NOVEL CHEMOPREVENTIVE AGENTS IN EXPERIMENTAL MAMMARY CARCINOGENESIS

乳腺癌实验中的新型化学预防剂

• 批准号: 6100875
• 负责人: A B ROBERTS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6100875
• 关键词: 13 cis retinoate; breast neoplasms; cancer prevention; chemical carcinogen; chemical carcinogenesis; chemoprevention; drug screening /evaluation; genistein; laboratory rat; methylnitrosourea; retinoids; tamoxifen; terpenes; tissue /cell culture

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.

乳腺癌是美国女性中第二常见的癌症， 每年约有18.3万例，1995年估计有4.6万人死亡。这个 该项目的目的是寻找新的化学预防药物。 在动物模型中积极对抗乳腺癌，最终形成一种 预防人类乳腺癌的临床可接受方案 处于高危状态的人群。我们已经诱导了55例乳腺癌的发生- 新生SD大鼠经N-甲基-D-天冬氨酸诱导 亚硝脲(NMU)。我们已经研究了它的疗效、效力和 不同潜在化学预防药物单独使用的毒性 或者通过在饮食中混合它们来组合。我们一直专注于 化合物被广泛地归类为萜类，包括这两种已知的化合物 类固醇受体超家族的配体，如维甲酸， Deltanid，和经典的类固醇，以及三萜(如 齐墩果酸和熊果酸以及异黄烷类染料木素)。这 该项目现已完成，齐墩果酸的功效取得了成果。 酸与9-顺式维甲酸、他莫昔芬或两者同时使用。 结果表明齐墩果酸本身的化学预防活性较弱， 但是，与熊果酸和染料木素的结果相似，有很强的 与他莫昔芬的协同作用，以及与9-顺式维甲酸的协同作用 酸，如通过测量总肿瘤负荷和 肿瘤数/只。总体而言，研究表明，有效性 通过组合使用几种不同的方法来最大化和降低毒性 通过不同机制起作用的化学预防药物，以及 这些药物联合治疗乳腺癌的临床评价 高危女性的化学预防或辅助治疗 应考虑发展为乳腺癌。