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)

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

XR11576, a novel phenazine, was developed as an inhibitor of both topoisomerase I and II. This study characterized the ability of XR11576 to inhibit both enzymes, and determined its in vitro and in vivo antitumor efficacy against a number of murine and human tumor models. XR11576 was a potent inhibitor of purified topoisomerase I and IIalpha, and exhibited similar potency for both enzymes. The compound stabilized enzyme-DNA cleavable complexes indicating that it acted as a topoisomerase poison. The DNA cleavage patterns obtained with XR11576 were different from those induced by camptothecin and etoposide, which are topoisomerase I and II poisons, respectively. XR11576 demonstrated potent cytotoxic activity against a variety of human and murine tumor cell lines (IC50=6-47 nM). Its activity profile was comparable to or better than that of many widely used anticancer drugs. Moreover, XR11576 was unaffected by multidrug resistance (MDR) mediated by overexpression of either P-glycoprotein or MDR-associated protein, or by down-regulation of topoisomerase II. The latter property supports the dual inhibitory mechanism of action of the compound. XR11576 exhibited a similar pharmacokinetic profile in mice and rats after either i.v. or p.o. administration. In vivo XR11576 showed marked efficacy against a number of tumors including sensitive (H69/P) and multidrug-resistant (H69/LX4) small cell lung cancer and the relatively refractory MC26 and HT29 colon carcinomas following i.v. and p.o. administration. The efficacy of XR11576 was at least comparable to that of TAS-103, originally proposed as a dual inhibitor of topoisomerase I and II. These results suggest that XR11576 is a promising new antitumor agent with oral and i.v. activity, and warrants further development.
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PMID:In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II. 1191 37

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU). the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen 1, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.
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PMID:Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. 1191 83

Small cell lung cancer continues to recur and claim the lives of most of its victims. Thus, management of the patient with recurrent disease remains an active area of research. This review provides an update of clinical research experience over the past decade with relatively new conventional cytotoxins in this setting, such as the topoisomerase I inhibitors and the taxanes. Additionally, novel molecular targeted approaches with specific relevance for small cell lung cancer are discussed.
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PMID:Recurrent small cell lung cancer: update. 1263 91

F 11782 is a novel epipodophyllotoxin that targets eukaryotic topoisomerases and inhibits enzyme binding to DNA. While F 11782 has not been found to stabilize either topoisomerase I or topoisomerase II covalent complexes, drug treatment appears to result in DNA damage. F 11782 has also been shown to inhibit the DNA nucleotide excision repair (NER) pathway. Bisdioxopiperazine-resistant small cell lung cancer (SCLC) OC-NYH/Y165S and Chinese hamster ovary (CHO) CHO/159-1 cells having functional Y49F and Y165S mutations in the topoisomerase II alpha isoform were both resistant to F 11782. The catalytic activity of purified human Y50F and Y165S mutant topoisomerase II alpha (Y50F in the human protein corresponds to Y49F in the CHO protein) was likewise resistant to the inhibitory action of F 11782. F 11782 was also found to induce a non-covalent salt-stable complex of human topoisomerase II with DNA that was ATP-independent. F 11782 thus displays a dual mechanism of action on human topoisomerase II alpha, reducing its affinity for DNA while also stabilizing the protein bound in the form of a salt-stable complex. Our results suggest that topoisomerase II alpha is a target of F 11782 in vivo, and that F 11782 may act as a novel topoisomerase II poison.
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PMID:A dual mechanism of action of the anticancer agent F 11782 on human topoisomerase II alpha. 1290 27

Substantial improvements in treatment outcome for limited-disease small-cell lung cancer (LD SCLC) have been achieved in the last two decades owing to the introduction of chemotherapy (CHT) consisting of cisplatin and etoposide (PE), and the understanding that thoracic radiation therapy (TRT) is an essential component in improving treatment outcome. In addition, a recent metaanalysis confirmed the importance of prophylactic cranial irradiation (PCI) in general treatment plans for patients who show a complete response to treatment. However, numerous questions remain unanswered regarding this disease. While TRT/PE/PCI is considered to be the standard treatment in the majority of centers worldwide, the emergence of new and effective drugs (e.g., topoisomerase I inhibitors and paclitaxel) for the treatment of LD SCLC will likely affect therapy strategies in the near future. Important issues regarding optimal doses and fractionation regimens, as well as the timing of TRT, remain to be resolved. While most centers currently use b.i.d. fractionation as a result of the Intergroup findings, high-dose standard TRT may also be beneficial. TRT volumes are also considered an important issue, since they likely relate to the incidence of both local failure and toxicity. Finally, the optimization of PCI (total dose, fractionation regimen, and timing) is already under way. The value of surgery is limited to peripheral tumors and poorly responding cancer, and to confirm histology or improve local control and survival.
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PMID:Limited-disease small-cell lung cancer. 1450 48

The overall treatment results in metastatic small-cell lung cancer have not been changed in the last decades. The prognosis of the disease is still poor with median survival times of less than one year and nearly no chance of cure. This article intends to summarize the current status of treatment in m-SCLC and especially focuses on the aspects of choice of drugs and efforts of treatment intensification either by dose escalation or shortening of treatment intervals. Furthermore the currently available data about the activity of newer drugs, including taxanes and topoisomerase I inhibitors are reported. These cytostatic agents widen the therapeutic options in the treatment of SCLC and will hopefully improve the outcome of the patients in the next years.
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PMID:First-line chemotherapy in metastatic small-cell lung cancer (SCLC). 1555 3

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

Gefitinib ("Iressa", ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non-small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan, SN-38, and mitoxantrone resistance, and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells. Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the K(i) value was 1.01 +/- 0.09 micromol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.
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PMID:Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance. 1573 43

In the treatment of extensive disease of small cell lung cancer (ED SCLC) there is an urgent need for more effective and better-tolerated drug regimens. We report on a prospective phase II trial performed to evaluate the efficacy and safety of a platinum-free regimen--containing topotecan and etoposide--in the first-line treatment of ED SCLC. Between December 1999 and July 2001, 28 chemotherapy-naive patients with ED SCLC were recruited; 9 patients had stage IIIB disease and 19 patients had stage IV disease. Based on phase I results, patients received treatment with intravenous topotecan 1 mg/m2 (days 1-5) followed by intravenous etoposide 75 mg/m2 (days 8-10). Treatment courses were repeated every 28 days for a maximum of 6 cycles. A confirmed response rate of 46.4% with 1 complete response (CR) and 12 partial responses (PR) (95% CI=27.5-66.1%) was observed. Stable disease (SD) was observed in 18% of patients. The median time to response was 7.9 weeks (range: 7.7-15.1 weeks) and median survival was 29.9 weeks (range from 3.3 to 91.4 weeks). Main toxicities encountered were haematological with Grade III/IV neutropenia in 2.6/1.5% of courses and Grade III/IV thrombocytopenia in 1.8%/0.7% of courses. These toxicities were manageable and were not associated with clinical sequels. Non-haematological toxicities were generally mild with no Grade III/IV toxicities reported apart from Grade III alopecia. The combination therapy of topotecan and etoposide is active in first-line chemotherapy for patients with ED SCLC. The regimen showed a tolerable safety profile. Since drug scheduling plays a critical role in the combination of topoisomerase I and II inhibitors, concurrent administration of topotecan and etoposide might increase the efficacy.
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PMID:Topotecan and etoposide as first-line therapy for extensive disease small cell lung cancer: a phase II trial of a platinum-free regimen. 1589 10


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