Exceptional chemopreventive activity of low-dose dehydroepiandrosterone in the rat mammary gland.

To determine if the chemopreventive activity of dehydroepiandrosterone (DHEA) in the rat mammary gland can be dissociated from its toxicity, two studies were conducted in which low doses of DHEA were administered alone and in combination with other agents to rats treated with N-methyl-N-nitrosourea. Beginning 1 week prior to administration of 35 mg N-methyl-N-nitrosourea per kg body weight, groups of 20 female Sprague-Dawley rates were fed AIN-76A diet supplemented with DHEA alone (800 or 400 mg/kg diet), DHEA + tamoxifen (80 or 40 microgram/kg diet), DHEA + carbenoxolone (3500 or 1750 mg/kg diet), or DHEA + tamoxifen + carbenoxolone. When administered alone at either 800 or 400 mg/kg diet, DHEA reduced mammary cancer incidence from >70% in dietary controls to 0%; mammary cancer incidence from >70% in dietary controls to 0%; mammary cancer incidence in all DHEA combination regimens was also < or = 5%. The dose levels of DHEA used induced no toxicity or alteration in body weight gain. These results indicate that dietary supplementation with low doses of DHEA has chemopreventive efficacy greater than or equal to that of endocrine ablation. This protection may be mediated by the induction of differentiation in the mammary parenchyma.

Differential growth response to exogenous calcium in normal and carcinogen-exposed primary human keratinocyte cell cultures.

The purpose of these studies was to examine an early carcinogen-induced change in primary human epithelial cell cultures and to attempt to reverse this change with retinoic acid. Primary cultures of human foreskin keratinocytes were prepared and exposed to the carcinogen, propane sultone. After each passage, a portion of cells were plated into medium containing increasing amounts of calcium. In a series of experiments it became evident that carcinogen exposed cells continued to grow in the presence of added calcium. Solvent control cell growth was decreased under such conditions. This new phenotype became apparent after the third subculture, but was pronounced after the fourth subculture. The addition of retinoic acid to the culture medium at each medium change reduced this effect and the keratinocytes grew more slowly, similar to control cells, in the presence of added calcium. The results suggest that carcinogen-exposed human keratinocytes acquire a resistance to calcium-induced differentiation or growth cessation and that retinoic acid can ameliorate this process. Although the mechanism of retinoic acid's inhibition remains unclear, these studies do provide a human cell model system which can be used to screen potential chemopreventive agents and for further mechanistic research.