Cancer chemoprevention by dietary constituents: a tale of failure and promise.
Although the results of clinical intervention trials of beta-carotene to prevent lung cancer, and of dietary augmentation with fibre or fruit and vegetables to reduce the occurrence of colonic polyps have so far been negative, a structured path for the development of diet-derived constituents as cancer chemopreventive agents is emerging. Putative agents are identified on the basis of epidemiological and preclinical mechanistic studies. Some examples of promising diet-derived chemopreventive agents are folate, curcumin, genistein, and tea catechins. Long-term supplementation of the diet with folate seems to lower the risk of colorectal cancer. Curcumin in the spice turmeric, genistein in soya, and catechins in tea have tumour-suppressing properties in rodent models of carcinogenesis, and they interfere with cellular processes involved in tumour promotion and progression. Kinases, telomerase, cyclooxygenase-2, triggers of apoptosis, and transcription factors AP1 and nuclear factor kappaB are among the cellular targets. The investigation of dietary constituents should follow a structured design, incorporating parallel preclinical studies of the food source and the isolated agent in terms of efficacy, toxicity, biological mechanisms, and pharmacokinetics. Either the food source or the isolated agent should be selected for further development on the basis of dose-efficacy and toxicity data. Pilot clinical trials on the pharmacokinetics and mechanism-based markers of efficacy of the selected intervention should precede phase I-III development in suitable populations.
Gescher
A J
AJ
Department of Oncology, University of Leicester, UK. ag15@le.ac.uk
Sharma
R A
RA
Steward
W P
WP
D000971:Antineoplastic Combined Chemotherapy Protocols; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000178:diet therapy* / Q000188:drug therapy / Q000517:prevention & control*; D010601:Pharmacology, Clinical; D017211:Treatment Failure