| ABSTRACT: |
|
A primary goal of the National Cancer Institute's Chemoprevention
Program is the development of safe and effective chemoprevention drugs.
The means to attain this goal is primarily via an applied drug development
science program, with clinical trials as the endpoint. Twenty-two drugs
and three drug combinations have reached an advanced stage of development
in the Chemoprevention Program. The first generation of drugs are the
furthest advanced, now being in Phase II and Phase III clinical trials.
These drugs include several retinoids (retinol, 13-cis-retinoic acid,
all-trans-N(4-hydroxyphenyl)retinamide), calcium, B-carotene, tamoxifen,
and finasteride. The second generation drugs are those in Phase I clinical
trials and include 2-difluoromethylornithine, sulindac, piroxicam,
oltipraz, N-acetyl-1-cysteine, aspirin, ibuprofen, carbenoxolone,
B-glycyrrhetinic acid, and the combination of DFMO 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 cysteine, phenhexyl
isothiocyanate, curcumin, ellagic acid, fumaric acid, fluasterone, and the
combinations of 4-HPR with oltipraz and 4-HPR with tamoxifen. This
research will soon begin to yield practical applications for the reduction
of cancer incidence. However, the time and resources required to carry out
full clinical evaluations of the reduction of cancer incidence by
chemopreventive agents has led the Chemoprevention Program to begin
expanding the role of Phase II clinical studies and preclinical research
on markers in predysplastic and dysplastic tissue as endpoints for
evaluation of chemopreventive agents. A brief discussion of the mechanism
of action of the promising agents, the most promising intermediate
endpoint biomarkers, and cohorts for phase II trials are presented. |