NOVEL CHEMOPREVENTIVE AGENTS IN EXPERIMENTAL MAMMARY CARCINOGENESIS

乳腺癌是美国女性中第二常见的癌症， 每年约有183，000个病例，1995年估计有46，000人死亡。的 本项目的目的是鉴定新的化学预防剂 在动物模型中对乳腺癌有效，并最终开发出一种 预防人类乳腺癌的临床上可接受的方案 高危人群。我们已经在55个- 1日龄未交配Sprague-Dawley大鼠，用N-甲基- 亚硝基脲（NMU）。我们研究了其功效、效力和 单独使用的各种潜在化学预防剂的毒性 或者通过将它们混合在饮食中来组合。我们专注于 广泛分类为萜类的化合物，包括已知的 类固醇受体超家族的配体，如类视色素， δ烷类化合物和经典的类固醇，以及三萜类化合物（如 油酸和熊果酸以及异黄烷类染料木黄酮）。这 项目现已完成，结果的功效， 酸与9-顺式-视黄酸、他莫昔芬或两者的组合。 结果表明，油酸本身的化学预防活性较弱， 但是，与熊果酸和染料木黄酮的结果相似， 与他莫昔芬协同，与9-顺式视黄酸协同程度较低 酸，如通过测量总肿瘤负荷和 肿瘤数量/大鼠。总的来说，研究表明， 通过组合使用几种不同的 化学预防剂通过不同的机制起作用， 这些药物联合治疗乳腺癌的临床评价 化学预防或辅助治疗的妇女在高风险的 发展中的乳腺癌应予以考虑。

Breast cancer is the second most common cancer among U.S. women with about 183,000 cases annually and an estimated 46,000 deaths in 1995. The purpose of this project is to identify novel chemopreventive agents active against breast cancer in animal models and eventually develop a clinically acceptable regimen for prevention of breast cancer in human populations at high risk. We have induced breast carcinogenesis in 55- day old virgin Sprague-Dawley rats by initiation with N-methyl- nitrosourea (NMU). We have investigated the efficacy, potency and toxicity of various potential chemopreventive agents used either alone or in combination by mixing them in the diet. We have focused on compounds classified broadly as terpenes and including both known ligands for the steroid receptor superfamily, such as retinoids, deltanoids, and classical steroids, as well as triterpenoids (such as oleanolic and ursolic acids and the isoflavanoid genistein). This project is now completed with the results of the efficacy of oleanolic acid in combination with either 9-cis-retinoic acid, tamoxifen, or both. Results show weak chemopreventive activity of oleanolic acid itself, but, similar to results with ursolic acid and genistein, there is strong synergism with tamoxifen, and to a lesser extent with 9-cis retinoic acid, as assessed by measurements of the total tumor burden and the number of tumors/rat. Overall, the studies suggest that effectiveness is maximized and toxicity minimized by combined use of several different chemopreventive agents which act by distinct mechanisms, and that clinical evaluation of the combination of these agents for breast cancer chemoprevention or for adjuvant therapy in women at high risk of developing breast cancer should be considered.