MECHANISM OF GLUCARATE INHIBITION OF MAMMARY CANCER

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This study will focus on the mechanism of prevention of N- methylnitrosourea (MNU)-induced rat mammary carcinogenesis by a dietary precursor of D-glucaro-1,4-lactone. The glucarolatone is a natural, non-toxic compound which is produced in small amounts in mammals, including humans, and also in plants. It is known as a potent inhibitor of the ubiquitous enzyme B-glucuronidase. The glucarolactone, by inhibiting B-glucuronidase and reducing de- glucuronidation rates, may control conjugation of steroid hormones and their levels in tissues and body fluids. The long-term objective of this study is to elucidate the mechanism of glucarate inhibition of mammary carcinogenesis by demonstrating that dietary calcium glucarate, a precursor of D-glucaro-1,4-lactone, inhibits chemically induced mammary cancers by changing the hormonal environment in the rat. Specific aims include: (1) investigation of dose-dependency of inhibition of mammary tumorigenesis by dietary glucarate and its effect on the estrous cycle; (2) determination of the effect of time and duration of exposure to dietary glucarate on induction and hormone-dependency of mammary tumors; (3) investigation of glucarate-mediated changes in DNA synthesis; (4) a comparison of the inhibitory effects of glucarate and a known antiestrogen, tamoxifen (TAM) and assessment of the effectiveness of combined regimens of dietary glucarate and TAM in the prevention of mammary cancer. This study will utilize a well established model of mammary carcinogenesis induced in female rats of the Sprague Dawley strain by the direct-acting carcinogen N- methylnitrosourea. The animals will be fed purified diets supplemented for various periods of time with calcium glucarate or non-inhibitory calcium tartrate (control diet), with or without TAM. Mammary tumor incidence, multiplicity, and growth rates will be recorded in experimental and control groups and correlated with changes in the endogenous hormones.