Multiagent chemopreventive agent combinations.

Cancer chemoprevention is a new discipline whose foundation rests upon epidemiologic evidence suggesting that dietary components such as beta-carotene, vitamin E, calcium and selenium may be inhibitors of carcinogenesis. Over the last decade, as molecular and biochemical mechanisms of the carcinogenesis process have been elucidated, the rationale of combining chemopreventive agents to target multiple pathways has strengthened. The process of identifying potential synergistic combinations of chemoprevention agents should be based upon a systematic process of preclinical development in vitro followed by testing in animal models of carcinogenesis. Surrogates of anticarcinogenesis effects might include biochemical, molecular and pathologic assessment of tissue from animal carcinogenesis models. If evidence of chemopreventive effect is found in animal models, systematic studies in humans are indicated. These studies should include a careful Phase I trial to describe optimal chemoprevention doses for all agents being tested in combination followed by Phase II trials to assess efficacy upon carcinogenesis biological and pathological surrogates.