Androgen deprivation therapy for prostate cancer chemoprevention: Current status and future directions for agent development

Prostate cancer chemoprevention is defined as the administration of natural and synthetic agents that inhibit greater than or equal to 1 steps in the natural history of prostate carcinogenesis. The goal is to find agents that modulate the progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and systemic disease. Another important goal for chemoprevention is the mainte nance of an androgen-sensitive clinical state and delay of the emergence of androgen independence. There is a strong rationale for androgen deprivatio n therapy (ADT) as a chemoprevention strategy for prostate cancer based on evidence from epidemiologic, experimental, molecular pathophysiologic, and randomized, controlled clinical trials. This includes the fact that HGPIN, the most likely precursor of invasive cancer, is androgen dependent and res ponds to ADT. Although the large, phase-3 Prostate Cancer Prevention Trial (PCPT) of finasteride versus placebo has established the feasibility and ro le of ADT for primary prevention, nevertheless, limitations of the anticipa ted treatment-effect size (eg, 25% reduction) and the potential for selecti on of androgen resistance provide incentive for finding other effective che mopreventive agents. The availability of novel noncytotoxic pharmaceutical and natural products in clinical development create opportunities for impro ving the therapeutic index through the principles of combination therapy. T he emergence of new powerful tools, such as gene chip complementary DNA mic roarrays for multiplex gene expression profiling, will accelerate the ident ification of new molecular targets and the design of rational combinations. Several agent classes have a strong basis for combination with ADT, includ ing antiproliferatives, antioxidant micronutrients (selenium), antiestrogen s, and nonsteroidal anti-inflammatory drugs (selective cyclooxygenase-2 inh ibitors). (C) 2001, Elsevier Science Inc.