| ABSTRACT: |
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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)
identifying and validating predysplastic and early dysplastic lesions that
can be used instead of cancers as endpoints for measuring chemopreventive
activity; (b) identifying and testing candidate agents based on
considerations 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 article
discusses 22 drugs and three drug combinations which have reached an
advanced stage of development as chemopreventive agents. The first
generation of drugs are the most advanced, now being in Phase II and Phase
III clinical trials. These drugs include several retinoids [vitamin A,
13-cis-retinoic acid, all-trans-N-(4-hydroxyphenyl)retinamide], calcium,
beta-carotene, tamoxifen, and finasteride. The second generation drugs are
those in Phase I clinical trials. From most to least advanced, these drugs
are 2-difluoromethylornithine, sulindac, piroxicam, oltipraz,
N-acetyl-I-cysteine, aspirin, ibuprofen, carbenoxolone, 18
beta-glycyrrhetinic acid, and the combination of 2-difluoromethylornithine
with piroxicam. The third generation includes agents with significant
evidence of chemopreventive activity in animal models. These agents are
now in preclinical toxicity testing. They are S-allyl-I-cysteine,
phenhexyl isothiocyanate, curcumin, ellagic acid, fumaric acid,
fluasterone, and the combinations of
all-trans-N-(4-hydroxyphenyl)retinamide with oltipraz and
all-trans-N-(4-hydroxyphenyl) retinamide with tamoxifen. |