Mechanismrasfd Anticancer Drug Discovery

Although cytotoxicity assays and animal tumor models still play a critical role in the evaluation of lead compounds and selection of development candidates, mechanism-based approaches are increasingly used for initial detection of leads and to guide synthetic efforts. Specific biochemical assays can be used to discover and develop cytotoxic drugs which work by mechanisms similar to those of established anticancer drugs; e.g., production of DNA damage, inhibition of nucleic acid biosynthesis, or interference with tubulin function. Such approaches are also being employed to identify lead compounds which selectively interfere with the expression of oncogenes or the function of oncogene products demonstrated to play a role in the malignant phenotype.

Topoisomerase Inhibitors - Among mechanism-based approaches to anticancer drug discovery, the design and synthesis of topoisomerase inhibitors has received a great deal of attention recently. Many of the clinically important anticancer agents marketed at present appear to work by inhibiting topoisomerase II, an enzyme linked to cellular proliferation (60). Camptothecin and its close analogs are the only known specific inhibitors of topoisomerase I, and derivatives are currently under development. Because toxicities of camptothecin could be related to its poor water-solubility, two groups have concentrated on introducing polar side groups to the alkaloid so as to facilitate solubility while maintaining inhibition of topoisomerase I. CPT-11 (22) appears to be a water-soluble prodrug that hydrolyzes to an active enzyme inhibitor in vivo: SK&F 104864 (24) is a water-soluble derivative of camptothecin that retains potent topoisomerase I inhibition. Both 23 and 24 demonstrate a broad spectrum and high degree of activity in murine and human tumor xenograft models and are in early clinical trial (61,62). The water-insoluble analog, 9-aminocamptothecin (25), has recently been reported to have striking activity in human colon cancer xenografts in mice (63).

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