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)

Several provocative studies in gynecologic cancer were recently presented. Long-term follow-up of ovarian cancer patients has confirmed the clinical impression of a low survival. Novel classes of active chemotherapeutics are the second-generation topoisomerase I inhibitors, irinotecan (CPT-11) and topotecan, and the taxanes, Taxol (Bristol-Meyers, Wallingford, CT) and Taxotere (Rhone-Poulenc Rorer, Antony, France). Dose intensity remains an intriguing issue. Biologic agents, including monoclonal antibodies, are being developed for palliation of ascites. In cervical cancer, use of retinoids and interferons has opened up a new avenue of investigation. Use of the World Health Organization sophisticated scoring criteria has improved the primary treatment of trophoblastic disease. Advances in salvage therapy have been noted. Progress in the treatment of advanced endometrial cancer and uterine sarcomas is beginning.
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PMID:Systemic therapy for gynecologic cancer. 810 75

Irinotecan hydrochloride (CPT-11) is a water-soluble semisynthetic derivative of camptothecin. CPT-11 is a prodrug that undergoes deesterification in vivo to produce SN-38, a metabolite that is 1,000-fold more potent than the parent compound in vitro. CPT-11 is a potent topoisomerase I inhibitor with a broad spectrum of experimental antitumor activity. Recent clinical trials also reveal that CPT-11 is very effective in the treatment of cancers including lung cancer, cervix cancer, ovary cancer, etc. Now, comparative trials of combination chemotherapy in responsive tumors are indicated from these excellent clinical results.
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PMID:[Irinotecan hydrochloride (CPT-11)]. 815 99

Irinotecan hydrochloride (CPT-11), topotecan, sobuzoxane, NC-190, and IST-622 are unique topoisomerase inhibitors and are investigational in Japan. CPT-11 is a water-soluble, semisynthetic derivative of camtothecin. CPT-11 shows its anticancer activity by inhibiting topoisomerase I activity, now a target of anticancer agents with major interest. Recent clinical trials reveal that CPT-11 is very effective in the treatment of cancer including lung cancer, cervical cancer, ovary cancer, stomach cancer, colon cancer, and non-Hodgkin's lymphoma. Major dose limiting toxicities are leukopenia and diarrhea, and are dose related. Topotecan is an another semisynthetic derivative of camtothecin and is also topoisomerase I inhibitor. Topotecan has undergone phase I clinical evaluations in USA, europe, and recently in Japan. DLF are leukopenia and neutropenia. Topotecan is more hydrophilic than its parent compound and shows lesser protein binding. Renal excretion appears to be the major route of elimination. Sobuzoxane (MST-16) is a unique derivative of dioxopiperazine, an inhibitor of topoisomerase II. In phase II studies, definite anticancer effects are observed in patients with non-Hodgkin's lymphoma and adult T-cell leukemia/lymphoma. Responses are seen even in pretreated cases. Leukopenia is also dose-limiting. Non-hematologic toxicities are mild and include alopecia and G.I. toxicities. NC-190 is a novel benzophenazine derivative with excellent antitumor activities against murine tumors. NC-190 also inhibits topoisomerase II. Now the drug is an early clinical phase II studies in Japan. Toxicities include bone marrow suppression, transient mild to moderate liver enzyme elevation, alopecia and mild G.I. toxicities. Tumor responses are occasionally encountered. IST-622 is a semisynthetic derivative of chartreusin. The drug is an inhibitor of topoisomerase II (and I in high concentration). IST-622 shows excellent, broad anticancer activity against murine tumors. The drug is well absorbed from small intestine. IST-622 is now in phase I clinical trial in Japan.
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PMID:[Topoisomerase inhibitors developing in Japan]. 842 86

Advanced stage ovarian cancer is the most lethal gynecologic cancer. Despite initial response rates of 60-80% with platinum-based chemotherapy, more than 75% of women with this malignancy die of complications associated with this disease. There is a pressing need to find new chemotherapeutic agents for patients with advanced ovarian cancer. Phase II studies have identified paclitaxel as the most active drug in ovarian cancer since the introduction of cisplatin in the 1970s. Phase III studies will define the role of paclitaxel as initial therapy. Camptothecins (topotecan, CPT-11, 9-amino-camptothecin) inhibit topoisomerase I. CPT-11 and topotecan have shown activity in Phase II trials. Gemcitabine, a pyrimidine antimetabolite, has shown activity in Phase II trials. Other promising drugs (docetaxel, treosulfan) are under investigation. Modulation of drug resistance is being explored in Phase I/II studies. Clinical trials have been initiated with buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, which decreases the ability of resistant cells to inactivate platinum compounds and alkylating agents. Cyclosporin has been shown to increase cisplatin cytotoxicity. Phase I trials have demonstrated the feasibility of combining cyclosporin and cisplatin. Phase II trials of cyclosporin analogs (PSC 833) and paclitaxel in refractory ovarian cancer are ongoing. Promising leads in drug development should provide new therapies for patients with ovarian cancer. Further research in the modulation of drug resistance may identify new mechanisms or strategies with which to prevent the emergence of drug resistance.
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PMID:Promising new therapies in the treatment of advanced ovarian cancer. 863 95

DNA topoisomerases, nuclear enzymes that regulate DNA topology, are recognized as the primary targets of effective anti-tumor drugs. These enzymes may also have a role in the repair of DNA damage induced by alkylating agents and platinum compounds; therefore, their expression may be a determinant of tumor response to chemotherapy. Our study was undertaken in an attempt to establish a correlation between the enzyme expression and response of ovarian cancer to cisplatin-based chemotherapy. The expression of topoisomerase I, II alpha and II beta genes was assessed by RNase protection assay in tumor specimens obtained from 37 untreated patients with advanced epithelial ovarian cancer at initial surgery and from 13 pre-treated patients at subsequent laparotomy. The expression levels were compared with those found in 5 specimens from benign ovarian tissue and 5 specimens from normal ovarian tissue. The expression levels in untreated patients were used to establish a correlation with response to high-dose cisplatin therapy. A significant intertumor variability of mRNA expression was noted for all the genes examined. However, a comparison of median values indicated a remarkable increase of expression in malignant tumors over benign or normal tissues only for topoisomerase II alpha. This change is not related to alterations or amplification of topoisomerase II alpha gene. Interestingly, a correlation was found between tumor response to chemotherapy and the expression level of the isoform alpha (but not of topoisomerase II beta and topoisomerase I). The observed correlation suggests a contribution of the enzyme in determining tumor sensitivity. Alternatively, increased expression levels of the alpha isoenzyme gene in responsive tumors might reflect higher fractions of proliferating tumor cells that may be more drug-sensitive than resting cells.
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PMID:Gene expression of DNA topoisomerases I, II alpha and II beta and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. 875 4

Anticancer drug development has recently shifted in part to development of more innovative anticancer agents. The increasing knowledge of the pathogenetic mechanisms involved in cancer cell growth has enabled the introduction of drug screening that is more mechanism-based. The realization that new targets should be preferentially evaluated as sites for anticancer drug treatment has led to the introduction of drugs such as the taxanes. Following this logic, several new drugs are being developed. Minor groove-binding agents such as carzelesin and oral platins lacking organ toxicity, such as JM216, have recently entered clinical studies. The activity of gemcitabine is a result of its being a cytidine analogue and being competitively incorporated by DNA; the drug has shown interesting activity in non-small-cell lung cancer and, although registration is imminent, issues regarding the optimal dose and administration schedule have yet to be resolved. Tomudex is a thymidylate synthase inhibitor with interesting activity in colorectal cancer. Activity in colorectal cancer is also of interest for irinotecan, the first clinically applied topoisomerase I inhibitor, an enzyme that is another example of a new target for anticancer drugs. Irinotecan has produced consistent response rates of 20-30% in six different studies in colorectal cancer. The other topoisomerase I inhibitor that is in the advanced stage of development is topotecan. This drug has shown activity in second-line chemotherapy for ovarian cancer and small-cell lung cancer. Another interesting feature of topotecan is the availability of an oral formulation with consistent bioavailability. Drugs interfering with cellular signal transduction, such as the protein kinase C inhibitors, are in the development spotlight. Finally, the use of old drugs in new ways, such as immunoconjugates of doxorubicin, holds promise for the near future.
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PMID:New promising anticancer agents in development: what comes next? 876 8

Topotecan (Hycamtin), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase I in vitro and has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer. Now approved in the US, topotecan has completed single-agent phase I testing; phase II/III trials are ongoing. Under physiological conditions the lactone moiety of topotecan undergoes a rapid and reversible pH-dependent conversion to a carboxylated open-ring form, which lacks topoisomerase I inhibiting activity. At equilibrium at pH 7.4 the open-ring form predominates. Topotecan is stable in infusion fluids in the presence of tartaric acid (pH < 4.0), but is unstable in plasma, requiring immediate deproteinisation with cold methanol after blood sampling and storage of the extract at -30 degrees C to preserve the lactone form. Topotecan has been administered in phase I trials in several infusion schedules ranging from 30 minutes to 21 days. The plasma decay of topotecan concentrations usually fits a 2-compartment model. Rapid hydrolysis of topotecan lactone results in plasma carboxylate levels exceeding lactone levels as early as 45 minutes after the start of a 30-minute infusion. The peak plasma concentrations and the area under the plasma concentration-versus-time curves (AUC) show linear relationship with increasing dosages. No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days. Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t1/2 beta) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability. The oral bioavailablity of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed. Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition. Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.
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PMID:Clinical pharmacokinetics of topotecan. 885 31

The glucose-regulated stress response in mammalian cells is characterized by the increased synthesis of glucose-regulated proteins (GRPs). In this study, we found that GRP-inducing conditions in culture led to induction of resistance to the topoisomerase I-targeted drug camptothecin in human colon cancer HT-29 and ovarian cancer A2780 cells. The induction of camptothecin resistance was accompanied by decreased levels of camptothecin-induced cleavable complexes, as measured by a topoisomerase I band depletion assay. However, topoisomerase I protein levels were the same in both stressed and non-stressed cells. Furthermore, when isolated nuclei from stressed and non-stressed cells were treated with camptothecin, similar levels of cleavable complexes were obtained, suggesting that the activity of topoisomerase I did not change in stressed cells. In contrast, intracellular accumulation of camptothecin decreased in stressed cells. Our results indicate that stress-induced camptothecin resistance could be explained by reduced camptothecin accumulation, leading to decreased numbers of cleavable complexes, without quantitative or qualitative changes in topoisomerase I levels. In addition, cell cycle analysis revealed that the GRP-inducing treatments resulted in an accumulation of G1/G0-phase cells. As camptothecin shows an S-phase-specific cytotoxicity, the G1/G0-phase accumulation is another mechanism for camptothecin resistance. Since a glucose-regulated response is produced by hypoxia and nutrient deprivation that occur naturally in solid tumors, the resistance observed here can occur in some solid tumors and can be an obstacle to chemotherapy.
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PMID:Glucose-regulated stresses induce resistance to camptothecin in human cancer cells. 890 83

Over the past 20 years ovarian cancer has provided a vivid illustration of the successes, failures and challenges for the medical oncologist. During that time the results of treatment have substantially improved; in the West of Scotland for example, for women aged under 55, 3-year survival rates have increased from 36% to 50%. One reason for this was probably the introduction of effective agents such as cisplatin in the mid-1970s and then carboplatin in the mid-1980s. The recent introduction of taxoids promises further improvement in the future. It is important to remember, however, that the best results will be obtained by an optimal organization for the delivery of treatment; national audit studies have shown that factors such as management in integrated clinics can have a major impact on outcome. Nevertheless, the majority of patients still die from the disease; when relapse occurs, clinical drug resistance eventually proves fatal despite further treatment. What are the fundamental mechanisms by which this resistance develops, and what means are available to attempt its circumvention? Factors involved could be described as pharmacological or cellular. Pharmacological resistance might best be addressed by increasing the doses of the drugs used, particularly, cis- or carboplatin. Three years ago we published the results of a randomized trial of 2 doses of cisplatin in 191 patients. At that stage a highly significant median survival advantage for the higher dose (100 mg/m2) of cisplatin was seen. However, a recent updated analysis with a median follow-up of 4 1/2 years shows a reduction in the survival benefit, with 4-year overall survival rates for high- and low-dose cisplatin of 32.4% and 26.6%, respectively. This suggests that a population of drug resistant ovarian cancer cells will eventually emerge despite the use of initial higher doses of cisplatin. A more dose-intensive approach is being pursued with carboplatin, and it seems clear that dose-increments over standard therapy of at least 4-fold will be necessary, to justify further randomized trials. Meanwhile, the alternative approach to delivering high drug concentrations, i.e. intraperitoneal (i.p.) chemotherapy, clearly merits further study, particularly in the light of a recently reported study in patients with minimal disease, which showed a significant survival benefit for i.p. cisplatin treatment. Cellular factors will probably prove to be crucial; studies using various cell lines suggest that multiple mechanisms are likely to be involved and these will need to be examined in relevant clinical material. After DNA damage induced by a range of cytotoxic agents has taken place in ovarian cancer cells, the key to sensitivity/resistance may well be the ability of these cells to engage the process of apoptosis. Several genes are involved in control of this process; these include the p53 gene, mutations of which have been linked to cisplatin resistance in our laboratory studies, as well as in clinical trials with carboplatin. We have also demonstrated an association in ovarian cancer cell lines between cisplatin resistance and microsatellite instability (indicative of defective mismatch repair) and the clinical relevance of this link is also being pursued. A thorough understanding of underlying mechanisms may lead to the rational development of therapeutic means for circumventing cisplatin-resistance in ovarian cancer; the emergence of new classes of drug such as taxoids as topoisomerase I inhibitors offers further promise of improvement in outcome in the next few years.
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PMID:Ovarian cancer, from the laboratory to the clinic: challenges for the future. 908 99

Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) has emerged as a promising new chemotherapy drug for patients with refractory and progressive stage III and IV epithelial ovarian carcinoma. A semisynthetic analog of camptothecin, topotecan exerts its antitumor effects through inhibition of the nuclear enzyme topoisomerase I. Phase I trials found antitumor activity in many topotecan dosing schedules, one of which involved the administration of topotecan daily as a 30-minute infusion for 5 consecutive days, with the cycle repeated every 21 days. With this schedule, the maximum tolerated dose was found to be 1.5 mg/m2/d. In a series of phase II investigations in platinum-resistant ovarian cancer patients, response rates have ranged from 13% to 25%. In addition, a number of patients exhibit prolonged disease stabilization, with overall rates of nonprogression ranging from 37% to 81%. Activity in paclitaxel-resistant patients is also seen, with a multicenter phase II trial showing a response rate of 13% among first-line paclitaxel failures and 14.3% among second-line failures. A phase III trial compared topotecan and paclitaxel as second-line therapies in 226 advanced ovarian cancer patients who had been previously treated with platinum-containing regimens. Preliminary data show that patients treated with topotecan evidenced a higher response rate (23% v 14%), longer response duration (32 weeks v 20 weeks), and significantly longer time to progression (23 weeks v 14 weeks; P = .002). Additional schedules are still being evaluated, with a phase II trial of prolonged infusion of relatively low-dose topotecan over 21 days demonstrating a 37% response rate in 16 patients. All phase II and III trials analyzed thus far indicate that topotecan is well tolerated with an acceptable toxicity profile, with myelosuppression as the dose-limiting toxicity. Hematologic toxicities are predictable, of short duration, and noncumulative. Mild to moderate nonhematologic toxicities are manageable. These findings demonstrate that topotecan is a viable new second-line or salvage treatment for patients with advanced ovarian cancer who are refractory or resistant to prior chemotherapy, including platinum-based agents and/or paclitaxel.
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PMID:Efficacy and safety of topotecan in the treatment of advanced ovarian carcinoma. 912 38


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