LH-RH ANALOGS IN BREAST AND OVARIAN CANCER

给予促黄体生成激素释放激素（LH-RH）类似物 单独和组合将在以下动物模型中进行测试： 裸鼠和裸大鼠乳腺癌细胞系 携带移植的MCF-7、Beta T-20和其他人乳腺癌 细胞系、人卵巢肿瘤（例如OVCAR-3系）和 子宫内膜腺癌 我们的研究将包括 以下物质诱导乳腺肿瘤生长抑制的研究：1） 基于微胶囊的控释系统，或 在聚（D，L-丙交酯-L）中的激动剂D-Trp-6-LH-RH的微粒， 共-乙交酯）（pLGA），每月给药一次; 2） D-Trp-6-LH-RH微胶囊与a）其它 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-Nh 2（RC-160）类和微胶囊 B）与抗雌激素如他莫昔芬; c） 化疗剂，如异环磷酰胺、丝裂霉素C和 顺铂; 3）基于顺铂的控制输送系统 新LH-RH的微胶囊（pLGA）或植入制剂 X-R1-R2-D-Trp-Ser-Tyr-R6-Leu-Arg-Pro-R10-NH 2类拮抗剂; 4)LH-RH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LH-RH类似物， 美法仑、氮丙啶、丝裂霉素C及其在模型中的评价 乳腺癌和卵巢癌作为靶向激素载体， 化疗药物; 6）直接作用的体外评价 LH-RH类似物、生长抑素类似物和 具有人乳腺癌细胞系上的α自由基的肽; 7)LH-RH，生长抑素， 肿瘤组织中的催乳素和生长因子如EGF和IGF-1 以及血液和组织水平 8）D-Trp-6-LH-RH和EGF和IGF-1的微胶囊; LH-RH拮抗剂单独或与化疗联合给药 还将在各种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价， 将形态学变化与肿瘤消退相关联。 的目的 该项目将改善对LH-RH激动剂的反应， 与其他药物联合治疗乳腺癌，特别是 生长抑素类似物，评估LH-RH的有用性 具有抑制细胞生长的自由基的拮抗剂和类似物 并探讨LH-RH的可能应用 用于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.