CAMPTOTHECIN ANALOGS IN THE TREATMENT OF NONSMALL 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/m(2) 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/m(2), was found to be 60 mg/m(2). Dose limiting toxicities were diarrhoea and leukopenia. Interestingly, responses were observed in half of the patients. CPT-11 has been also combined in Phase I studies with etoposide. Due to severe neutropenia, G-CSF had to be given concomitantly to this combination chemotherapy in order to allow the administration of effective doses of both agents. Different mechanisms of resistance to camptothecin analogs have already been identified including topoisomerase alteration and P-Glycoprotein. In preclinical models topoisomerase I inhibitors have shown interesting synergistic activity when combined with topoisomerase II inhibitors, cisplatin, alkilators and radiation. These combinations are presently undergoing clinical evaluation.