Carcinogenesis Advance Access published online on September 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgl174
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1 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, 97339; Current address: Carcinogen-DNA Interactions Section, LCCTP, Center for Cancer Research, Building 37, Room 4032, National Cancer Institute, Bethesda, Maryland 20892
* To whom correspondence should be addressed. Chlorophyllin (CHL) is a potent antimutagen in vitro, an effective anticarcinogen in several animal models, and significantly reduced urinary biomarkers of aflatoxin B1 (AFB1) exposure in a human population. Here we report an expanded analysis of CHL chemoprevention using the potent environmental hydrocarbon dibenzo[a,l]pyrene (DBP). A dose-dose matrix design employed over 12,000 rainbow trout to evaluate the interrelationships among dietary carcinogen dose, anti-carcinogen dose, carcinogen-DNA adduct levels at exposure, and eventual tumor outcome in two target organs. Included was an evaluation of the pharmaceutical CHL preparation (Derifil) used previously in a study of individuals chronically exposed to AFB1. CHL was pre-, co-, and postfed at doses of 0-6000 ppm and co-fed with DBP at doses of 0-371.5 ppm for four weeks. This protocol generated a total of 21 dose-dose treatment groups, each evaluated with three or more replicates of 100 animals. The DBP-only treatment produced dose-responsive increases in liver and stomach DBP-DNA adducts, whereas increasing CHL co-treatment doses produced successive inhibition in liver (49-83%) and stomach (47-75%) adduct levels at each DBP dose examined. Ten months later the remaining 8711 trout were necropsied. DBP treatment alone produced a logit incidence vs. log [DBP] dose-response curve in stomach that was linear; CHL co-treatment provided dose-dependent tumor inhibition which ranged from 30-68% and was predictable from the adduct response. The Derifil CHL preparation was also found to effectively reduce DNA adduction and final tumor incidence in stomach (as well as liver), with a potency compatible with its total chlorin content. Liver tumor incidence in the DBP-only groups appeared to plateau near 60%. At DPB doses of 80 ppm and lower, increasing CHL doses generally reduced tumor incidence and multiplicity consistent with early DNA adducts as biomarkers. At 225 ppm DBP, however, very high CHL doses were required to reduce tumor incidence below the 60% plateau. Apparent tumor multiplicity in liver was neither linear nor monotonic with DBP dose, but peaked at 80 ppm DBP and declined at 225 ppm, where it was increased by all but one CHL dose. Consequently, the effects of a given CHL dose and the predictivity of DNA adducts as biomarkers were highly dependent on carcinogen dose. These results underscore the critical importance of establishing carcinogen-end point dose-response relationships in chemoprevention studies, and the potential otherwise for misleading interpretations in chemoprevention studies carried out solely at high carcinogen dose. (Supported by USPHS grants ES03850, ES00210, CA34732, ES07060, ES06052 and ES03819.)
Received April 17, 2006
Revised August 9, 2006
Accepted September 1, 2006
CANCER PREVENTION
The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between, dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers, and final tumor outcome
M. Margaret Pratt 1 *, Ashok P. Reddy 2, Jerry D. Hendricks 3, Cliff Pereira 4, Thomas W. Kensler 5, and George S. Bailey 3
2 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, 97339; Current address: Center for Biomarker Discovery, Clinical Genomics & Proteomics Program, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97201
3 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, 97339
4 Department of Statistics, Oregon State University, Corvallis, Oregon, 97339
5 Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 21205
M. Margaret Pratt, E-mail: prattm{at}mail.nih.gov
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