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)

The topoisomerase I inhibitor, topotecan, is approved for the treatment of recurrent small-cell lung cancer (SCLC) and ovarian cancer (OC). Patients with recurrent SCLC and OC typically experience multiple relapses and receive multiple rounds of chemotherapy. In these settings, disease stabilisation is considered a treatment benefit, and quality-of-life effects and cumulative toxicities of treatments should be considered. Many patients with recurrent cancer may be predisposed to treatment-related adverse events because of advanced age, renal impairment or extensive prior therapy. The standard regimen of topotecan, 1.5 mg/m(2) on days 1-5 of a 21-day cycle, has generally mild nonhaematological toxicity and a well-defined haematological toxicity profile characterised by reversible and noncumulative neutropenia. Alternative regimens may lower the incidence of haematological toxicities and maintain antitumour efficacy. Topotecan may provide physicians with a versatile therapeutic option for the treatment of patients with relapsed SCLC or OC.
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PMID:Safety of topotecan in the treatment of recurrent small-cell lung cancer and ovarian cancer. 1718 52

The topoisomerase I agents are established as a therapy in recurrent ovarian cancer. Karenitecin, an analog of topotecan with solubility and pharmacologic advantages, was tested in a phase II trial in previously treated patients with recurrent or persistent ovarian cancer. The drug was administered intravenously over 1 h at a dose of 1.0 mg/m(2) daily for 5 days every 21 days. Patients were treated until disease progression, intolerable toxicity, or voluntary withdrawal. Response was evaluated according to modified RECIST criteria. Twenty-seven patients were entered into the study. One patient was inevaluable for not receiving any treatment. Of the 26 evaluable patients, there were two partial responses and one complete response for a total response rate of 12%. This response rate was insufficient to justify accrual to the second stage. The most common grade 3 or 4 toxicities were neutropenia (19%) and gastrointestinal (15%). Karenitecin is a well-tolerated topoisomerase compound but has minimal activity in extensively pretreated ovarian cancer with the dose-schedule employed.
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PMID:Phase II multicenter open-label study of karenitecin in previously treated epithelial ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. 1785 32

A new series of indolocarbazole glycosides containing disaccharides were synthesized and their in vitro antiproliferative activity was evaluated against three human cancer cell lines (A2780, H460, and GLC4). Cytotoxicity appeared to be remarkably affected by the regio- and stereochemical features of the disaccharide moiety. In vivo antitumor activity of the compounds studied, two of which having IC(50)<100 nm, was determined using ovarian cancer cell line A2780 xenografted on nude mice. One compound showed an efficacy similar to that of the reference compound edotecarin, though with a lower long-lasting activity. The topoisomerase I inhibitory properties of some compounds were also examined. Molecular dynamics simulations of the ternary topoisomerase I-DNA-ligand complexes were performed to analyze the structural features of topoisomerase I poisoning with this class of indolocarbazoles. A plausible explanation of their biological behavior was provided. These theoretical results were compared with the recently published crystal structure of an indolocarbazole monosaccharide bound to the covalent human topoisomerase I-DNA complex.
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PMID:Synthesis, biological evaluation, and molecular modeling studies of rebeccamycin analogues modified in the carbohydrate moiety. 1815 56

Ovarian cancer remains one of the most difficult gynecologic cancers to treat, owing to its aggressive biology and high relapse rate, as well as the toxic side effects of available chemotherapeutic agents used to treat recurrent disease. Topoisomerase I inhibitors, including topotecan and irinotecan, are some of the most effective and tolerable treatment options for recurrent ovarian cancer. The ideal dosing, timing of administration, role in combination with other chemotherapies or biologics and potential role in up-front therapy remains an area of active research. This article reviews the mechanism of action of topoisomerase I inhibitors and the efficacy, dosing, schedule and toxicity for topotecan, irinotecan, 9-nitrocamptothecin, DX-8951 and 9-aminocamptothecin. Conclusions include a discussion of future avenues of research and ongoing projects.
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PMID:Key role of topoisomerase I inhibitors in the treatment of recurrent and refractory epithelial ovarian carcinoma. 1847 Oct 53

Camptothecin is a topoisomerase I inhibitor that acts against a broad spectrum of cancers. However, its clinical application is limited by its insolubility, instability, and toxicity. The aim of the present study was to develop acoustically active nanoemulsions for camptothecin encapsulation to circumvent these delivery problems. The nanoemulsions were prepared using liquid perfluorocarbons and coconut oil as the cores of the inner phase. These nanoemulsions were stabilized by phospholipids and/or Pluronic F68 (PF68). The nanoemulsions were prepared at high drug loading of approximately 100% with a mean droplet diameter of 220-420 nm. Camptothecin in these systems showed retarded drug release. Camptothecin in nanoemulsions with a lower oil concentration exhibited cytotoxicity against melanomas and ovarian cancer cells. Confocal laser scanning microscopy confirmed nanoemulsion uptake into cells. Hemolysis caused by the interaction between erythrocytes and the nanoemulsions was investigated. Formulations with phosphatidylethanolamine as the emulsifier showed less hemolysis than those with phosphatidylcholine. Using a 1 MHz ultrasound, an increased release of camptothecin from the system with lower oil concentration could be established, illustrating a drug-targeting effect.
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PMID:Acoustically active perfluorocarbon nanoemulsions as drug delivery carriers for camptothecin: drug release and cytotoxicity against cancer cells. 1855 79

The abundant nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), represents an important novel target in cancer therapy. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA) 1 and 2 genes. This theory of selectively exploiting cells defective in one DNA repair pathway by inhibiting another is a major breakthrough in the treatment of cancer. BRCA1/2 mutations are responsible for the majority of genetic breast/ovarian cancers, known as the hereditary breast ovarian cancer syndrome. This review summarizes the preclinical and clinical evidence for the potential of PARP inhibitors in genetic breast and ovarian cancers.
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PMID:The potential of PARP inhibitors in genetic breast and ovarian cancers. 1883 94

The camptothecins, which target the intranuclear enzyme topoisomerase I, have advanced to the forefront of several areas of developmental chemotherapy of cancers. In the present study, we investigated the potential anti-human ovarian cancer effects of NSC606985, a novel and rarely studied camptothecin analog, and its combination with cisplatin (CDDP). Human ovarian cancer cell line COC1 cells were treated with different nanomolar of NSC606985 with or without CDDP, and cell growth and apoptosis were evaluated, respectively, by MTT assay and annexin-V assay on flow cytometry. Chou-Talalay analysis was used to evaluate combined effect of NSC606985 and CDDP. Western blot was used to detect protein kinase Cdelta (PKCdelta), caspase-3 and hypoxia-inducible factor-1alpha (HIF-1alpha) proteins. Our results showed that NSC606985 at nanomolar concentration induced apoptosis with the activation of PKCdelta in COC1 cells. Especially, NSC606985 presented the significant combined effects on COC1 cells in terms of growth inhibition and apoptosis induction. In addition, NSC606985 significantly antagonized the accumulation of HIF-1alpha stabilized by hypoxia or hypoxia-mimetic agent. These results suggest that NSC606985 and its combination with CDDP present the therapeutic potential on ovarian cancer, and deserve further preclinical and clinical studies.
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PMID:NSC606985 induces apoptosis, exerts synergistic effects with cisplatin, and inhibits hypoxia-stabilized HIF-1alpha protein in human ovarian cancer cells. 1933 7

Owing to its central role in multiple cellular functions, p53 is an attractive candidate for gene replacement therapy. We studied the role of adenovirus-mediated p53 gene (p53Ad) therapy on sensitivity of two ovarian cancer cell lines, OVCAR-3 (p53(mut)) and SK-OV-3 (p53(wt)), to docetaxel, CPT-11 and SN-38 exposures. Expressions of Bcl-XL, Bcl-XS, p53, Gadd45, c-fos, p21(waf1/cip1), Bax, Bcl-2 and Mcl-1 were measured after concomitant p53Ad and drug exposures. In SK-OV-3 cells containing a normal p53 gene, p53Ad alone or concomitantly with docetaxel, CPT-11 or SN-38 exposures did not have an effect on cell growth, cell cycle distribution or induction of apoptosis. In OVCAR-3 cells, p53 gene therapy inhibited the cell growth and sensitized cells to CPT-11/SN-38, but not to docetaxel. Growth inhibition and sensitization were results of G2M cell cycle arrest and increased apoptosis. In SK-OV-3 cells, but not in OVCAR-3 cells, CPT-11/SN-38 exposures alone increased p21(waf1/cip1) expression. The p53Ad therapy induced strong p21(waf1/cip1) expression in both cell lines. In addition, the expression of Bax and expression ratios Bax/Bcl-2 and Bax/Bcl-XL increased in p53Ad-infected OVCAR-3 cells, but not in SK-OV-3 cells. These expression ratios were further increased in p53Ad+CPT-11/SN-38-exposed OVCAR-3 samples. These results support the combination of p53 gene therapy with topoisomerase I inhibitors SN-38/CPT-11 when tumour cells contain mutated p53. When p53 status is normal, p53 gene therapy is not effective alone or concomitantly with CPT-11/SN-38. Increased expression ratios of Bax/Bcl-2 and Bax/Bcl-XL might serve as positive markers for effective p53 gene therapy and concomitant topoisomerase I inhibitor therapy.
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PMID:Concomitant exposure of ovarian cancer cells to docetaxel, CPT-11 or SN-38 and adenovirus-mediated p53 gene therapy. 1949 54

Recently, we have observed the emergence of a new series of pyrophosphate-bridged coordination complexes. Such complexes have been prepared by overcoming the ready hydrolysis of the pyrophosphate moiety. To date, no exploration has been conducted on the cytotoxicity of such complexes. Three pyrophosphate-bridged complexes, namely {[Ni(phen)(2)](2)(mu-P(2)O(7))}.27H(2)O, {[Cu(phen)(H(2)O)](2)(mu-P(2)O(7))}.8H(2)O and {[Co(phen)(2)](2)(mu-P(2)O(7))}.6MeOH, (where phen is 1,10'-phenanthroline) were chosen for their comparative structural similarities and suitable aqueous solubility. Cytotoxicity studies in the adriamycin-resistant ovarian cancer cell line A2780/AD demonstrated highly significant efficacy, with values as low as 160pM for the cobalt complex at 72h. The underlying mechanism for such exceptional toxicity is investigated focusing on DNA interactions, topoisomerase I enzyme inhibition and oxidative stress (followed by intracellular glutathione levels). The role of hydrolysis in uptake and toxicity is also explored (followed by electronic absorption spectroscopy, (31)P NMR, and confocal microscopy) and the complexes are compared to cisplatin controls. Overall a clear picture of the extraordinary toxicity emerged. The results demonstrate a new class of prodrugs with significant potential for future development for the treatment of drug-resistant cancer cell lines.
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PMID:Pyrophosphate-bridged complexes with picomolar toxicity. 1966 93

The effects of Lewis Y antigen on the gene expression of multiple drug resistance-associated proteins in human ovarian cancer RMG-I-H cells were unclear by now. In this study, we detected the gene expression of multiple drug resistance-associated proteins (MRP) in RMG-I-H cells and RMG-I-H cells treated with anti-Lewis Y monoclonal antibody to investigate the association between Lewis Y antigen and the gene expression of drug resistance-associated proteins. Compared with RMG-I cells, the expression of MRP1, MRP2, protein kinase C-alpha (PKC-alpha), and topoisomerase I (Topo I) mRNAs in RMG-I-H cells were significantly upregulated, while the MDR-1 mRNA was downregulated. Immunochemistry analyses indicated that the in vitro and in vivo expression levels of MDR-1 protein (P-gp) in RMG-I-H cells were significantly higher than those in RMG-I cells. After RMG-I-H cells were treated with anti-Lewis Y monoclonal antibody, the expression levels of MDR-1, MRP1, MRP2, PKC-alpha, and Topo I mRNAs gradually decreased with the prolongation of treatment duration. In contrast, no obvious changes were noted in the expression levels of these mRNAs in the non-treatment group. At 6 h after treatment, the relative levels of MDR-1, MRP1, MRP2, PKC-alpha, and Topo I mRNAs in the antibody treatment group were significantly lower than those in the non-treatment group. In conclusion, Lewis Y antigen is closely associated with regulating the gene expression of multiple drug resistance-associated proteins.
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PMID:Effects of Lewis Y antigen on the gene expression of multiple drug resistance-associated proteins in human ovarian cancer RMG-I-H cells. 1977 31


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