AU - Alberts, Steven Robert. AU - Pitot, Henry Clement. PY - 2009/6/10. Y1 - 2009/6/10. N2 - Purpose: The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods: Patients who experienced treatment failure with one prior FU-based therapy and had not received ...
The chemotherapy agent irinotecan is highly effective against several types of cancer, but its use is limited due to severe intestinal toxicity. Green tea polyphenols (1 g per liter) used for seven days before and three days after treatment reduced the toxicity. "Green tea polyphenols supplied orally protected against oxidation in our experimental model and could be one approach to reducing the risk of chemotherapy induced side effects in a clinical setting.". The chemotherapeutic agent irinotecan (IT) is highly effective against several types of cancer, although its use is limited due to severe intestinal toxicity. The aim of this study was to evaluate inflammatory and oxidative stress-related processes contributing to small intestinal mucosa damage and to determine the extent to which green tea polyphenols could ameliorate the detrimental effects induced by IT. In Expt. 1, mice were challenged intraperitoneally with IT or saline on 2 consecutive days. For time kinetic measurements, the ...
ImClone Systems Incorporated (NASDAQ: IMCL), a global leader in the development and commercialization of novel antibodies to treat cancer, today announced that ERBITUX(R) (cetuximab) has received marketing authorization in Japan for use in treating patients with advanced or metastatic colorectal cancer (mCRC). Specifically, this approval allows for the use of ERBITUX to treat patients with epidermal growth factor receptor (EGFR)-positive, curatively unresectable (inoperable), advanced or recurrent CRC, and allows the use of ERBITUX plus irinotecan in second and further lines of mCRC. With this approval, ERBITUX is the first ever EGFR-targeted monoclonal antibody to be submitted for and receive marketing authorization in Japan. "This approval is a major milestone for ImClone, first and foremost because we and our ERBITUX partners Merck KGaA and Bristol-Myers Squibb are now able to provide a new treatment option to cancer patients in Japan, where colorectal cancer is one of the fastest growing and ...
We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG
To further explore whether BRCA1 enrichment and its associated exclusion of 53BP1 from the IRIF core correlates with inhibition of 53BP1-dependent repair at DSB sites during S phase, we analysed cells recovering from acute treatment with camptothecin (CPT), a topoisomerase I inhibitor that induces DSBs in S phase when replication forks encounter trapped Top1-DNA cleavage complexes (Pommier et al., 2003). In BRCA1-deficient cells, CPT-induced chromosomal aberrations are 53BP1 dependent; indicating BRCA1 normally counteracts 53BP1-mediated repair activities in this context (Bunting et al., 2010). Consistent with this notion, CPT-induced foci closely resembled S-phase IRIF by 3D-SIM, with BRCA1 and 53BP1 adopting equivalent focal positions (Fig. 4C). The repair of DSBs by HR in S phase also relies on CtIP-mediated DNA-end resection (Sartori et al., 2007). Consistent with a model in which the focus core corresponds to sites of HR in S-phase cells, 3D-SIM analysis of CtIP localisation in irradiated ...
"Discovery of Camptothecin and Taxol". National Historic Chemical Landmarks. American Chemical Society. Retrieved 2012-10-28. " ... of frozen foods conducted at the USDA-ARS Western Regional Research Center between 1948 and 1965 The discovery of Camptothecin ...
Camptothecin · Topotecan · Irinotecan · Rubitecan · Belotecan); 2. Podophyllum (Etoposide · Teniposide); 3a. Anthracyclines ( ...
The article Camptothecin lists other analogues of camptothecin and the article Topoisomerase inhibitor lists other compounds ... Camptothecin analogues irinotecan and topotecan, which inhibit TOP1, are among the most effective FDA-approved anticancer ... Irinotecan is an analogue of the cytotoxic natural alkaloid camptothecin, obtained from the Chinese tree Camptotheca acuminata ... "A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity". Proc. Natl. Acad. Sci. ...
"Dendrimer-Encapsulated Camptothecins". Cancer Research. 66 (24): 11913-21. doi:10.1158/0008-5472.CAN-06-2066. PMID 17178889. ...
... is a semi-synthetic derivative of camptothecin. Camptothecin is a natural product extracted from the bark of the tree ... "Topoisomerase I inhibitors: camptothecins and beyond". Nature Reviews Cancer. 6 (10): 789-802. doi:10.1038/nrc1977. Staker, B.L ... It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its ... 2002). "The mechanism of topoisomerase I poisoning by a camptothecin analog". PNAS. 99 (24): 15387-15392. doi:10.1073/pnas. ...
... is a semi-synthetic analog of camptothecin with antineoplastic activity. Liposomal lurtotecan was in clinical trials ... "Convergent catalytic asymmetric synthesis of camptothecin analog GI147211C". Tetrahedron. 53 (32): 10953. doi:10.1016/S0040- ...
It is made from the natural compound camptothecin. Its main use is in colon cancer, in particular, in combination with other ...
Alfonso LF, Srivenugopal KS, Arumugam TV, Abbruscato TJ, Weidanz JA, Bhat GJ (March 2009). "Aspirin inhibits camptothecin- ...
The direct nitration of camptothecin results in regioselectivity problems. One way that has been used to synthesize Rubitecan ...
"Antifungal Activity of Camptothecin, Trifolin, and Hyperoside Isolated fromCamptotheca acuminata". Journal of Agricultural and ...
... camptothecin". Biochemistry. 25 (6): 1216-21. doi:10.1021/bi00354a004. PMID 3008823. Vasudevachari, M; Antony, A (1982). " ...
Type 1 topoisomerase is inhibited by irinotecan, topotecan and camptothecin. The human topoisomerase type IB enzyme forms a ...
Li, S.; Zhang, Z.; Cain, A.; Wang, B.; Long, M.; Taylor, J. (2005). "Antifungal Activity of Camptothecin, Trifolin, and ...
Albihn A, Mo H, Yang Y, Henriksson M (2007). "Camptothecin-induced apoptosis is enhanced by Myc and involves PKCdelta signaling ...
... lowreyana S.Y.Li The bark and stems of C. acuminata contain the alkaloid camptothecin. Several chemical derivatives ... Li, S.; Zhang, Z.; Cain, A.; Wang, B.; Long, M.; Taylor, J. (2005). "Antifungal Activity of Camptothecin, Trifolin, and ... of camptothecin are under investigation for or used as drugs for cancer treatment, including irinotecan, topotecan, rubitecan. ...
... "p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells". Tumour Biology. 31 (6): 575-82. ...
Effect of Camptothecin on Collagen Synthesis in Fibroblasts From Patients With Keloid. Annals of Plastic Surgery July 2009 - ... Czuwara-Ladykowska J, Makiela B, Smith EA, Trojanowska M, Rudnicka L.: The inhibitory effects of camptothecin, a topoisomerase ... Makiela, B; Barusińska, A; Czuwara, J; Majewski, S; Jablonska, S; Rudnicka, L. (1995) "The effect of camptothecin, an apoptosis ... Czuwara-Ladykowska, J; Makiela, B; Smith, EA; Trojanowska, M; Rudnicka, L (2001). "The inhibitory effects of camptothecin, a ...
Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells. International ...
Fungi can synthesize podophyllotoxin and camptothecin, precursors to etoposide, teniposide, topotecan, and irinotecan. Lentinan ...
His group conjugated cyclodextrin to the anti-cancer compound camptothecin to improve the bio-availability and exhibit efficacy ... Schluep, T. (1 March 2006). "Preclinical Efficacy of the Camptothecin-Polymer Conjugate IT-101 in Multiple Cancer Models". ...
Several groups have encapsulated anti-cancer medications such as: Camptothecin, Methotrexate, and Doxorubicin. Results from ...
2010). Correlation of camptothecin-producing ability and phylogenetic relationship in the genus Ophiorrhiza. Planta Med. in pub ... 2004). Camptothecin production by in vitro cultures of Ophiorrhiza liukiuensis and O. kuroiwai. Plant Biotechnology 21:4 275. ... Species of the genus contain camptothecin, an alkaloid used to make chemotherapeutic agents. So many of Ophiorrhiza species are ... 2007). Organogenesis from leaf and internode explants of Ophiorrhiza prostrata, an anticancer drug (camptothecin) producing ...
... is a drug which is an analogue of camptothecin with antineoplastic activity. Abou-Alfa, GK; Letourneau, R; Harker, G; ...
A 1991 synthesis of the important anti-cancer agent camptothecin illustrates many of these features. The synthesis takes place ... camptothecin. J. Am. Chem. Soc. 1992, 114, 5863-5864. doi 10.1021/ja00040a060 Horváth, I. T.; Rábai, J., "Facile catalyst ...
Wall, ME; Wani, MC (1995). "Camptothecin and taxol: Discovery to clinic-thirteenth Bruce F. Cain Memorial Award Lecture". ...
... and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I". Cancer Res. 63 (21): ... There are several advantages of these novel non-camptothecin Top1 inhibitors as compared to the FDA-approved camptothecin ... Pommier Y (2004). "Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with ... Camptothecins are among the most effective anticancer agents recently introduced into clinical practice. In this regard, the ...
Eukaryotic Top1s are the cellular target of the plant-derived anticancer indole alkaloid camptothecin (CPT), which reversibly ... identifies genes associated with biosynthesis of camptothecin, an anti-carcinogenic molecule. *B L Manjunatha. , H R Singh. , + ... Structural insight of DNA topoisomerases I from camptothecin-producing plants revealed by molecular dynamics simulations.. *. ... Eukaryotic Top1s are the cellular target of the plant-derived anticancer indole alkaloid camptothecin (CPT), which reversibly ...
Protocol for Camptothecin-induced Apoptosis:. *Prepare a 1 mM stock solution of Camptothecin (Sigma Cat. No. C-9911) in DMSO. ... Camptothecin has been shown to induce apoptosis in a dose-dependent manner in vitro. Camptothecin is routinely used as a ... Induction of Apoptosis by Treatment with Camptothecin. Camptothecin, an extract of the Chinese tree Camptotheca acuminata, is a ... Add 4-6 µM (final concentration) Camptothecin to cell suspension (eg, 5 x 105 cells/ml in tissue culture medium). ...
In the 1950s, National Cancer Institute researchers in the U.S. isolated the alkaloid camptothecin from the leaves, and today, ...
... but not in response to camptothecin. Increased chemosensitivity to this drug may sensitize cancer cells to camptothecin. ... DNA damage which results in apoptosis camptothecin cytotoxicity may signal the Ku autoantigen RCD-8 which may signal the ... treatment involved in DNA damage-induced RPA2 induced apoptosis was augmented camptothecin-induced RPA2 phosphorylation. RPA ... activation undergoes hyperphosphorylation in response to cellular genotoxic insults predominantly mediated by camptothecin ...
... in which the 1-ethyl of camptothecin is replaced by various members of substitutents such as alkyls (except ethyl), alkenyls, ... Camptothecin analogues showing more potent anti-tumor activity than a naturally occurring alkaloid camptothecin, which also ... Camptothecin derivatives. US4604463 *. Jul 5, 1984. Aug 5, 1986. Kabushiki Kaisha Yakult Honsha. Camptothecin derivatives and ... Camptothecin analogues showing more potent anti-tumor activity than a naturally occurring alkaloid camptothecin, which also ...
The plant alkaloid camptothecin (CPT) has demonstrated the ability to inhibit replication of the equine anemia virus (E1AV) and ... X. Isolation of camptothecin and 9-methoxy-camptothecin fromErvatamia heyneana. J Nat Prod 42:275-277;1977.Google Scholar ... Biochemistry of camptothecin. In Potmesil M, Pinedo H, eds. Camptothecins: New Anticancer Agents. Boca Raton, CRC Press, 9-19; ... camptothecin. In: Potmesil M, Pinedo H, eds. Camptothecins: New Anticancer Agents. Boca Raton, CRC Press; 59-65;1995.Google ...
"Curran Synthesis of Camptothecin". "Comins Synthesis of Camptothecin". "Rapaport Synthesis of Camptothecin". Takimoto CH, Calvo ... Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening ... A. J. Lu; Z. S. Zhang; M. Y. Zheng; H. J. Zou; X. M. Luo; H. L. Jiang (2007). "3D-QSAR study of 20 (S)-camptothecin analogs". ... D. J. Adams; M. L. Wahl; J. L. Flowers; B. Sen; M. Colvin; M. W. Dewhirst; G. Manikumar; M. C. Wani (2005). "Camptothecin ...
MXR confers cross-resistance to a variety of camptothecins. A, cross-resistance profiles for the camptothecins tested; relative ... To further characterize the resistance to the camptothecins, cytotoxicity assays were performed using a series of camptothecins ... The cell lines demonstrated much less resistance to camptothecin and to several camptothecin analogues. Reduced accumulation ... Camptothecin Resistance. Mariafiorella Brangi, Thomas Litman, Marco Ciotti, Kenryu Nishiyama, Glenda Kohlhagen, Chris Takimoto ...
The T/C camptothecin is designated with "+++." An increment or decrement of 10% as compared to the camptothecin T/C on day 14 ... Highly lipophilic Camptothecin derivatives. US6150343 *. Aug 29, 1997. Nov 21, 2000. University Of Pittsburgh. Camptothecin ... Thus, 7-trimethylsilyl-11-flouro camptothecin is more efficacious than camptothecin in its antitumor effects in vivo. ... 7-trimethylsilyl camptothecin showed better activity than camptothecin against sarcoma 180 in B6D2F1 mice at several equivalent ...
No inhibitory effect of camptothecin on RNA transcription was observed with human topoisomerase I isolated from a camptothecin- ... Camptothecin-stabilized topoisomerase I-DNA adducts cause premature termination of transcription.. Bendixen C1, Thomsen B, ... The antitumor agent camptothecin stabilizes type I topoisomerase-DNA complexes. One of the primary cellular responses to ... Taken together, the data suggest that part of the cytotoxicity of camptothecin is mediated through adduct formation on ...
... Lars Wagner ... Over the past decade, camptothecin agents such as topotecan and irinotecan have demonstrated activity against Ewing sarcoma, ... Previous studies have shown camptothecin-based combinations to be tolerable outpatient strategies that are attractive for ... and activity of commonly used camptothecin-based regimens. Also discussed are strategies for incorporating these regimens into ...
Lars Wagner, "Camptothecin-Based Regimens for Treatment of Ewing Sarcoma: sPast Studies and Future Directions," Sarcoma, vol. ... Camptothecin-Based Regimens for Treatment of Ewing Sarcoma: sPast Studies and Future Directions. Lars Wagner ...
The camptothecin analog CPT-11 has recently been approved for the treatment of 5-fluorouracil (5-FU)-resistant colorectal ... The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85 (4): 271-291.PubMedCrossRefGoogle ... Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985; 260 (27): 14873-14878. ... The camptothecins (CPT) are potent radiation sensitizers and are in their infancy in clinical studies. The combination of CPT ...
IC50 Value: 50 nM(in MDA-MB-231 cell line) Target: topoisomerase Camptothecin (CPT) has recently been undergoing phase I ... In 3D fluorescence spectra, Camptothecin presented 3 fluorescence peaks wi... ... Camptothecin (CPT) is a potent DNA enzyme topoisomerase I (topo I) inhibitor with an IC50 and IC70 of 50 nM and 0.225 μM for ... Camptothecin (CPT) The report - posted in Immunology Products: Biological Activity of Campathecin ...
Drugs used in chemotherapy such as polyglutamate camptothecin may be able to deliver the drug directly to tumor cells while ... Patients receive polyglutamate camptothecin (CT-2106) IV over 10 minutes on day 1. Courses. repeat every 21 days in the absence ... Determine the maximum tolerated dose of polyglutamate camptothecin (CT-2106) in. patients with advanced malignancies.. - ...
Several camptothecin and non-camptothecin derivatives are being developed to further increase anti-tumour activity and reduce ... Characterization of DNA Topoisomerase-1 in Spodoptera exigua for Toxicity Evaluation of Camptothecin and Hydoxy-Camptothecin. ... Camptothecin: Roles of the D and E Rings in Binding to the Topoisomerase I-DNA Covalent Binary Complex. Hecht, Sidney M. // ... 3D-QSAR study of 20 ( S)-camptothecin analogs. Ai-jun Lu; Zhen-shan Zhang; Ming-yue Zheng; Han-jun Zou; Xiao-min Luo; Hua-liang ...
The present invention relates to water soluble, camptothecin derivatives of formula (I), ##STR1## wherein: 1) R 1 and R 2 ... 7-Substituted camptothecin derivatives US4473692A (en) * 1981-09-04. 1984-09-25. Kabushiki Kaisha Yakult Honsha. Camptothecin ... 7-Substituted camptothecin derivatives US4473692A (en) * 1981-09-04. 1984-09-25. Kabushiki Kaisha Yakult Honsha. Camptothecin ... Synthesis of camptothecin and analogs thereof US5122526A (en) 1992-06-16. Camptothecin and analogs thereof and pharmaceutical ...
Water-soluble derivatives of camptothecin have the formulae: ##STR1## wherein R is selected from the group consisting of R=CO ... Production of camptothecin and camptothecin-like compounds US3903276A (en) * 1972-03-20. 1975-09-02. American Home Prod. N- ... Production of camptothecin and camptothecin-like compounds US3903276A (en) * 1972-03-20. 1975-09-02. American Home Prod. N- ... Nitrogen-based homo-camptothecin derivatives US20040034050A1 (en) * 2002-06-03. 2004-02-19. Yang Li-Xi. Homo-camptothecin ...
Right-hand panels: upon release from the thymdine block into Camptothecin containing medium (CPT; 10 µm), again Cdt1 is ... Mutations in Cullin 4B result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA ... We show that these patient-derived cells exhibit sensitivity to camptothecin (CPT), impaired CPT-induced topoisomerase I (Topo ... Mutations in Cullin 4B result in a human syndrome associated with increased camptothecin-induced topoisomerase I-dependent DNA ...
We nasally administered the anti-tumor drug camptothecin (CPT) in solution and in methoxy poly(ethylene glycol) (MPEG)/poly(e- ... Intranasal Delivery of Camptothecin-Loaded Tat-Modified Nanomicells for Treatment of Intracranial Brain Tumors. Hiroyuki Taki † ... We nasally administered the anti-tumor drug camptothecin (CPT) in solution and in methoxy poly(ethylene glycol) (MPEG)/poly(e- ... "Intranasal Delivery of Camptothecin-Loaded Tat-Modified Nanomicells for Treatment of Intracranial Brain Tumors." ...
Malignant Neoplasm of Stomach Recruiting Phase Trials for Camptothecin (DB04690). Back to Malignant Neoplasm of Stomach ...
Metabolism and Pharmacokinetics of the Camptothecin Analogue CPT-11 in the Mouse. Norimasa Kaneda, Hiroshi Nagata, Tomio Furuta ... These values were markedly higher than those of camptothecin (CPT, 0.98 and 3.7 ng/ml) or 7-ethyl-10-hydroxycamptothecin (SN-38 ... A new water-soluble derivative of camptothecin, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), did ... Metabolism and Pharmacokinetics of the Camptothecin Analogue CPT-11 in the Mouse ...
... camptothecin-induced cellular DNA damage, and cellular camptothecin sensitivity. Our results show that the PS506 epitope is an ... and increased sensitivity to camptothecin. In contrast, PS506 was not detected in normal cells or cancer cell lines with lower ... Topoisomerase I is the target for a potent class of chemotherapeutic drugs derived from the plant alkaloid camptothecin that ...
Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 ... inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[( ... Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. ... Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of ...
... camptothecin diastereoisomer of 5(RS)-(2-hydroxyethoxy)-20(S)-camptothecin is described that is characterized by having an X- ... camptothecin.. 5(RS)-(2-hydroxyethoxy)-20(S)-camptothecin is a 5-alkoxy substituted 20(S)-camptothecin analog having a penta ... camptothecin is described chemically as 5(R)-(2-hydroxyethoxy)-20(S)-camptothecin. 5(S)-(2-hydroxyethoxy)-20(S)-camptothecin ... No.5,734,056 describes camptothecin analogues. Topotecan, an analogue of camptothecin, is discussed in U.S. Pat. No. 5,004,758 ...
  • This paper highlights important issues related to drug dosing, schedule of administration, pharmacokinetics, toxicity, and activity of commonly used camptothecin-based regimens. (hindawi.com)
  • Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. (aacrjournals.org)
  • Conclusions: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen. (elsevier.com)
  • We nasally administered the anti-tumor drug camptothecin (CPT) in solution and in methoxy poly(ethylene glycol) (MPEG)/poly(e-caprolactone) (PCL) amphiphilic block copolymers (MPEG-PCL) and cell penetrating peptide, Tat analog-modified MPEG-PCL (MPEG-PCL-Tat) MPEG-PCL-Tat to rats bearing intracranial glioma tumors and quantified the cytotoxicity against glioma cells, and the therapeutic effects. (mdpi.com)
  • The novel supramolecular complexes were prepared with a water-insoluble anticancer drug camptothecin (CPT) loading onto functionalized multiwalled carbon nanotubes via π-stacking, in order to improve their solubility and antitumor activity. (ingentaconnect.com)
  • 1. Hsiang Y-H, Hertzberg R, Hecht S, and Liu L. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. Journal of Biological Chemistry. (jddtonline.info)
  • In the current study, we show that treatment of mammalian cells or yeast cells expressing human DNA TOP1 with camptothecin (CPT) induces covalent modification of the TOP1 by SUMO-1/Smt3p, a ubiquitin-like protein. (pnas.org)
  • In this study, we designed and synthesized the conjugates TAT-CPT and TAT-2CPT by attaching camptothecin (CPT) to the N-terminus of the cell penetrating peptide TAT. (ovid.com)
  • 10. Kang C, Sun Y, Wang M, and Cheng X. Nanosized camptothecin conjugates for single and combined drug delivery. (jddtonline.info)
  • All the formulations were designed firstly to increase the solubility of camptothecin in aqueous environment and secondly to reduce the toxicity problems related to the administration of this drug. (core.ac.uk)
  • Taken together, the data suggest that part of the cytotoxicity of camptothecin is mediated through adduct formation on transcribed DNA, resulting in interference with transcriptional elongation. (nih.gov)
  • Depletion of TOP1 using siRNA was then able to rescue EV71 infection from camptothecin inhibition. (ovid.com)
  • Our findings reveal camptothecin to be a limited spectrum antiviral against enteroviruses that functions in a TOP1-dependent but cytotoxicity-independent manner. (ovid.com)
  • In this study, we have shown that camptothecin (CPT), a TOP1-specific poison, can induce rapid and extensive conjugation of SUMO-1/Smt3p to human DNA TOP1. (pnas.org)
  • In contrast, assays of growth in the presence of the Top1 poison camptothecin (CPT) indicate that the structure-specific nucleases dependent on RAD1 and MUS81 can contribute independently of TDP1 to repair, presumably by cutting off a segment of DNA along with the topoisomerase. (pnas.org)
  • Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bondcontact for the 10-amino to the side chain of Glu-356 ofCore Subdomain I of top1 in addition to known contactsfound for other camptothecins. (ulster.ac.uk)
  • We studied resistance to the camptothecins in two sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells and MCF-7 AdVp3000 isolated from parental MCF-7 breast cancer cells. (aacrjournals.org)
  • The lack of selection for higher levels of UGT capacity in the colon cells suggests that high levels of expression of MXR alone are sufficient to confer resistance to the camptothecins. (aacrjournals.org)
  • Resistance to the camptothecins has been explored in model systems, and several putative mechanisms have been identified. (aacrjournals.org)
  • Ubiquitin, SUMO-1, and UCRP in camptothecin sensitivity and resistance. (springer.com)
  • Whereas camptothecins are active against a wide range of solid tumors, resistance can be a significant hindrance to therapy. (aacrjournals.org)
  • Reported mechanisms of camptothecin resistance include down-regulation or mutation of topo I, reduced drug uptake, and defects in apoptotic response ( 3 ). (aacrjournals.org)
  • 1999 Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. (springer.com)
  • 3: Beretta GL, Gatti L, Perego P, Zaffaroni N. Camptothecin resistance in cancer: insights into the molecular mechanisms of a DNA-damaging drug. (medkoo.com)
  • extra chapters describe what's recognized concerning the biochemistry, the pharmacology, and the chemistry of the camptothecins, together with the mechanism of topoisomerase and the way camptothecins poison this enzyme, using animal types in defining the anticancer capability of camptothecins, and the query of camptothecin resistance. (seamolec.org)
  • Consistent with the observed drug-binding mode, mutations at position Arg364 (14) would be expected to destabilize the topotecan binding site and are known to result in camptothecin resistance. (seamolec.org)
  • 1997 Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis. (seamolec.org)
  • 2007). Especially, reflection of BCRP in set up cancer tumor cell lines and growth biopsy examples provides been linked with level of resistance to camptothecins (Kawabata et al. (biodigestor.net)
  • A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment but not after camptothecin treatment. (aacrjournals.org)
  • The antitumor agent camptothecin stabilizes type I topoisomerase-DNA complexes. (nih.gov)
  • Results obtained by using an in vitro transcription system supplemented with eukaryotic topoisomerase I show that this inhibition can be attributed to physical blockage of the RNA polymerase by camptothecin-stabilized topoisomerase I-DNA complexes on the DNA template. (nih.gov)
  • CMMDC is an interesting hybrid that combines the ability to bind and stabilize the topo I-DNA complexes typical of the camptothecins with a DNA-alkylating capacity characteristic of the nitrogen mustards or nitrosoureas ( 5 , 6 ). (aacrjournals.org)
  • The copolymer-coated multiwalled carbon nanotubes can effectively form non-covalent supramolecular complexes with camptothecin. (ingentaconnect.com)
  • Determine the maximum tolerated dose of polyglutamate camptothecin (CT-2106) in patients with advanced malignancies. (knowcancer.com)
  • Camptothecin was originally isolated from the stem wood of the Camptotheca acuminata tree and was shown to exhibit antileukemic/antitumour activity, and reversibly inhibit Mitochondrial Topo I (nuclear Topo I (topoisomerase I)) by binding to and stabilizing the topoisomerase-DNA covalent complex. (protocol-online.org)
  • Camptothecin: Roles of the D and E Rings in Binding to the Topoisomerase I-DNA Covalent Binary Complex. (ebscohost.com)
  • Camptothecins stabilize this covalent intermediate by preventing topo I-mediated religation of the DNA strand ( 1 ). (aacrjournals.org)
  • Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. (aacrjournals.org)
  • 5: Beretta GL, Zuco V, De Cesare M, Perego P, Zaffaroni N. Namitecan: a hydrophilic camptothecin with a promising preclinical profile. (medkoo.com)
  • Cao ZS, Giovanella BC (2003) Halo-alkyl esters of camptothecin and methods of treating cancer using these compounds. (springer.com)
  • 1: Bala V, Rao S, Boyd BJ, Prestidge CA. Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38. (medkoo.com)
  • These studies demonstrated the feasibility of developing a safe and efficacious oral formulation for a sparingly soluble camptothecin analog that may provide a viable, patient compliant and, cost effective option for the treatment of solid tumors. (eurekaselect.com)
  • Camptothecin (CPT) has recently attracted increasing attention as a promising anticancer agent for a variety of tumors. (biomedcentral.com)
  • This essay has discussed various ways by which two or more than two drugs have been combined with Camptothecin through nanoparticles in order to yield anti-cancer therapy effectiveness. (jddtonline.info)
  • The camptothecin analog CPT-11 has recently been approved for the treatment of 5-fluorouracil (5-FU)-resistant colorectal cancer (1) , thus opening a new chapter in chemotherapeutic radiation sensitization. (springer.com)
  • The aim of this study was to formulate polyethylene glycol (PEG) based nanoparticulate camptothecin analog for oral administration and to evaluate its pharmacological activity. (eurekaselect.com)
  • The authors speak about new camptothecin analog improvement, drug supply concerns for optimizing their anticancer task, and their power use in numerous diversified cancers. (seamolec.org)
  • 13. Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Stewart L. 2002 The mechanism of topoisomerase I poisoning by a camptothecin analog. (seamolec.org)
  • Intro AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin, also known as DB-67) (Fig. 1) can be a third-generation camptothecin analog that goes to the course of 7-silylcamptothecins (Bom et al. (biodigestor.net)
  • The authors speak about new camptothecin analog improvement, drug supply matters for optimizing their anticancer job, and their strength use in various varied cancers. (usacubiczirconia.com)
  • Characterization of DNA Topoisomerase-1 in Spodoptera exigua for Toxicity Evaluation of Camptothecin and Hydoxy-Camptothecin. (ebscohost.com)
  • CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. (aacrjournals.org)
  • The sodium salt of camptothecin was relatively inactive with significant toxicity in clinical trials ( 6 , 7 ). (aacrjournals.org)
  • CT-2106, a poly- l -glutamic acid-glycine-camptothecin conjugate, has the potential to deliver higher active camptothecin doses to tumor tissue compared with normal tissues, thereby reducing toxicity due to the enhanced permeability and retention effect of the poly-glutamate backbone. (aacrjournals.org)
  • It is a member of the camptothecin family that demonstrates less toxicity than its parent compound. (bertin-bioreagent.com)
  • Camptothecin is an alkaloid isolated from the stem wood of the Chinese tree, Camptotheca acuminata Decsne. (google.com)
  • 20-(S)-camptothecin (CPT) is a cytotoxic alkaloid extracted from the Chinese tree Camptotheca acuminata . (biomedcentral.com)
  • Camptothecin is a natural alkaloid product first extracted from the stem wood of the Chinese tree Camptotheca acuminata . (cancernetwork.com)
  • With the aim of improving the production of these pharmaceuticals , the contents of camptothecin and 10-hydroxycamptothecin in different tissues including roots, stems, leaves, young flower buds, opening flowers , fading flowers and seeds from Camptotheca acuminata, were investigated. (bvsalud.org)
  • Camptothecin (CPT) is an alkaloid isolated from the stem of the tree Camptotheca acuminata with its chemical structure identified by Wall et al. (biomedcentral.com)
  • This study aims to explore the role of MPTP in the process of apoptosis induced by camptothecin (CPT) in Spodoptera exigua so as to further reveal the mechanisms of CPT-induced apoptosis in insects. (insect.org.cn)
  • MPTP dependency in mitochondrion-mediated apoptosis induced by camptothecin in Spodopetera exigua (Lepidoptera: Noctuidae)[J]. ACTA ENTOMOLOGICA SINICA, 2017, 60(10): 1105-1113. (insect.org.cn)
  • Camptothecin has been shown to induce apoptosis in a dose-dependent manner in vitro . (bdbiosciences.com)
  • Camptothecin is routinely used as a general method for inducing apoptosis. (bdbiosciences.com)
  • No inhibitory effect of camptothecin on RNA transcription was observed with human topoisomerase I isolated from a camptothecin-resistant cell line. (nih.gov)
  • Giovanella BC, Hinz HR, Kozielski AJ, Stehlin JS, Silber R, Potmesil M. Complete growth inhibition of human cancer xenografts in nude mice by treatment with 20(S)-camptothecin. (springer.com)
  • CONCLUSION: By comparing the transcription profile of two glioblastoma cell lines treated with camptothecin, we were able to identify the common cellular pathways activated upon Topo I inhibition. (unimi.it)
  • Camptothecin (CPT) has recently been undergoing phase I clinical trials. (protocol-online.org)
  • The parent camptothecin molecule is compromised in its clinical utility by several factors: it is poorly water soluble ( 2 ), and it undergoes conversion at physiologic pH to the inactive carboxylate form ( 3 ) of the drug, which binds avidly to human serum albumin ( 3 - 5 ). (aacrjournals.org)
  • 9,The original preparation (camptothecin sodium) was evaluated in clinical trials in the late 1960s and early 1970s. (cancernetwork.com)
  • The clinical efficacy of camptothecin (CPT), a drug specifically targeting topoisomerase I (TopoI), is under evaluation for the treatment of malignant gliomas. (unimi.it)
  • Nothapodytes nimmoniana is the major source of camptothecin and has been widely exploited by researchers for procuring camptothecin because synthetic procedures are still not available for this natural product. (zhadin.net)
  • The present book encompasses various important techniques prominently HPTLC for the quantification of camptothecin in Nothapodytes nimmoniana.The relevance of the contents of the book in PDF the modern contemporary natural product research makes it center of attraction in the scientific world. (zhadin.net)
  • So far with regards to the book we have Quantification of Camptothecin in Nothapodytes Nimmoniana by Hptlc opinions users are yet to however quit his or her overview of the experience, or not see clearly yet. (zhadin.net)
  • Your own comments to reserve Quantification of Camptothecin in Nothapodytes Nimmoniana by Hptlc -- some other audience is able to determine with regards to a publication. (zhadin.net)
  • The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S)-camptothecin (CPT) in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. (biomedcentral.com)
  • GSMMDC was synthesized and found to be nearly as active as 10,11-methylenedioxy-20(S)-camptothecin in a topoisomerase (topo) mediated DNA nicking assay. (rti.org)
  • The effect of 7-alkyl substitutions on growthinhibition in seven Camptothecin (CPT) ring systemswith various groups at the ten position was evaluated inthree human breast cancer cell lines that model (1)hormone-sensitive (MCF-7/wt), (2) hormone insensitive(MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. (ulster.ac.uk)