| SOURCE: |
|
Non-serial; Anticarcinogenesis and Radiation Protection, 4th
International Conference: Mechanisms, Biomarkers, Molecular Diagnostics
and Preventive Strategies. April 18-23, 1993, Baltimore, Maryland, p. 63,
1993.: 1993 UI: 94699779 |
| ABSTRACT: |
|
Our chemoprevention drug development program has the goal of
identifying safe and effective chemopreventive agents for clinical use.
The program is an applied drug development science effort with clinical
trials as the endpoint. Several distinctive strategies are pursued in
developing chemopreventive agents: (1) identifying and validating
predysplastic and early dysplastic lesions that can be used instead of
cancers as endpoints for measuring chemopreventive activity, (2) basing
identification and testing of candidate agents on considerations of
mechanisms of action, (3) evaluating combinations of agents with potential
for maximizing efficacy and minimizing toxicity, and (4) applying a
systematic methodology for identifying and ranking candidate agents at
each stage of development to insure discovery of the best agents and most
effective use of available resources. In the program, twenty-two drugs and
three drug combinations have reached an advanced stage of development as
chemopreventive agents. The first generation of drugs are the furthest
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 (4-HPR)], 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 (DFMO), sulindac, piroxicam, oltipraz,
N-acetyl-l-cysteine, aspirin, ibuprofen, carbenoxolone, 18
beta-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-l-cysteine, phenbexyl
isothiocyanate, curcumin, ellagic acid, fumaric acid, fluasterone, and the
combinations of 4-HPR with oltipraz and 4-HPR with tamoxifen. |