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。 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， 临床上可接受的预防乳腺癌的方案， 高危人群。 我们已经诱导了乳腺癌的发生 在55日龄未交配Sprague-Dawley大鼠中， N-甲基-亚硝基脲（NMU）。 我们研究了它的功效， 和毒性的各种潜在的化学预防剂， 单独或通过将它们混合在饮食中组合。 我们重点 广泛分类为萜烯的化合物，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，并进行了功效测试 油酸与9-顺式-视黄酸， 他莫昔芬或两者。 总的来说，研究表明， 最大化和毒性最小化， 通过不同机制起作用的不同化学预防剂，以及 这些药物联合治疗乳腺癌的临床评价 癌症化学预防或用于高危女性的辅助治疗 患乳腺癌的风险应该考虑。

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 coming to completion with the testing of the efficacy of oleanolic acid in combination with either 9-cis-retinoic acid, tamoxifen, or both. 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.