Evaluation of Dietary Dehydroepiandrosterone for Chemoprotection against Tumorigenesis in Premalignant Colonie Epithelium of Male F344 Rats1

EpidemiolÃ3gica! and experimental studies suggest that dehydroepiandrosterone (DHEA), an adrenal cortical steroid, has chemoprotective properties. Rat colonie epithelium which had been induced to a premalignant state by the colonie carcinogen azoxymethane was used as a model for patients at high risk of colorectal carcinoma, and the efficacy of dietary DHEA for Chemoprotection against tumorigenesis was evaluated. Ten-week-old male F344 rats (n = 100) were given 10 weekly s.c. injections of azoxymethane at a dose of 10 mg/kg/week. One day after the final dose of carcinogen, DHEA was added to the diet of SO rats (0.5% DHEA chow), and the other rats were used as pair-fed controls. DHEA-fed rats lost body weight throughout the 17-week study, in contrast to their pair-fed controls. Serum DHEA in DHEA-fed rats at the end of the study was 6 times that of controls (120 ±30 versus 18 ± 14 pmol/ml), and serum DHEA sulfate was 23 times that of controls (1311 ± 13 rc»-.v«.v 55 ± 13 pmol/ml). Addition of DHEA to the diet produced no significant Chemoprotection in our model. Tumor-related mortality was somewhat increased in DHEA-fed rats (20% versus 6% in week 16 of DHEA feeding, /' not significant). The cumulative prevalence of left colonie tumors, identified by weekly colonoscopic examinations, was somewhat lower in DHEA-fed rats than in controls during weeks 10 through 13 (17% irrmv 33% in week 12, /' not significant), but in week 14 the prevalence in DHEA-fed rats became similar to that in controls (39% versus 41 %). Growth curves of autochthonous left colonie tumors, as assessed for 8 weeks by computerized image analysis of colonoscopic photographs, were similar for DHEA-fed and control rats. Prevalence, mean frequency, multiplicity, and diameter of colonie tumors at necropsy of colonoscopically negative rats ¡nweek 17 were somewhat lower in the DHEA-fed rats (e.g., prevalence of 47% versus 67%), but the differences from controls were not significant. Parameters of colonie epithelial pro liferation after tritiated thymidine incorporation in DHEA-fed rats were similar to those in control rats (labeling index of 8.3 ±0.7% versus 8.4 ±0.6% in week 17), despite higher serum DHEA and DHEA sulfate levels. Our findings indicate that DHEA did not have significant postinduction chemoprotective activity against azoxymethane-induced colonie tumorigenesis in this model utilizing pair-fed controls. Further preclinical studies appear to be needed before dietary DHEA can be recommended for Chemoprotection trials in patients with premalignant colorectal epi thelium.