USE OF LH-RH AGONISTS & ANTAGONISTS IN PROSTATE CANCER

给出促黄体生成素释放激素的类似物 单独和组合将在携带雄激素的大鼠身上进行测试- 依赖性Dunning R3327H腺癌，Dunning R-3327AT 雄激素非依赖性间变性前列腺癌和其他模型 前列腺癌和裸鼠或裸鼠移植瘤的研究 人前列腺癌细胞系，如LNCaP、DU-145和PC-3。 我们的研究将包括：(1)前列腺癌的调查 由以下物质引起的生长抑制：(A)以 激动剂D-色氨酸-6-黄体生成素-RH在聚(D，L-RH)中的微胶囊研究 丙交酯-乙交酯)(PLGA)每月一次给药，并 微囊单独给药与微囊给药效果的比较 以各种组合抑制肿瘤生长；(B) D-色氨酸-6-黄体生成素-RH微囊与阿司匹林微囊的组合物 生长抑素超类似物D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH (C)新的促黄体生成素释放激素拮抗剂，如(Ac-D-NAL(2)，D-Phe (Pc1)2、D-Tr3p、D-Cit6、D2-Ala10)Lh-RH、(Sb-30)或其他 相关拮抗剂，以微胶囊形式给药 D)黄体生成素受体拮抗剂微囊与 生长抑素类似物RC-160。研究(1阿尔法-d)将包括长期- 在Dunning R3327H模型中建立持续时间的期限实验 回应的问题。(2)各种激动剂的连续合成和 含有细胞毒性自由基的促黄体生成素释放激素拮抗剂 马法兰、氮杂环丙啶和丝裂霉素C的评价 促黄体生成素释放激素受体的结合及其在动物体内的作用 前列腺癌作为靶向荷尔蒙携带者的模型 化疗药物；(3)大鼠和人的体外评价 黄体生成素-RH对前列腺癌细胞株的直接抑制作用 激动剂和拮抗剂、生长抑素类似物RC-160和抗肿瘤 含有细胞毒性自由基的多肽的作用；(4)生化研究 例如DNA合成和蛋白质磷酸化的测量。 (5)肿瘤膜促黄体生成素受体的测定， 促黄体生成素释放激素和催乳素对动物生长抑素和催乳素的影响 生长抑素类似物。类固醇(雄激素)受体也将 量过了。(6)血清IGF-1、肿瘤水平的测定 EGF、IGF-1含量及EGF、IGF受体水平 1.(7)组织学和组织形态计量学评价 随着肿瘤消退，细胞形态发生改变。这样做的目的是 项目将是：a)改善对促黄体生成素释放激素激动剂的反应 生长抑素类似物RC联合治疗前列腺癌 160；b)评估新的促黄体生成素释放激素拮抗剂的有用性和 靶向的含细胞毒自由基的促黄体生成激素类似物的抑制作用 C)阐明这些物质的作用机制 类比。

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.