Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149925 (small cell lung cancer)
 6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan, a soluble semisynthetic derivative of camptothecin, is a specific inhibitor of topoisomerase I and is endowed of potent antiproliferative effect in vitro and in vivo on tumoral cell lines as well as on endothelial cells. Moreover, topotecan is able to interfere with the development of blood vessels in many in vivo experimental models. During the last years, several phase I clinical studies have demonstrated that the five-daily schedule is the most effective for the treatment of neoplastic diseases of children and adults. In particular, the best clinical results have been obtained in patients affected by metastatic ovarian cancer, small cell (SCLC) and non-small cell lung carcinoma (NSCLC), as well as mammary and gastrointestinal neoplasms. High response rates have been observed in myelodysplastic syndromes and myeloma. The clinical effectiveness of topotecan has been also demonstrated in ovarian carcinoma, even after failure of first or second line chemotherapy and in SCLC, where the response rate is 39%, while the percentage decreases up to 7% in case of drug resistance, with a median survival of 5.4 months. Toxicologic profile of topotecan is foreseeable and manageable, and the most frequent and severe toxicity is represented by myelosuppression. Leukopenia and neutropenia, which follow the administration of topotecan, are non-cumulative and self-limiting and unfrequently complicated by infections, whereas non-hematologic toxicities are uncommon and generally of mild-to-moderate degree. Topotecan is under continuous clinical evaluation for the treatment of neoplasms other than those reported above, alone or in combination with antineoplastic drugs in poly-chemotherapeutic protocols.
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PMID:[Preclinical pharmacology and clinical uses of topotecan]. 1078 94

Topotecan, a semi-synthetic derivative of the alkaloid camptothecin is an antitumor drug that like other camptothecin derivatives, targets DNA topoisomerase I, an enzyme that is present in cells in concentration relatively independent of the stage in the cell cycle. Topotecan stabilizes the complex formed between topoisomerase I and DNA, leading to DNA strand breakage and cell death. In accordance with preclinical studies, clinical efficacy of topotecan was documented in ovarian carcinoma, in small cell lung cancer and in childhood solid tumors. Myelosuppression is the dose-limiting toxicity and nonhematologic side effects are generally mild. The activity of topotecan against a number of hematological malignancies is now increasingly exploited as well as its role in high-dose chemotherapy programs with stem cell support. In both lymphoblastic and myeloid acute leukemias, topotecan has been widely utilised both as single agent or associated to other cytostatic drugs with proven efficacy in these diseases. Most of the published phase II studies demonstrated that heavily pre-treated, relapsing patients achieve a high percentage of overall responses with manageable toxicity. In myelodisplastic syndromes and acute myelomonocitic leukemias a recently published study shows positive results for the combination of topotecan and cytarabin. Topotecan seems to preferentially affect the abnormal cytogenetic clones and in patients achieving a complete response, a conversion from an aneuploid to a diploid karyotipe was documented. In non-Hodgkin lymphomas, several schedules have been tested in the phase I setting. When utilized alone and at very low dosage, the drug yielded 15% of objective responses and a lack of extrahematologic toxicity. Of particular interest seems to be the association of topotecan with taxanes that needs to be supported by growth factors. In multiple myeloma Topotecan has been utilized as single agent in heavily pre-treated patients. The obtained results show good activity and again myelosuppression as preminent toxicity. The use of topotecan in high-dose chemotherapy regimens for multiple myeloma has been proposed. The utilization of topotecan in high-dose chemotherapy is one of the newer and more interesting applications. Solid tumors (i.e. ovarian cancer and small cell lung cancer) are actually investigated by many authors, who have indicated that this drug can be used preferentially as a part of diversified programs containing overlimit dosages of different cytostatics. Furthermore, topotecan demonstrated to be an effective drug to mobilize CD34+ cells for autografting. A general conclusion is that topotecan is an interesting addition to the actual chemotherapy scenario, both because of its mechanism of action and its toxicity profile. The present review of the new possibility of utilization, give us the idea that topotecan has activity in several hematologic neoplasias; further investigations in these diseases (i.e., induction treatment, combination chemotherapy) are then warranted. The broad spectrum of antitumor activity and the characteristics of toxicity make it also interesting for use in both the circulating progenitor cell mobilization and in the consolidation phase of high-dose chemotherapy programs.
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PMID:[Topotecan: a new field of use]. 1078 97

The camptothecins are a maturing class of anticancer agents. In this article, we review the pharmacology and antitumor activity of the camptothecin analogues that are approved for clinical use and those investigational agents undergoing clinical evaluation. Camptothecin is a naturally occurring cytotoxic alkaloid that has a unique intracellular target, topoisomerase I, a nuclear enzyme that reduces the torsional stress of supercoiled DNA during the replication, recombination, transcription, and repair of DNA. Topotecan and irinotecan are synthetic analogues designed to facilitate parenteral administration of the active lactone form of the compound by introducing functional groups to enhance solubility. They are now well-established components in the chemotherapeutic management of several neoplasms. Topotecan has modest activity in patients treated previously with ovarian and small cell lung cancer and is currently approved for use in the United States as second-line therapy in these diseases. Preliminary evidence of activity against hematological malignancies is also promising. Irinotecan is a prodrug that undergoes enzymatic conversion to the biologically active metabolite 7-ethyl-10-hydroxy-camptothecin. It is presently the treatment of choice when used in combination with fluoropyrimidines as first-line therapy for patients with advanced colorectal cancer or as a single agent after failure of 5-fluorouracil-based chemotherapy. Encouraging preliminary results suggest that irinotecan may have an increasing role in the treatment of other solid tumors, including small and non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer, and malignant gliomas. Several additional camptothecin analogues are in various stages of clinical development, including 9-aminocamptothecin, 9-nitrocamptothecin, 7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin, exatecan mesylate, and karenitecin. Efforts to further optimize therapeutic effectiveness through drug delivery strategies that prolong tumor exposure to these S phase-specific agents, such as improving oral bioavailability through structure modification and innovative formulation approaches, alternative parenteral dosage forms, and administration schedules, are being actively pursued. Combining camptothecins with other anticancer drugs and treatment modalities, as well as gaining a better understanding of the factors contributing to tumor sensitivity and resistance, continues to be the object of considerable interest.
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PMID:Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. 1189 91

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m2 given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m2 given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m2 of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously over 5 days every 28 days is recommended.
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PMID:Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies. 1219 19

Extensive-stage small cell lung cancer (SCLC) is an aggressive disease with a median survival of approximately 8 months. Although current combination chemotherapy regimens provide high initial tumor response rates, they have not translated into large gains in survival. Topotecan and paclitaxel have nonoverlapping mechanisms of action and are active agents in SCLC. Additionally, these two agents demonstrate in vitro synergy in animal and human tumor models. We investigated the maximum tolerated dose of 3-day topotecan in combination with paclitaxel in previously untreated patients with extensive SCLC. Seventeen patients were enrolled in an open-label, phase I, dose-escalation study and were treated with intravenous paclitaxel 135-175 mg/m(2) over 1 hour on day 1, followed by intravenous topotecan 1.25-1.5 mg/m(2) over 30 minutes on days 1-3 of a 21-day course. Sixty-nine courses of therapy were administered with no delays due to hematologic toxicity. Prophylactic hematologic support was required for 24% of patients. The topotecan/paclitaxel combination was well tolerated, with 24%, 12%, and 6% of patients experiencing grade 3/4 neutropenia, anemia, or thrombocytopenia, respectively. Dose-limiting neutropenia was seen in three of five patients treated with topotecan 1.5 mg/m(2) and paclitaxel 175 mg/m(2). Therefore, topotecan 1.5 mg/m(2) with paclitaxel 135 mg/m(2) was determined to be the maximum tolerated dose. Of the 17 evaluable patients, 53% achieved a partial response and 18% achieved stable disease. In summary, we have identified a regimen of topotecan 1.5 mg/m(2) and paclitaxel 135 mg/m(2) that was well tolerated and active in this patient group. Additional studies of topotecan and paclitaxel at these dose levels are needed to fully elucidate the efficacy of this combination in extensive SCLC.
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PMID:Phase I study of paclitaxel and topotecan for the first-line treatment of extensive-stage small cell lung cancer. 1260 34

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.
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PMID:Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430). 1466 44

Topotecan is the only single-agent therapy approved by the U.S. Food and Drug Administration for the treatment of patients with recurrent small cell lung cancer (SCLC). Poor performance status (PS) at the time of relapse can hinder the ability of a patient to tolerate second-line chemotherapy. To investigate the feasibility of topotecan in the treatment of relapsed SCLC patients with PS 2 scores, we retrospectively analyzed data from five clinical trials that included 479 patients who were treated with single-agent topotecan at a dose of 1.5 mg/m2/day on days 1-5 of a 21-day course. Of these patients, 381 had a PS 0 or 1 and 98 had a PS 2. Topotecan was well tolerated by both patient groups. Hematologic toxicities were generally manageable, and neutropenia was noncumulative. With the exception of grade 3/4 anemia, the incidences of severe hematologic toxicities were not statistically different between the two groups. The nonhematologic toxicity profiles were also similar in the two patient groups. Treatment provided similar benefits, including antitumor response rates and symptom palliation, in PS 0/1 and PS 2 patients. As expected, the median overall survival time was shorter in patients with worse PS scores; the median overall survival times were 36.3 weeks, 25.4 weeks, and 16 weeks for PS 0, PS 1, and PS 2 patients, respectively. In conclusion, treatment with topotecan is feasible and well tolerated in patients with relapsed SCLC with suboptimal PS scores.
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PMID:Topotecan in the treatment of relapsed small cell lung cancer patients with poor performance status. 1504 21

Small cell lung cancer (SCLC) is generally sensitive to first-line chemotherapy, but limited disease often recurs and extensive disease is rarely curable. The most common first-line therapy regimen is cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) plus etoposide (Etopophos; Bristol-Myers Squibb)--PE, which is associated with overall response rates >80% in patients with limited SCLC. Although it is associated with median survival times of approximately 18-20 months for limited disease, PE yields median survival times of only approximately 8-12 months in patients with extensive disease, and symptom palliation becomes the primary therapeutic goal. The toxicities of PE may undermine quality of life and leave patients more susceptible to adverse events during subsequent therapies. Topotecan (HYCAMTIN; GlaxoSmithKline; Philadelphia, PA), an established treatment for recurrent SCLC, is being investigated in the first-line setting because of its novel mechanism of action; predictable, noncumulative, and manageable toxicities; and potential synergy with other active agents. Several recent phase II trials have generated promising results for topotecan-based combination regimens, including topotecan/paclitaxel (TAXOL; Bristol-Myers Squibb) (overall response rates 45%-100%), topotecan/etoposide (overall response, 95%), and topotecan, paclitaxel, and platinum agent triplets (overall response rates 51%-93%). The most frequent serious toxicity associated with these regimens was reversible and noncumulative neutropenia, which was generally manageable with supportive care. Additional clinical trials to investigate topotecan-based combination regimens and confirm their role in the first-line treatment of SCLC are under way.
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PMID:Topotecan in the first-line treatment of small cell lung cancer. 1561 48

Non-small cell lung cancer (NSCLC) is an aggressive disease that is generally resistant to chemotherapy. As a result, the prognosis for patients with NSCLC is poor. Currently, platinum-based regimens are the standard of care for patients with advanced NSCLC. However, these regimens are associated with severe and often cumulative hematologic and nonhematologic toxicities, limiting dose intensity. Therefore, novel chemotherapeutic agents and combination regimens may improve the outcome for these patients. A variety of new agents and combinations have been investigated in the treatment of NSCLC. However, to date, no clearly superior single-agent or combination regimen has emerged. Topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA), a topoisomerase I inhibitor, is currently approved for the treatment of patients with relapsed small cell lung cancer (SCLC) and is associated with manageable, noncumulative, hematologic toxicities. In addition, topotecan demonstrates a favorable nonhematologic tolerability profile compared with agents currently used in the treatment of patients with NSCLC. The success of topotecan in patients with SCLC has made it an attractive option in the NSCLC setting. Topotecan-based combination regimens in the first-line treatment of NSCLC have demonstrated promising antitumor activities with favorable toxicity profiles. Many topotecan combination regimens have induced stable disease, a response that may offer meaningful clinical benefit in the palliative treatment of patients with advanced disease. Topotecan plus gemcitabine (Gemzar; Eli Lilly and Company; Indianapolis, IN) and single-agent topotecan may be particularly appropriate for patients in the second-line setting, in which palliation of symptoms is an important outcome of chemotherapy. Herein, the future role of topotecan in the first- and second-line treatment of NSCLC and the potential role of resistance mechanisms obtained from in vivo dose-response studies in designing future combination regimens are discussed.
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PMID:Update on the role of topotecan in the treatment of non-small cell lung cancer. 1561 49

We examined how the effect of topotecan is modulated by transient hypoxia in three different tumor lines, Lewis lung carcinoma (LLC), U87 human glioblastoma and DMS273 human small cell lung cancer. Four groups of tumor bearing mice were treated with saline or a single dose of topotecan, immediately followed by 6-h or 72-h exposure to a hypoxic environment (10% O(2)) or normal air. Topotecan + hypoxia resulted in significantly greater suppression of tumor growth than normoxic topotecan or hypoxia alone. Correspondingly, the sensitivity of LLC cells to topotecan in a clonogenic survival assay was significantly higher under hypoxia. This effect of hypoxia was not a general phenomenon, since the tumor growth inhibitory effect of the alkylating agent cisplatin was not changed by hypoxic environment. In a parallel series of in vitro experiments, cell cultures were exposed to hypoxia (0.1% or 0.7% O(2)) in a hypoxic chamber or normoxia for 24 h. We found a dose-dependent downregulation of HIF-1alpha by topotecan (30-270 nM). The hypoxic upregulation of Glucose transporter-1 and VEGF secretion to the culture medium was inhibited by the addition of topotecan, while doses up to 270 nM had no effect on VEGF under normoxia. VEGF protein levels in tumors were also reduced by topotecan. These data show that the effect of topotecan is increased by transient hypoxia, and this may be a direct effect on the ability of cells to survive under hypoxia as well as an antiangiogenic effect, mediated through the HIF-1 inhibitory effect of topotecan.
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PMID:Augmenting tumor sensitivity to topotecan by transient hypoxia. 1589 31


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