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.
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