UMLS:C0149925 - FACTA Search

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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 (Hycamtin(R)) is a topoisomerase I inhibitor which demonstrated a wide spectrum of antitumor activity in preclinical models. During phase I assessment, evidence of activity was most promising when topotecan was administered on an i.v. daily x 5 schedule and a dose of 1.5 mg/m(2)/day was selected for phase II/III evaluation. This regimen has been shown to have activity in a wide range of tumor types, including recurrent ovarian cancer, relapsed small cell lung cancer (SCLC), non-small cell lung cancer, colon cancer, and breast cancer, as well as hematological malignancies. In patients with ovarian cancer who had failed standard therapy, topotecan demonstrated response rates of 13% to 25%, with median times to progression of 12 to 19 weeks. Compared with paclitaxel, the response rates were similar, 20.5% and 14.0%, respectively, as were median times to progression (19 weeks for topotecan versus 15 weeks for paclitaxel). Results in recurrent SCLC have also been encouraging. Patients sensitive to previous chemotherapy have shown response rates of 19% and 39%, and even patients resistant or refractory to previous chemotherapy have had responses of 3% and 7%. Survival ranged from 20 weeks in refractory disease to 12 months in both sensitive and resistant/refractory disease combined. The safety profile of topotecan is well established. The principal toxicity is noncumulative myelosuppression, and serious sequelae are uncommon. Nonhematological toxicities are generally mild. The use of topotecan in combination regimens is promising, although clinical results are currently at an early stage. To date, topotecan has demonstrated its activity in recurrent ovarian cancer and offers a valuable addition to treatment options in relapsed SCLC.
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PMID:Topotecan: An Oncologist's View. 1038 30

Treatment for small cell lung cancer has not improved substantially in the past 15 years. Some advances are being made in supportive care and by use of more intense concurrent thoracic radiotherapy. New agents such as the taxanes and the topoisomerase I inhibitors hold promise and are currently in phase III evaluation. The question whether dose intensity can improve the outcome of patients with small cell lung cancer has been raised for many years. Improving supportive care enhances our ability to test this question more thoroughly. This paper reviews the historical and current experience using high-dose therapy with hematopoietic stem cell support for the treatment of small lung cancer. Future directions are identified.
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PMID:Hematopoietic stem cell transplantation for small cell lung cancer. 1061 26

Gemcitabine (2'-2'-difluorodeoxycytidine, dFdC), an analog of deoxycytidine, is an antineoplastic agent with clinical activity against several types of cancer. Irinotecan (CPT-11), a topoisomerase I inhibitor, is a drug with a broad spectrum of anticancer activity. Since these drugs have different mechanisms of cytotoxicity and dose-limiting toxicity profiles, preclinical combination studies were performed on the MCF-7 breast cancer and the SCOG small cell lung cancer (SCLC) cell lines. Both gemcitabine and CPT-11 as single agents were effective growth inhibitors in these cell lines. Isobologram analysis revealed for the first time that the combination of these drugs exerted synergy over a wide range of concentrations in MCF-7 and SCOG cells. Moreover, combination index (CI) analysis revealed that at low concentrations, combinations of gemcitabine and CPT-11 show a synergistic growth inhibitory effect on MCF-7 cells. However, in SCOG cells CI analysis showed synergy at concentrations of gemcitabine and CPT-11 greater than 1 microM but antagonism at combination concentrations less than 1 microM. These preclinical cytotoxicity data provide an experimental basis for conducting clinical trials using combinations of gemcitabine and CPT-11, especially in patients with breast and lung cancers.
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PMID:Synergistic effect of gemcitabine and irinotecan (CPT-11) on breast and small cell lung cancer cell lines. 1069 72

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

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.
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PMID:Therapeutic advances in small cell lung cancer. 1106 Jun 96

CPT-11, developed by Yakult Honsha, has achieved the position of standard chemotherapy for colorectal cancer in the United States and in Western countries because CPT-11 + 5FU + LV showed survival benefit compared with 5FU-LV in two randomized controlled trials. CPT-11 has been distributed to almost all countries. In Japan, combination therapy of CDDP + CPT-11 was significantly superior to CDDP-VP-16 in the treatment of extensive disease small cell lung cancer. This combination is also active against non-small cell lung cancer. Daiich Pharmaceutical Co. developed a more active nonmasked form of camptothecin derivative, DX-8915f. The phase I study of a new camptothecin inhibitor, DX-8915f, has just been completed. The new topoisomerase I inhibitors of indolocarbazol derivatives, NB-506 and J107088, developed by Banyu Co., have strong antitumor activity and a wide therapeutic ratio. The phase I trial of J107088 is currently ongoing in the United States and Japan. These do not show any cross-resistance to MDR drugs.
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PMID:Preclinical and clinical trials of topoisomerase inhibitors. 1119 28

Among the numerous clinical regimens used in combination chemotherapy, synergy is particularly marked in combinations containing cisplatin (CDDP). However, the clinical use of CDDP is sometimes limited due to its nephrotoxicity. Nedaplatin (NDP) is a second-generation platinum complex with reduced nephrotoxicity that may substitute for CDDP or even surpass it for use in combination with other drugs. We investigated the effects of combinations of NDP and other anticancer drugs on the growth of human small cell lung cancer cells (SBC-3) and non-small cell lung cancer cells (PC-14) using a three-dimensional analysis model. Among the combinations tested, the combination of NDP and irinotecan (CPT-11) showed the most marked synergistic interaction, and the synergism has also been observed against PC-14 cells. With regard to treatment schedule, a remarkable synergistic interaction was produced by concurrent exposure to NDP and CPT-11. On the other hand, sequential exposure to the two drugs led only to additivity. To analyze the interaction between the drugs, the effect of NDP on the 7-ethyl-1-hydroxy-CPT (the active form of CPT-11)-induced inhibitory effect on DNA topoisomerase I was examined. The topoisomerase I-inhibitory effect of 7-ethyl-1-hydroxy-CPT was enhanced 10-fold in the presence of NDP at microgram/milliliter concentrations. These biochemical interactions might be responsible for the synergistic interaction between NDP and CPT-11. These results suggest that the combination of NDP with CPT-11 may be clinically useful for the chemotherapy of lung cancer.
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PMID:In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction. 1120 10

Inhibitors of topoisomerases are widely used in the treatment of cancer, including inhibitors of topoisomerase I (camptothecin analogs such as irinotecan and topotecan) and topoisomerase II (etoposide and doxorubicin). The novel bis-phenazine, XR5944, is a joint inhibitor of topoisomerase I and II as shown by the stabilization of topoisomerase-dependent cleavable complexes. XR5944 demonstrated exceptional activity against human and murine tumor cells in vitro and in vivo. In a range of cell lines XR5944 (IC50 0.04-0.4 nM) was significantly more potent than TAS-103, originally proposed as a joint topoisomerase I and II inhibitor, as well as agents specific for topoisomerase I or II (topotecan, doxorubicin and etoposide). In addition, XR5944 was unaffected by atypical drug resistance and retained significant activity in cells overexpressing P-glycoprotein or multidrug resistance-associated protein. Antitumor efficacy of XR5944 was demonstrated in human carcinoma xenograft models (H69 small cell lung cancer and HT29 colon). In the HT29 model, which is relatively unresponsive to chemotherapy, XR5944 (15 mg/kg i.v., q4dx3) induced tumor regression in the majority of animals (six of eight), whereas TAS-103, dosed at its maximum tolerated dose (45 mg/kg i.v., q7dx3), only induced a delay in tumor growth compared with control animals. In the H69 model, low doses of XR5944 (5 mg/kg i.v., qdx5/week for 2 weeks or 10-15 mg/kg i.v., q4dx3), induced complete tumor regression in the majority of animals. In contrast, topotecan (20 mg/kg i.v., q4dx3) or etoposide (30 mg/kg i.v., q5dx5) only slowed the tumor growth rate. These studies show that XR5944 is a highly active novel anticancer agent that is well tolerated at efficacious doses.
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PMID:Antitumor activity of XR5944, a novel and potent topoisomerase poison. 1133 93

7-ethyl-10-[4-(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, a topoisomerase I (topo I) inhibitor, is one of the most active agent against lung cancer, and its radiosensitizing effect has been reported recently. We evaluated a combination in vitro effect of irradiation and 7-ethyl-10-hydroxy-CPT (SN-38), an active metabolite of 7-ethyl-10-[4- (1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, on a human small cell lung cancer cell line (SBC-3) and its cisplatin-resistant subline (SBC-3/CDDP). Growth-inhibitory effects of irradiation with or without SN-38 were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A modified isobologram method was used to evaluate the treatment interaction. The combination of irradiation and SN-38 showed a synergistic inhibitory effect on the growth of SBC-3/CDDP despite its cross-resistance to irradiation and SN-38. In contrast, the same combination showed only an additive effect on the growth of parental SBC-3 cells. There was no significant difference in topo I protein expression between these two cell lines. In SBC-3 cells, topo I catalytic activity was suppressed by 4 Gy of irradiation, without a decrease of nuclear topo I protein, whereas the exposure of SBC-3 cells to 1 microM SN-38 subsequent to irradiation showed no remarkable additional effects on both topo I activity and protein content. On the other hand, in SBC-3/CDDP cells, topo I activity was unchanged by irradiation, but the subsequent exposure to SN-38 gave rise to a decrease in topo I activity, which was accompanied by a significant decrease in the topo I protein content (P = 0.02). These observations may indicate that SN-38 induces sequestration of topo I onto DNA in radiation-treated SBC-3/CDDP cells and suggest that the synergistic effect of irradiation and SN-38 in SBC-3/CDDP cells was considered attributable to DNA repair-related enhanced recruitment of topo I onto the damaged DNA.
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PMID:Synergistic effects of topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin, and irradiation in a cisplatin-resistant human small cell lung cancer cell line. 1180 71

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