MECHANISM OF GLUCARATE INHIBITION OF MAMMARY CANCER

本研究将着重探讨N- 甲基亚硝基脲（MNU）诱导的大鼠乳腺癌 D-葡糖-1，4-内酯的饮食前体。 葡萄糖醛酸内酯是 一种天然无毒的化合物， 包括人类在内的哺乳动物，以及植物。 被誉为 一种普遍存在的酶B-葡萄糖醛酸酶的有效抑制剂。 的 葡萄糖醛酸内酯，通过抑制β-葡萄糖醛酸酶和减少脱- 葡萄糖醛酸化率，可能控制类固醇激素的结合 以及它们在组织和体液中的水平。 长期 本研究的目的是阐明葡萄糖二酸的作用机制 通过证明饮食中 葡糖二酸钙是D-葡糖-1，4-内酯的前体， 通过改变荷尔蒙化学诱导乳腺癌 环境中的老鼠 具体目标包括：（1）调查 抑制乳腺肿瘤发生的剂量依赖性 日粮葡萄糖二酸盐及其对发情周期的影响;（2） 测定暴露时间和持续时间对 饮食中葡萄糖二酸盐对乳腺癌的诱导和乳腺癌依赖性的影响 肿瘤;（3）研究葡萄糖二酸盐介导的DNA变化 葡萄糖二酸酯的合成;（4）葡萄糖二酸酯的抑制作用比较 和已知的抗雌激素，他莫昔芬（TAM）和评估 饮食中葡萄糖二酸盐和TAM联合方案对 乳腺癌的预防。 这项研究将利用一口井 雌性大鼠乳腺癌模型的建立 Sprague道利菌株的直接致癌物N- 甲基亚硝基脲 这些动物将被喂食纯净的饲料 补充葡萄糖二酸钙不同时间段，或 非抑制性酒石酸钙（对照饲料），含或不含 TAM。 乳腺肿瘤的发病率、多样性和生长率将 在实验组和对照组中记录，并与 内源性激素的变化。

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.