| ABSTRACT: |
|
Twenty-two drugs and three drug combinations have reached an advanced
stage of development in the Chemoprevention Program of the National Cancer
Institute. The first generation of drugs now in Phase II and Phase III
clinical trials include several retinoids (retinol, 13-cis retinoic acid,
all trans N-(4-hydroxyphenyl) retinamide), calcium, beta carotene,
tamoxifen, and finasteride. The second generation of drugs now in Phase I
clinical trials include difluoromethylornithine (DFMO), sulindac,
piroxicam, oltipraz, N-acetylcysteine, aspirin, ibuprofen, carbenoxolone,
beta glycyrrhetinic acid, and the combination of DFMO with piroxicam. The
third generation of drugs includes those agents which have significant
chemopreventive activity in animal models and which are in preclinical
toxicity testing. They are S-allylcysteine, phenylhexyl isothiocyanate,
curcumin, ellagic acid, fumaric acid, fluasterone, and the combinations of
4-HPR with oltipraz and 4-HPR with tamoxifen. There is now an intensive
search for intermediate endpoint biomarkers which can be used as endpoints
for less expensive, shorter term clinical trials. A discussion of the
mechanism of action of promising agents and of the most promising
intermediate endpoint biomarkers is presented. |