USE OF LH-RH AGONISTS AND ANTAGONISTS IN PROSTATE CANCER

单独给药和联合给药的促性腺激素释放激素（LH-RH）类似物 将在携带Dunning R-3327 H的大鼠中检测联合给药 前列腺肿瘤的Noble和Pollard大鼠模型 肿瘤和移植人前列腺肿瘤的裸鼠或裸鼠 线 我们的研究将包括前列腺肿瘤生长的调查 抑制诱导（1）连续控制输送系统的基础上， 激动性类似物D-Trp-6-LH-RH的微胶囊制剂 可生物降解的聚（D，L-丙交酯-共-乙交酯）（pLGA），每月一次 （2）D-Trp-6-LH-RH微囊的组合方案 与a）其它肽，特别是生长抑素类似物，以及与B） 抗雄激素RU-23908（Anandron）和氟吡嗪（SCH 13521），和c） 化疗剂如环磷酰胺、米托蒽醌和 比生群;（3）基于 微胶囊（pLGA）制剂， N-Ac-D-p-Cl-Phe-1，2，D-Trp-3，D-Arg-6，D-Ala-10-LH-RH（拮抗剂I）， Ac-Beta-D-Nal（2）-1、D-p-Cl-Phe-2、D-Trp-3、D-Arg-6、D-Ala-10-LH-RH（拮抗剂 （4）LH-RH拮抗剂的组合方案 与生长抑素类似物、抗雄激素和化疗剂;（5） 含细胞生长抑制基团D-Trp-6-LH-RH类似物的合成 （烷化剂美法仑[连接苯丙氨酸的氮芥]） 及其在前列腺癌动物模型中作为激素的评价 化疗剂的载体。 一些生物化学研究，如DNA， RNA和蛋白质合成以及蛋白质磷酸化的测量， 前列腺细胞质和细胞核蛋白激酶活性 将进行肿瘤和组织学评价，以提供数据， 与肿瘤消退有关。 该项目的目的是 通过联合应用改善前列腺癌对LH-RH激动剂的反应 与其他药物的治疗，并提供新的数据， LH-RH拮抗剂单独给药或联合给药方案抑制 这个肿瘤。

Analogs of luteinizing hormone-releasing hormone (LH-RH) given alone and in combination will be tested in rats bearing Dunning R-3327H hormone-dependent prostate tumors, Noble and Pollard rat models of prostate tumors and nude mice or nude rats with transplanted human prostate tumor lines. Our studies will include the investigation of prostate 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 administration; (2) combination regimens of D-Trp-6-LH-RH microcapsules with a) other peptides, especially somatostatin analogs, as well as with b) antiandrogens RU-23908 (Anandron) and Flutamide (SCH 13521), 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, antiandrogens, and chemotherapeutic agents; (5) synthesis of an analog of D-Trp-6-LH-RH containing a cytostatic radical (alkylating agent Melphalan [nitrogen mustard attached to Phenylalanine]) and its evaluation in animal models of prostate cancer 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 cytoplasma and nuclei of prostate tumors and histological evaluations will be performed to provide data to correlate with tumor regression. The aim of this project will be to improve the response to LH-RH agonists in prostate 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.