Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerase I represents a unique new target that can be exploited for development of new antineoplastic agents. There are now two new topoisomerase I inhibitors that are in early clinical trials that have generated a tremendous amount of interest. Topotecan (SKF 104864-A) is a topoisomerase I inhibitor that has been explored in phase I trials using a variety of dosages and schedules. The dose-limiting toxicity of the agent is neutropenia. Other toxicities include alopecia, very mild nausea and vomiting, anemia, and occasional fever. Responses have already been noted in patients with advanced, refractory ovarian cancer and non--small-cell lung cancer. The drug is currently undergoing intense phase II testing. Irinotecan (CPT-11) is also a topoisomerase I inhibitor, which has already undergone extensive phase I and early phase II clinical testing in both Japan and the United States. Dose-limiting toxicities of the agent have included neutropenia and diarrhea. Responses have been noted in patients with refractory colorectal cancer, non--small-cell lung cancer, lymphoma, ovarian cancer, head and neck cancer, pancreatic cancer, and breast cancer. There is no doubt both of these agents will be important additions to our chemotherapy armamentarium.
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PMID:Clinical trials with the topoisomerase I inhibitors. 133 79

Recombinant human tumor necrosis factor (rHuTNF) synergistically potentiates the cytotoxicity of the topoisomerase I inhibitor camptothecin, and the topoisomerase II inhibitors epidoxorubicin, etoposide, mitoxantrone, ellipticine, actinomycin D and 4'-(9-acridinylamino)methanesulfon-m-anisidide on A2780 human ovarian cancer cell line. Similar synergy was not observed with a combination of rHuTNF and cis-platinum or mitomycin C. When A2780 cells were incubated with rHuTNF simultaneously with camptothecin or mitoxantrone or VP16, increased numbers of DNA single-strand breaks were produced. rHuTNF alone did not induce DNA strand breakage. These data provide evidence that the enhancing effect of rHuTNF is closely related to the DNA damage mediated by topoisomerase-targeted drugs. These observations may have relevance for ovarian cancer treatment.
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PMID:Potentiation of topoisomerase I and II inhibitors cell killing by tumor necrosis factor: relationship to DNA strand breakage formation. 133 89

As part of an ongoing rational drug design programme aiming to develop monosubstituted anthracenyl-peptides as potential anticancer drugs, three novel dipeptide conjugates have been synthesized and evaluated as inhibitors of topoisomerase (topo) I and II. Each of the three conjugates (designated NU/ICRF 600-602) was shown to inhibit the catalytic activity of both topoisomerase I and II, of which NU/ICRF 602 was the most active [100% inhibition of both enzymes at 5 micrograms/ml (approximately 15 microM) or less]. In a topo I/DNA unwinding assay, none of the compounds bound to DNA, suggesting genuine inhibition of catalytic activity. NU/ICRF 600 stabilized topo I cleavable complexes, although none of the compounds induced topo II-mediated DNA cleavage. Using a panel of Chinese hamster ovary cell lines along with the human ovarian cancer cell line, A2780, none of the three compounds were actively cytotoxic at concentrations < 100 microM. Subsequent drug uptake studies with NU/ICRF 600 and 602, using a method developed to correlate the chemosensitivity of A2780 cells with the uptake of anthracenyl-amino acid conjugates, revealed a lack of cellular uptake for both dipeptide conjugates. The significance of this finding in relation to drug design and the future development of this series of compounds is discussed.
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PMID:Identification of anthracenyl-dipeptide conjugates as novel topoisomerase I and II inhibitors and their evaluation as potential anticancer drugs. 749 76

Anthracenyl amino acid/dipeptide conjugates (AADC) represent novel structures rationally designed for their DNA-binding properties. A high-performance liquid chromatography method is described for simultaneous determination of five compounds that exhibit novel mechanisms of action as topoisomerase I and II inhibitors. The method uses an Apex ODS-2 column and a mobile phase of 0.25 M ammonium acetate/trifluoroacetic acid (pH 3) in methanol with gradient elution. Selective detection is achieved by monitoring at 545 nm, with limits of detection ranging between 2 and 4 ng on the column. AADC are recovered from cell sonicates by solid-phase extraction using C2 cartridges, with extraction efficiencies ranging from 84% to 95%. Drug uptake studies were performed with three active compounds in the human ovarian cancer cell line A2780 and its multi-drug-resistant counterpart 2780AD. Marked differences were observed in the pattern of cellular accumulation produced by each compound. NU/ICRF 505 (tyrosine derivative) was taken up most avidly, reaching plateau levels of 4000 pmol/10(6) cells after 2 h, with no difference being apparent between A2780 and 2780AD. NU/ICRF 510 (arginine derivative) accumulated slowly in A2780, failing to achieve an equilibrium after 4 h, and appeared to be completely excluded from 2780AD. NU/ICRF 500 (serine derivative) was most rapidly taken up by A2780, producing a plateau of 800 pmol/10(6) cells after only 30 min with approximately 3-fold less accumulation in 2780AD. These results are correlated to the chemosensitivity of the two cell lines to the three compounds.
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PMID:Accumulation of anthracenyl-amino acid topoisomerase I and II inhibitors in drug-sensitive and drug-resistant human ovarian cancer cell lines determined by high-performance liquid chromatography. 749 78

CPT-11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-drug that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro-drug analog of camptothecin, DX-8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti-proliferative activity of DX-8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastric adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK&F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug resistance. These data suggest that DX-8951f has a high antitumor activity and is a potential therapeutic agent.
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PMID:A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. 755 2

Since the beginning of its clinical development 20 years ago, etoposide has become an important and widely used agent in clinical oncology. Its integral role in the treatment of germ cell tumors and small-cell lung cancer seems unlikely to diminish in the future, and its use in non-Hodgkin's lymphoma and in various high dose regimens will probably continue to increase. Active investigation continues regarding the optimal dose and schedule of etoposide, and it is likely that these investigations will result in further improvement of its clinical activity in patients with sensitive tumor types. Continued clinical investigation may result in the identification of active etoposide containing combination regimens for ovarian cancer, breast cancer, and some of the childhood malignancies. Exciting possibilities for the future include exploration of etoposide in combination with the topoisomerase I inhibitors, as well as the development of drugs to reverse drug resistance. During the next 10 years, the applications and importance of this unique drug will continue to increase.
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PMID:Etoposide: twenty years later. 761 47

Advanced epithelial ovarian cancer is a highly chemosensitive solid tumor with response rates of 70-80% to first-line chemotherapy, including a high proportion of complete responses. The majority of patients, however, eventually relapse and ultimately die of chemoresistant disease. Response rates to salvage agents are modest, and duration of response is relatively short. Important new agents have been identified in the salvage setting, however, and all patients with ovarian cancer recurring or persisting after front-line therapy should be encouraged to enroll in clinical trials. Phase II trials should include multiple adequately sized cohorts, for patients with platinum-sensitive disease and those with platinum-refractory disease. In addition, patients should be stratified by treatment-free interval. An effort should be made to report standard response endpoints, such as median duration of response, median time to progression, and median survival. Retreatment with a platinum-containing compound is appropriate in patients with platinum-sensitive disease. Trials of high-dose chemotherapy with hematologic support may be most appropriate for patients with minimal disease following first-line therapy, but are unlikely to benefit patients with platinum-resistant or bulky disease. Paclitaxel should figure prominently in consideration of salvage therapy for patients with platinum-resistant disease. Responses to other single agents or combination chemotherapy have been modest and generally of short duration. Efforts at hormonal therapy have been disappointing. Promising new agents include topoisomerase I inhibitors, such as topotecan, 9-aminocamptothecin, irinotecan (CPT-11), and pyrazoloacridine. Therapies focusing on novel molecular targets include antiangiogenesis agents, antimetastatic agents, and signal transduction inhibitors. Immunotherapy, including radioimmunotherapy, immunotoxins, and direct antitumor effects of monoclonal antibodies, may be useful. Greater understanding of the molecular pathology of ovarian cancer may help us develop more rational and effective treatment.
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PMID:Salvage chemotherapy for epithelial ovarian carcinoma. 783 99

Camptothecin and taxol are secondary metabolites found, respectively, in the wood bark of Camptotheca acuminata, a native of China, and Taxus brevifolia, found in the northwest Pacific coastal region of the United States. The compounds were isolated guided by bioassay on various extracts and chromatographic fractions. Their unique and hitherto unknown structures were elucidated by nuclear magnetic resonance, mass spectrometry, and X-ray analysis. Both compounds have unique mechanisms of antitumor activity; camptothecin uniquely inhibits an enzyme, topoisomerase I, involved in DNA replication. Taxol binds to a protein, tubulin, thus inhibiting cell division. Taxol has been called the best new anticancer agent developed from natural products, showing particular efficacy against ovarian cancer. Camptothecin and analogues singly or combined with cisplatin show efficacy against solid tumors, breast, lung, and colorectal, which hitherto have been unaffected by most cancer chemotherapeutic agents.
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PMID:Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. 785 Jul 85

The therapeutic effects of intraperitoneal topotecan, a water-soluble camptothecin analogue, were investigated in two models of human ovarian carcinoma xenografted intraperitoneally into nude mice: the IGROV-1 tumour, which originated from an untreated patient, and the A2780 tumour, selected for resistance in vitro to cisplatin (A2780DDP). In IGROV-1 tumour-bearing mice, the optimal dose (10 mg kg-1) of topotecan, given intraperitioneally every 4 days for four occasions markedly increased survival time over control mice (300 T/C%) and cured 4/9 mice, and such effects were not achieved by any of the clinically available drugs tested, i.e. cisplatin carboplatin and doxorubicin delivered intraperitonally according to their optimal doses and schedules. In the treatment of A2780DDP tumour-bearing mice, topotecan was very effective since, at dose levels of 6.6 and 10 mg kg-1 every 4 days for four occasions, 15/18 mice survived more than 100 days, and most of them (12/15) were found to be tumour free. The high responsiveness of this tumour to topotecan might be related to the elevated expression of the target enzyme topoisomerase I. From these results, intraperitoneal treatment with topotecan appears to be a promising approach in the therapy of refractory ovarian cancer confined to the peritoneal cavity.
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PMID:Successful local regional therapy with topotecan of intraperitoneally growing human ovarian carcinoma xenografts. 788 Jul 34

The camptothecin derivative 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin (CPT-11) has attracted the attention of clinicians because of its high antitumor activity against refractory solid cancers. We established two CPT-11-resistant cell lines, a non-small-cell lung-cancer cell line (PC-7/CPT-11) from the parental PC-7 line and an ovarian cancer cell line (HAC-2/CPT-11) from the parental HAC-2 line. The mechanisms of resistance to CPT-11 in PC-7/CPT-11 cells were reduced conversion of CPT-11 to its active metabolite SN-38 and point mutation topoisomerase I. Those in HAC-2/CPT-11 cells were reduction of topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase I inhibitors. No point mutation of the topoisomerase was observed in HAC-2/CPT-11 cells. We conducted two phase I trials using CPT-11 in combination with other anticancer agents. One was a phase I trial of CPT-11 and cisplatin given with a fixed dose of vindesine to patients with advanced non-small-cell lung-cancer and the other was a phase I study on a topoisomerase-targeting combination of CPT-11 and etoposide (VP-16) in patients with various malignant solid tumors. The results of the first trial indicated that the recommended dose of CPT-11 for phase II studies was 80 mg/m2 combined with 3 mg/m2 vindesine on days 1 and 8 and 60 mg/m2 cisplatin on day 1. In the second trial, the recommended dose of CPT-11/VP-16 given with recombinant granulocyte colony-stimulating factor (on days 4-17) was found to be 60/60 mg/m2. In both trials, diarrhea and granulocytopenia were considered to be dose-limiting toxicities.
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PMID:7-Ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin: mechanism of resistance and clinical trials. 807 19


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