DISCOVERY OF CRYPTOPHYCIN-1 AND BCN-183577 - EXAMPLES OF STRATEGIES AND PROBLEMS IN THE DETECTION OF ANTITUMOR-ACTIVITY IN MICE

Historically, many new anticancer agents were first detected in a pres creen; usually consisting of a molecular/biochemical target or a cellu lar cytotoxicity assay. The agent then progressed to in vivo evaluatio n against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decremen ts, dose-schedules, number of groups, etc. However, in most large prog rams involving several hundred in vivo tests yearly, resource limitati ons and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in v ivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by dru g supply, dose-schedule by toxicities encountered, etc. In this flexib le design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active ag ents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both woul d have been missed if they were tested intraperitoneally, the usual dr ug route used in discovery protocols. It is also likely that they woul d have been missed with an easy to execute fixed protocol design, even if injected IV.