title: Evaluation of dietary dehydroepiandrosterone for chemoprotection against tumorigenesis in premalignant colonic epithelium of male F344 rats.
abstract: Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA), an adrenal cortical steroid, has chemoprotective properties. Rat colonic epithelium which had been induced to a premalignant state by the colonic 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 50 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 versus 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, P not significant). The cumulative prevalence of left colonic tumors, identified by weekly colonoscopic examinations, was somewhat lower in DHEA-fed rats than in controls during weeks 10 through 13 (17% versus 33% in week 12, P 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 colonic 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 colonic tumors at necropsy of colonoscopically negative rats in week 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 colonic epithelial proliferation 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 colonic 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 epithelium.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine and Hospital, Baltimore, Maryland 21205.
authors.forename: S R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: G B
authors.initials: GB
authors.lastname: Gordon
authors.forename: J
authors.initials: J
authors.lastname: Floyd
authors.forename: S
authors.initials: S
authors.lastname: Golightly
mesh_terms: D019813:1,2-Dimethylhydrazine; D000818:Animals; D000970:Antineoplastic Agents; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D003106:Colon / Q000187:drug effects / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000627:therapeutic use*; D004032:Diet; D004127:Dimethylhydrazines / Q000633:toxicity; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D011230:Precancerous Conditions / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D004127:Dimethylhydrazines; D003687:Dehydroepiandrosterone; D019813:1,2-Dimethylhydrazine; D001397:Azoxymethane