MODULATION OF METHYLNITROSOUREA-INDUCED BREAST-CANCER IN SPRAGUE-DAWLEY RATS BY DEHYDROEPIANDROSTERONE - DOSE-DEPENDENT INHIBITION, EFFECTSOF LIMITED EXPOSURE, EFFECTS ON PEROXISOMAL ENZYMES, AND LACK OF EFFECTS ON LEVELS OF HA-RAS MUTATIONS

Dehydroepiandrosterone (DHEA), the major steroid precursor of androgen s and estrogens produced in peripheral tissues in primates, is an effe ctive chemopreventive agent in the N-methyl-N-nitrosourea (MNU)-induce d rat mammary tumor model, Dietary DHEA (5-600 ppm; 600 mg/kg diet) wa s administered beginning 1 week before MNU and administered continuall y throughout the duration of the experiment, The highest dose of DHEA (600 ppm) significantly decreased tumor incidence from 95 to 45% and i ncreased tumor latency and decreased tumor multiplicity from 4.1 to 0. 5 tumors/rat, Lower doses of DHEA (5, 24, and 120 ppm) were also effec tive, decreasing tumor multiplicity by 28, 40, and 55%, respectively, increasing tumor latency in a dose-dependent manner but only minimally affecting final tumor incidence, DHEA in the diet caused a dose-depen dent increase in serum levels of DHEA, The 120-ppm dietary dose of DHE A resulted in serum levels of DHEA of similar to 42 pmol/ml levels, si milar to those seen in young humans, When we examined whole mounts of mammary glands derived from rats exposed to higher levels of DHEA (600 ppm), we observed a striking increase in lobular development. The dos es of DHEA used in these studies (less than or equal to 600 ppm) had m inimal effects on the induction of fatty acid CoA synthetase, a peroxi some-associated enzyme, In contrast, a dose of 2000 ppm substantially increased Levels of peroxisome-associated fatty acid CoA synthetase. T he varied and striking efficacy of DHEA was achieved in the absence of any significant effect on body weight gain in the treated rats, Furth ermore, tumors from rats treated with MNU alone or rats treated with M NU plus DHEA were examined for the presence of mutations in the Ha-Ras oncogene, There was a slight decrease in the percentage of tumors bea ring Ha-Rns mutations in tumors derived from MNU-control rats as contr asted with tumors from MNU-DHEA (120 and 600 ppm)-treated rats, Based on the striking chemopreventive efficacy of continual exposure to DHE, I, we examined the effects of more limited exposure to DHEA, Rats were treated with DHEA for a period of 7 weeks immediately before and afte r MNU injection, Rats were then placed on the control diet for the ens uing 15 weeks, Even this limited exposure to DHEA for a period of 7 we eks profoundly decreased final tumor incidence and multiplicity, Addit ionally, we examined the effects of intermittent dosing with DHEA, Rat s were treated alternatively at 3-week intervals either with diet cont aining DHEA or with control diet, It was found that this intermittent dosing with DHEA also substantially inhibited the formation of mammary tumors.