Camptothecin analogues in the treatment of non-small cell lung cancer.
Camptothecin is a natural product derived from the Oriental tree Camptotheca acuminata which has shown activity in a number of experimental tumors. Its clinical development was halted in the early-70s owing to its unpredictable and formidable toxicities. Two water-soluble camptothecin analogs have been synthesized recently and are currently in clinical trials: topotecan and CPT-11. Camptothecin and its derivatives are unique in that they represent the only family of topoisomerase I inhibitors. Topoisomerase I is a nuclear enzyme which modulates the topological structure of DNA by making transient single-stranded breaks. Pre-clinical studies have shown that CPT-11 and topotecan possess high and broad antitumor activity against a variety of experimental tumors including both non-small cell lung cancer (NSCLC) and small cell lung cancer. Lack of cross-resistance with most classical anticancer agents has been also demonstrated. Phase I studies have identified neutropenia to be the dose-limiting toxicity for topotecan while, for CPT-11, either neutropenia or diarrhoea were dose-limiting. Maximum Tolerated Doses (MTD) of both agents are greatly dependent upon the schedule used. A Phase II Japanese study of CPT-11 in advanced untreated NSCLC has been recently published. Given at the dose of 100 mg/m2 as a 90-min infusion, CPT-11 produced a 32% objective response rate out of 72 assessable untreated patients. Similar studies are in progress with topotecan. The same Japanese group has completed Phase I-II studies on the combination of CPT-11 with cisplatin. The optimal dose of CPT-11, which can be safely combined with cisplatin 80 mg/m2, was found to be 60 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Medical Oncology I, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D019772:Topotecan
D000970:Antineoplastic Agents; D019772:Topotecan; D002166:Camptothecin