MECHANISM OF GLUCARATE INHIBITION OF MAMMARY CANCER

本研究将重点探讨N-氨基丁酸的预防机制。 甲基亚硝脲(MNU)诱导的大鼠乳腺癌 D-葡萄糖-1，4-内酯的饮食前体。葡糖胺是 一种少量生产的天然无毒化合物 在哺乳动物中，包括人类，在植物中也是如此。它被称为 一种普遍存在的酶B-葡萄糖醛酸酶的有效抑制剂。这个 葡萄糖内酯，通过抑制B-葡萄糖醛酸酶和减少脱氢酶 葡萄糖醛酸化速率，可控制类固醇激素的结合 以及它们在组织和体液中的水平。长期的 本研究的目的是阐明葡萄糖酸盐的作用机制。 饮食对乳腺癌发生的抑制作用 D-葡萄糖基-1，4-内酯的前体葡萄糖酸钙抑制 通过改变荷尔蒙来化学诱发乳腺癌 老鼠体内的环境。具体目标包括：(1)调查 抑制乳腺肿瘤形成的剂量依赖性研究 日粮葡萄糖酸盐及其对发情周期的影响 确定接触的时间和持续时间的影响 膳食葡萄糖对乳腺的诱导和激素依赖作用 肿瘤；(3)葡萄糖酸介导的DNA变化的研究 (4)葡萄糖酸盐抑制作用的比较 和已知的抗雌激素，他莫昔芬()和评估 日粮葡萄糖酸盐与联合用药的疗效观察 预防乳腺癌。这项研究将利用一口井 诱发雌性大鼠乳腺癌模型的建立 直接致癌物质N-对SpragueDawley品系的影响 甲基亚硝脲。这些动物将被喂以净化的饲料 在不同的时间内补充葡萄糖酸钙或 非抑制性酒石酸钙(对照饮食)，加或不加 。乳腺肿瘤的发病率、多样性和增长率将 记录在试验组和对照组中，并与 内源激素的变化。

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.