USE OF LH-RH ANALOGS IN BREAST AND OVARIAN CANCER

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Analogs of luteinizing hormone-releasing hormone (LH-RH) given alone and in combination will be tested in animal models of hormone-dependent mammary carcinoma, ovarian cancer and neoplasms of the female genital tract and in nude mice or nude rats bearing transplanted MCF-7 human breast cancer cell line, human ovarian tumors (eg. OVCAR-3 line) and human endometrial adenocarcinoma. Our studies will include the investigation of mammary 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 administratio7; (2) combination regimens of D-Trp-6-LH-RH microcapsules with a) other peptides, especially somatostatin analogs, as well as with b) antiestrogens, tamoxifen (Nolvadex, ICI 46474), nafoxidine, Keoxifene (LY 156758), or LY 117018; 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, antiestrogens, and chemotherapeutic agents; (5) evaluation in some models of mammary cancer of an analog of D-Trp-6-LH-RH containing a cytostatic radical of alkylating agent Melphalan (nitrogen mustard attached to Phenylalanine) 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 cytoplasm and nuclei of mammary tumors and histological evaluations will be performed to provide data to correlate with tumor regression. The microcapsule formulations of D-Trp-6-LH-RH and of LH-RH antagonist given alone or in combination with chemotherapy will be also investigated in various models of ovarian and uterine tumors. The aim of this project will be to improve the response to LH-RH agonists in mammary 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 as well as to determine the possible application of both types of LH-RH analogs for the treatment of ovarian cancer and neoplasms of the female genital tract.