Molecular, cellular, and clinical aspects of the pharmacology of 20(S)camptothecin and its derivatives.

The discovery of the plant alkaloid 20(S)camptothecin (CPT), which displayed potent antitumor activity in preclinical trials, has led to the identification of a novel target of cancer chemotherapy: the nuclear enzyme topoisomerase I. The mechanism by which CPT induces cytotoxicity is the topic of continued research, but appears to be mediated by the stabilisation of transient "cleavable" topoisomerase I-DNA complexes. The pharmacology of CPT and its derivatives is complicated by the apparent requirement of an alpha-hydroxy-delta-lactone ring, which, unfortunately, is hydrolysed reversibly to form inactive carboxylates. Recent research has shown that the extent of hydrolysis in vivo varies between the various derivatives and that this may be an important factor in determining antitumoral activity. In this review, we discuss recent developments in our understanding of the molecular, cellular, and clinical pharmacology of CPT and several of the more promising derivatives.