Clinical and pharmacological studies on the topoisomerase I inhibitor topotecan

Abstract

During the 1950's the National Cancer Institute (NCI) started a screening program of natural products. Among the thousands of plants analyzed, campto· thecin, a plant alkaloid extract from the Camptotheca acuminata, an oriental tree which is cultivated throughout Asia, was found to be active against L 1210 murine leukemia. In the early 1970's camptothecin underwent clinical testing. Although antitumor activity was observed in patients with colorectal cancer, melanoma and non-small-cell lung cancer further clinical development was precluded because of severe and unpredictable toxicities including, myelosuppression, diarrhea and hemorrhagic cystitis. In the mid 1980's several developments renewed the interest in camptothecin. Firstly, Hsiang et al. identified topoisomerase I as the specific intracellular target of camptothecin. Secondly, overexpressed topoisomerase I level was found in advanced stages of human colon adenocarcinoma and other malignancies but not in normal tissue. This resulted in the development of several semisynthetic camptothecin analogues with more predictable toxicity profiles and consistent antitumor activity. One of these analogues is topotecan (SKF 104864, NSC 609699, (s)-9- dimethylaminomethyl-10-hydroxycamptothecin, Hycamtin®) which in preclinical studies demonstrated broad spectrum antitumor activity (10,11). Phase I studies revealed that topotecan was very well tolerated with generally a brief and noncumulative neutropenia being the dose-limiting toxicity on all schedules (12,13). Major responses were observed in carcinomas of the ovary, lung (both small and non-small), oesophagus and colon. Phase II studies were initiated with a daily x5 schedule based on the fact that most objective responses in phase I studies were observed with this schedule. This thesis includes clinical and pharmacological studies on topotecan which was focused towards the efficacy of the daily x5 schedule in patients with colorectal and ovarian cancer and towards the concept of prolonged exposure to the drug