CHEMOPREVENTIVE DRUG DEVELOPMENT - PERSPECTIVES AND PROGRESS

Chemoprevention drug development has the goal of identifying safe and effective chemopreventive agents for clinical use. Several distinctive strategies are pursued in developing chemopreventive agents: (a) iden tifying and validating predysplastic and early dysplastic lesions that can be used instead of cancers as endpoints for measuring chemopreven tive activity; (b) identifying and testing candidate agents based on c onsiderations of mechanisms of action; (c) evaluating combinations of agents with potential for maximizing efficacy and minimizing toxicity; and (d) applying a systematic methodology for identifying and ranking candidate agents at each stage of development to ensure discovery of the best agents and most effective use of available resources. This ar ticle discusses 22 drugs and three drug combinations which have reache d an advanced stage of development as chemopreventive agents. The firs t generation of drugs are the most advanced, now being in Phase II and Phase III clinical trials. These drugs include several retinoids [vit amin A, 13-cis-retinoic acid, all-trans-N-(4-hydroxyphenyl)retinamide] calcium, beta-carotene, tamoxifen, and finasteride. The second genera tion drugs are those in Phase I clinical trials. From most to least ad vanced, these drugs are 2-difluoromethylornithine, sulindac, piroxicam , oltipraz, N-acetyl-l-cysteine, aspirin, ibuprofen, carbenoxolone, 18 beta-glycyrrhetinic acid, and the combination of 2-difluoromethylorni thine with piroxicam. The third generation includes agents with signif icant evidence of chemopreventive activity in animal models. These age nts are now in preclinical toxicity testing. They are S-allyl-l-cystei ne, phenhexyl isothiocyanate, curcumin, ellagic acid, fumaric acid, fl uasterone, and the combinations of all-trans-N-(4-hydroxyphenyl)retina mide with oltipraz and all-trans-N-(4-hydroxyphenyl) retinamide with t amoxifen.