Mechanisms of cancer chemopreventive agents: a perspective.

A fundamental question addressed by drug development programs is how agents being tested function on a molecular level. Using resveratrol, curcumin and EGCG as examples, it is clear that a definitive mechanism of action for cancer chemopreventive agents is not available despite decades of exhaustive research. This is profoundly evident based on the myriad of biological responses that have been observed at the cellular level, and even more overwhelming when considering gene expression data that are now available. The situation is confounded further when chemopreventive agents are used in combination, even though superior clinical responses are anticipated. The best hope for delineating tangible, meaningful mechanisms resides in the use of complex physiological systems and computer models to decipher the most critical pathways that are appropriate for targeting with chemopreventive agents, their analogues, and combination treatments. Definitive answers concerning clinical efficacy are only available through human trials. Given the enormity of these tasks, together with the urgency of continuing the fight against cancer, it is adequate to move ahead with chemopreventive drug development on a semi-empirical basis, bearing in mind the importance of limiting toxic side effects.