PHARMACOLOGY OF CAMPTOTHECIN AND ITS DERI VATIVES

20 (S) Camptothecin was discovered in the early 60's as a result of th e intensive screening of natural products by the NCI. Camptothecin lac tone was poorly water soluble and,vas administered as the sodium sale in phase I trials. Despite some encouraging responses in early studies , continued evaluation of this compound revealed severe and unpredicta ble toxicities such as haemorrhagic cystitis and diarrhoea. The revers ible opening of the lactone ring of a camptothecin is pH-dependent and yields a ring-opened carboxylate form wich has greatly reduced activi ty in vivo and in vitro. Under physiological conditions, the carboxyla te farm predominates, buy the exact position of this equilibrium in vi vo also depends on others factors such as protein-binding and differen tial metabolism and elimination. The site of action of camptothecin is a complex formed by the nuclear enzyme topoisomerase I and DNA, which represents a novel target for cancer chemotherapy. The principal role of topoisomerase I is the relaxation of DNA required for transcriptio n and replication. The transient covalent complexes formed by the link ing of the enzyme and the 3' extremity of a nicked DNA strand are stab ilised in the presence of camptothecin and involved in collisions with replication forks. The ensuing arrest of the fork is accompanied by t he generation of permanent double-strand breaks which are thought to b e responsible for the antiproliferative properties of camptothecin. Th e acquisition of resistance to camptothecin in cell culture appears, i n general, to be due to a reduction in content and activity of topo-is omerase I. Single-point mutations of the gene of the enzyme have been detected in a number of these resistant variants. Camptothecin appears to be a poor substrate of P-glycoprotein and its intracellular accumu lation is not appreciably reduced in cells expressing the multidrug-re sistant phenotype. Several water soluble and active derivatives of cam ptothecin have been synthetized of which CPT-11 and topotecan are the most advanced in clinical trials. These compounds represent two differ ent approaches to the problem of the poor water solubility of camptoth ecin lactone. CPT-11 is a soluble prodrug wick is converted in vivo to the highly active SN-38, whereas topotecan itself is water-soluble du e to the presence of a tertiary amine substitution wich is charged at physiological pH. These two compounds present different pharmacologica l properties in the clinical setting.