LH-RH AGONISTS AND ANTAGONISTS IN PROSTATE CANCER

给予促黄体生成激素释放激素（LH-RH）类似物 将在携带雄激素的大鼠中测试单独和组合， 依赖性邓宁R3327 H腺癌 雄激素非依赖性间变性前列腺肿瘤和其他模型 前列腺癌和裸鼠或裸大鼠移植 人前列腺癌细胞系例如，LNCaP DU-145和PC-3。 我们的研究内容包括：（1）前列腺肿瘤的研究 生长抑制诱导：（a）基于控释系统 在激动剂D-Trp-6-LH-RH的聚（D，L- 丙交酯-共-乙交酯）（pLGA），每月给药一次， 单独给予的微胶囊和 与各种组合，抑制肿瘤生长;（B） D-Trp-6-LH-RH微胶囊与 生长抑素超类似物D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH （c）新的LH-RH拮抗剂，如（Ac-D-Nal（2），D-Phe （pCl）2、D-Tr 3 p、D-Cit 6、D2-Ala 10）LH-RH、（SB-30）或另一种 相关拮抗剂，作为微胶囊制剂给药， d）LH-RH拮抗剂微胶囊与pLGA的组合 生长抑素类似物RC-160。 研究（1 α-d）将包括长期- 在Dunning R3327 H模型中进行长期实验，以确定持续时间 的回应。 (2)继续合成各种激动剂， 含有细胞毒性自由基的LH-RH拮抗剂， 美法仑、氮丙啶和丝裂霉素C的评价 与LH-RH受体的结合及其在动物中的作用测试 前列腺癌模型作为靶向激素载体， 化疗药物;（3）在大鼠和人中的体外评价 LH-RH直接抑制前列腺癌细胞系的作用 激动剂和拮抗剂，生长抑素类似物RC-160和抗肿瘤 具有细胞毒性自由基的肽的作用;（4）生物化学研究 例如DNA合成和蛋白质磷酸化测量。 (5)肿瘤细胞膜LH-RH受体的测定， 促生长素抑制素和催乳素， 生长抑素类似物。 类固醇（雄激素）受体也将是 测定了 (6)IGF-1、肿瘤的血液水平的测定 EGF和IGF-1的含量以及EGF和IGF-1受体的水平 1. (7)组织学和组织形态学评价， 形态学改变伴肿瘤消退。 的目的 项目将：a）改善对LH-RH激动剂的反应， 前列腺癌与生长抑素类似物RC- B）评价新的LH-RH拮抗剂的有用性， 具有细胞毒性自由基的靶向LH-RH类似物 c）阐明这些药物的作用机制 类似物

Analogs of luteinizing hormone-releasing hormone (LH-RH) given alone and in combination will be tested in rats bearing androgen- dependent Dunning R3327H adenocarcinomas, Dunning R-3327AT androgen-independent anaplastic prostate tumors, and other models of prostate cancers and in nude mice or nude rats with transplanted human prostate cancer cell lines e.g., LNCaP, DU-145, and PC-3. Our studies will include: (1) the investigation of prostate tumor growth inhibition induced by: (a) controlled delivery system based on the microcapsules of the agonist D-Trp-6-LH-RH in poly (D,L- lactide-co-glycolide) (pLGA) for once-a-month administration and a comparison of the effectiveness of microcapsules given alone and with various combinations, in inhibiting tumor growth; (b) combinations of D-Trp-6-LH-RH microcapsules with microcapsules of somatostatin superanalog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH (RC-160); (c) New LH-RH antagonists such as (Ac-D-Nal (2), D-Phe (pC1)2, D-Tr3p, D-Cit6, D2-Ala10) LH-RH, (SB-30), or another related antagonist, administered as microcapsule formulations in pLGA; d) combinations of LH-RH antagonist microcapsules with somatostatin analog RC-160. Studies (1 alpha-d) will include long- term experiments in Dunning R3327H model to establish the duration of response. (2) continued synthesis of various agonists and antagonists of LH-RH containing cytotoxic radicals such as Melphalan, Aziridine and Mitomycin C, the evaluation of their binding to LH-RH receptors and testing of their effects in animal models of prostate cancer as targeted hormonal carriers for chemotherapeutic agents; (3) in vitro evaluation in rat and human prostate cancer cell lines of direct inhibitory effects of LH-RH agonists and antagonists, somatostatin analog RC-160 and antitumor effect of peptides with cytotoxic radicals; (4) Biochemical studies such as DNA synthesis and measurement of protein phosphorylation. (5) Determination of tumor membrane receptors for LH-RH, somatostatin and prolactin in animals treated with LH-RH and somatostatin analogs. Steroid (androgen) receptors will be also measured. (6) Determination of blood levels of IGF-1, tumor content of EGF, IGF-1, and the levels of receptors for EGF and IGF- 1. (7) Histological and histomorphometric evaluations to correlate morphological changes with tumor regression. The aim of this project will be to: a) improve the response to LH-RH agonists in prostate cancer by combined therapy with somatostatin analog RC- 160; b) evaluate the usefulness of the new LH-RH antagonists and targeted LH-RH analogs with cytotoxic radicals for the inhibition of this tumor; c) elucidate the mechanism of action of these analogs.