LH-RH ANALOGS IN BREAST AND OVARIAN CANCER

给出促黄体生成素释放激素的类似物 单独和组合将在动物模型中进行测试 荷尔蒙依赖性乳腺癌及裸鼠、裸鼠移植瘤的研究 携带MCF-7、Beta T-20等人乳腺癌移植瘤 细胞系、人卵巢肿瘤(如OVCAR-3细胞系)和 子宫内膜腺癌。我们的研究将包括 1)对乳腺肿瘤生长抑制作用的研究 基于微胶囊或 激动剂D-色氨酸-6-黄体生成素-RH在聚(D，L-丙交酯)中的微粒 乙交酯)(PLGA)，每月一次；2) D-色氨酸-6-黄体生成素-RH微囊与其他药物的联合方案 多肽，特别是D-Phe-Cys的超活性生长抑素类似物- TYR-D-Trp-Lys-Val-Cys-Trp-NH2(RC-160)类和微胶囊 B)抗雌激素，如三苯氧胺；c) 化疗药物，如异环磷酰胺、丝裂霉素C和 顺铂；3)基于 微囊(PLGA)或新型促黄体生成素-促性腺激素植入剂 X-R1-R2-D-Trp-Ser-Tyr-R6-Leu-Arg-Pro-R10-NH2类拮抗剂； 4)促黄体生成素受体拮抗剂与生长抑素类似物的组合， 抗雌激素和化疗药物；5)继续合成 含有细胞抑制基团的各种促黄体生成素类似物，如 马法兰、氮杂环丙啶、丝裂霉素C及其模型评价 乳腺癌和卵巢癌作为靶向荷尔蒙携带者 化疗药物；6)直接作用的体外评价 促黄体生成素-RH类似物、生长抑素类似物及其细胞抑制作用 人乳腺癌细胞系上含有抗肿瘤基团的多肽； 7)黄体生成素受体、生长抑素、 催乳素与肿瘤组织中EGF、IGF-1等生长因子的关系 在治疗过程中以及血液和组织水平 8)D-Trp-6-Lh-RH和An-Trp-6-Lh-RH微囊 促黄体生成素释放激素拮抗剂单独或联合化疗 也将在不同的卵巢和子宫模型中进行研究 肿瘤；9)将进行详细的组织学评估以 形态学改变与肿瘤消退的关系。的目的是 该项目将改善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，特别是 生长抑素类似物，评估促黄体生成素-RH的有效性 拮抗剂和具有细胞抑制自由基的类似物 并探讨促黄体生成素-促性腺激素的可能应用。 治疗卵巢癌的激动剂和拮抗剂 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 and in nude mice and nude rats bearing transplanted MCF-7, Beta T-20 and other human breast cancer cell lines, human ovarian tumors (e.g. OVCAR-3 line) and endometrial adenocarcinoma. Our studies will include the investigation of mammary tumor growth inhibition induced by: 1) controlled delivery systems based on the microcapsules or microparticles of the agonist D-Trp-6-LH-RH in poly(D,L-lactide- co-glycolide) (pLGA) for once-a-month administration; 2) combination regimens of D-Trp-6-LH-RH microcapsules with a) other peptides, especially superactive somatostatin analogs of D-Phe-Cys- Tyr-D-Trp-Lys-Val-Cys-Trp-Nh2 (RC-160) class and microcapsules thereof; b) with antiestrogens such as Tamoxifen; c) chemotherapeutic agents such as Ifosfamide, Mitomycin C and Cisplatinum; 3) controlled delivery systems based on the microcapsule (pLGA) or implant formulations of new LH-RH antagonists of X-R1-R2-D-Trp-Ser-Tyr-R6-Leu-Arg-Pro-R10-NH2 class; 4) combinations of LH-RH antagonists with somatostatin analogs, antiestrogens, and chemotherapeutic agents; 5) continued synthesis of various LH-RH analogs containing cytostatic radicals such as Melphalan, Aziridine, Mitomycin C and their evaluation in models of breast and ovarian cancer as targeted hormonal carriers for chemotherapeutic agents; 6) in vitro evaluation of direct effects of LH-RH analogs, somatostatin analogs and cytostatic effect of peptides with antineoplastic radicals on human breast cancer lines; 7) measurements of membrane receptors for LH-RH, somatostatin, prolactin and growth factors such as EGF and IGF-1 in tumor tissue in the course of the treatment as well as blood and tissue levels of EGF and IGF-1; 8) the microcapsules of D-Trp-6-LH-RH and of an LH-RH antagonist given alone or in combination with chemotherapy will be also investigated in various models of ovarian and uterine tumors; 9) detailed histological evaluations will be performed to correlate morphological changes with tumor regression. The aim of this project will be to improve the response to LH-RH agonists in mammary cancer by combined therapy with other agents, especially somatostatin analogs, evaluate the usefulness of the LH-RH antagonists and analogs with cytostatic radicals for the inhibition of this tumor, and investigate the possible application of LH-RH agonists and antagonists for the treatment of ovarian cancer and neoplasms of the female genital tract.