USE OF LH-RH ANALOGS IN BREAST AND OVARIAN CANCER

促黄体生成素释放激素类似物(黄体生成素-RH)单独给药和 这种组合将在荷尔蒙依赖性乳腺的动物模型中进行测试 癌症、卵巢癌和女性生殖道肿瘤 携带MCF-7人乳腺癌细胞移植瘤的裸鼠或裸鼠 线，人卵巢肿瘤(例如。OVCAR-3株)与人子宫内膜 腺癌。我们的研究将包括对乳房的调查 (1)连续控释对肿瘤的抑制作用 基于激动型类似物微胶囊制剂的系统 D-色氨酸-6-黄体生成素-RH在可生物降解聚(D-L-丙交酯-乙交酯)中的应用 每月给药一次7；(2)D-Trp-6-Lh-RH联合方案 含有a)其他多肽的微囊，特别是生长抑素类似物，如 以及b)抗雌激素，他莫昔芬(诺伐得，ICI 46474)，奈福辛， 可可昔芬(LY 156758)或LY 117018；以及c)化疗药物，如 环磷酰胺、米托蒽酮和双苯并三烯；(3)连续控制 基于微囊(PLGA)制剂的给药系统 N-Ac-D-p-Cl-Phe-1，2，D-Trp-3，D-Arg-6，D-Ala-10-Lh-RH(拮抗剂I)， Ac-β-D-Nal(2)-1，D-p-Cl-Phe-2，D-Trp-3，D-Arg-6，D-Ala-10-Lh-RH(拮抗剂 Ii)或另一种拮抗剂；(4)促黄体生成素-促性腺激素释放激素拮抗剂联合方案 生长抑素类似物、抗雌激素和化疗药物；(5) D-色氨酸-6-黄体生成素-RH类似物在某些乳腺癌模型中的评价 含有烷化剂Melphalan(氮)的细胞抑制基团 附着在苯丙氨酸上的芥末)作为荷尔蒙载体 化疗药物。一些生化研究，如DNA，RNA和 蛋白质合成和蛋白质磷酸化的测定以及 乳腺肿瘤胞浆和胞核中蛋白激酶活性的研究 将进行组织学评估，以提供相关数据 肿瘤消退。D-色氨酸-6-黄体生成素-RH微囊制剂 单用或联合化疗的促黄体生成素释放激素拮抗剂 在各种卵巢和子宫肿瘤模型中也进行了研究。其目的是 这个项目的目的是提高对促黄体生成素释放激素激动剂的反应。 乳腺癌与其他药物联合治疗并提供新数据 促黄体生成素释放激素拮抗剂单独或联合用药的有效性 抑制这种肿瘤的治疗方案，以及确定 两种类型的促黄体生成素-促性腺激素类似物在治疗卵巢癌中的可能应用 卵巢癌和女性生殖道肿瘤。

Analogs of luteinizing hormone-releasing hormone (LH-RH) given alone and in combination will be tested in animal models of hormone-dependent mammary carcinoma, ovarian cancer and neoplasms of the female genital tract and in nude mice or nude rats bearing transplanted MCF-7 human breast cancer cell line, human ovarian tumors (eg. OVCAR-3 line) and human endometrial adenocarcinoma. Our studies will include the investigation of mammary tumor growth inhibition induced by (1) continuous controlled delivery system based on the microcapsule formulation of the agonistic analog D-Trp-6-LH-RH in biodegradable poly(D-L-lactide-co-glycolide) (pLGA) for once a month administratio7; (2) combination regimens of D-Trp-6-LH-RH microcapsules with a) other peptides, especially somatostatin analogs, as well as with b) antiestrogens, tamoxifen (Nolvadex, ICI 46474), nafoxidine, Keoxifene (LY 156758), or LY 117018; and c) chemotherapeutic agents such as cyclophosphamide, Mitoxantrone and Bisantrene; (3) continuous controlled delivery system based on the microcapsule (pLGA) formulation of N-Ac-D-p-Cl-Phe-1,2,D-Trp-3,D-Arg-6,D-Ala-10-LH-RH (Antagonist I), Ac-Beta-D-Nal(2)-1,D-p-Cl-Phe-2,D-Trp-3,D-Arg-6,D-Ala-10-LH-RH (Antagonist II) or another antagonist; (4) combination regimens of LH-RH antagonists with somatostatin analogs, antiestrogens, and chemotherapeutic agents; (5) evaluation in some models of mammary cancer of an analog of D-Trp-6-LH-RH containing a cytostatic radical of alkylating agent Melphalan (nitrogen mustard attached to Phenylalanine) as a hormonal carrier for chemotherapeutic agent. Some biochemical studies such as DNA, RNA and protein synthesis and measurement of protein phosphorylation as well as protein kinases activities in cytoplasm and nuclei of mammary tumors and histological evaluations will be performed to provide data to correlate with tumor regression. The microcapsule formulations of D-Trp-6-LH-RH and of LH-RH antagonist given alone or in combination with chemotherapy will be also investigated in various models of ovarian and uterine tumors. The aim of this project will be to improve the response to LH-RH agonists in mammary cancer by combined therapy with other agents and provide new data on the usefulness of the LH-RH antagonist given alone or in combination regimens for the inhibition of this tumor as well as to determine the possible application of both types of LH-RH analogs for the treatment of ovarian cancer and neoplasms of the female genital tract.