Use of aflatoxin adducts as intermediate endpoints to assess the efficacy of chemopreventive interventions in animals and man.
Clinical cancer prevention studies that use disease as an endpoint are of necessity, large, lengthy, and extremely costly. Development of the field of cancer chemoprevention is being accelerated by the application of intermediate markers to preclinical and clinical studies. Sensitive and specific analytic methods have been developed for detecting and quantifying levels of covalent adducts of aflatoxins with cellular DNA and blood proteins at ambient levels of exposure. Such biomarkers can be applied to the preselection of exposed individuals for study cohorts, thereby reducing study size requirements. Levels of these aflatoxin-DNA and albumin adducts can be modulated by chemopreventive agents such as oltipraz and chlorophyllin in experimental models. Overall, a good concordance is seen between diminution of biomarkers and reductions in tumor incidence and/or multiplicity in these settings. Thus, these markers can also be used to rapidly assess the efficacy of preventive interventions. However, the successful application of these biomarkers to clinical prevention trials will be dependent upon prior determination of the associative or causal role of the marker to the carcinogenic process, establishment of the relationship between dose and response, and appreciation of the kinetics of adduct formation and removal. The general approach that has been utilized for the development, validation and application of aflatoxin-DNA and protein adduct biomarkers to cancer chemoprevention trials is summarized.
Kensler
T W
TW
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA. tkensler@jhsph.edu
Groopman
J D
JD
Roebuck
B D
BD
D000348:Aflatoxins / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015415:Biomarkers; D018736:DNA Adducts; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control; D011446:Prospective Studies
D000348:Aflatoxins; D016588:Anticarcinogenic Agents; D015415:Biomarkers; D018736:DNA Adducts