LH-RH AGONISTS AND ANTAGONISTS IN PROSTATE CANCER

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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.