Prostate cancer chemoprevention can be described as the administration of natural products and
pharmaceutical agents that inhibit one or more steps in the natural history of prostatic
carcinogenesis. The principle components of the
chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint
biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade
prostatic intraepithelial neoplasia (HGPIN) to locally invasive
cancer and metastatic disease. Another important target for
chemoprevention is to modulate progression to clinically aggressive disease and to maintain an
androgen-sensitive clinical state and delay the emergence of
androgen resistance. There is a rationale for use of
antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for
chemoprevention of
prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of
drug (
androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic
pharmaceutical and natural products already in clinical development create many opportunities for rational combination
therapy. Several agent classes have a pharmacodynamic basis for combination with
antiandrogens including antiproliferatives,
selective estrogen receptor modulators (
SERMs), proapoptotic
antioxidant micronutrients and selective
cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without
antiandrogens are feasible. It is anticipated that in the future, a selective
COX-2 inhibitor may be combined with other agent classes such as proapoptotic
antioxidant micronutrients,
receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators,
IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense
enzyme in precursors (HGPIN) and
prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and
secondary prevention that can be employed in both short-term developmental (translational) trials for proof of
biologic activity and in intermediate sized longer-term
chemoprevention trials for proof of efficacy against
prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term
biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip
cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted
proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.