Inhibition of rat mammary carcinogenesis by short dietary exposure to retinyl acetate.

tion has been achieved by beginning the retinoid supplement 7 days after a single dose of DMBA; at this time, the binding of the carcinogen to mammary panenchymalcell DNA and protein is complete, and unreacted DMBA is no longer detectable in the gland (8, 12). Comparatively little is known about possible inhibitory effects of retinoids on the early stage of mammary cancinogenesis and whether any effects on the early stage will alter the late stage inhibition. Retinoids exhibit several biological actions that could influ ence mammary tumor growth and development. Vitamin A compounds have been shown to influence epithelial differentia tion (14) and may act to arrest or reverse premalignant cells during their progression to a malignant lesion (12, 16). Influ ences on the immune system have been implicated, inasmuch as netinoids stimulate both cell-mediated (3, 10) and humoral (2) immune responses. Effects of retinoids on the mammary gland itself have been noted, because prolonged retinoid treat ment inhibits mammary end-bud proliferation (13). There is in vitro evidence suggesting that retinoids may also modify the first, or early, stage of cancinogenesis. Several retinoids inhibit the micnosomalmetabolism of benzo(a)pynene, DMBA, and 3-methylcholanthrene to their proximal carcino genic metabolites (7). Retinyl acetate treatment decreased induced anylhydrocarbon hydroxylase activity in epithelial cell cultures (19), and retinoids have been shown to decrease carcinogen binding to DNA in epithelial cells (19) and human diploid fibroblasts (9). Vitamin A deficiency increased carcin ogen binding to DNA in tracheal organ culture (4). The purpose of the present experiment was to determine whether mammary tumors could be inhibited when netinoid exposure was limited to specific periods corresponding to early and late phases of cancinogenesis and to determine whether short-term retinoid exposure would be additive with the inhibi tion of carcinogenesis seen with long-term, postcancinogen retinoid administration.