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 and in nude mice and nude rats bearing transplanted MCF-7, Beta T-20 and other human breast cancer cell lines, human ovarian tumors (e.g. OVCAR-3 line) and endometrial adenocarcinoma. Our studies will include the investigation of mammary tumor growth inhibition induced by: 1) controlled delivery systems based on the microcapsules or microparticles of the agonist D-Trp-6-LH-RH in 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 superactive somatostatin analogs of D-Phe-Cys- Tyr-D-Trp-Lys-Val-Cys-Trp-Nh2 (RC-160) class and microcapsules thereof; b) with antiestrogens such as Tamoxifen; c) chemotherapeutic agents such as Ifosfamide, Mitomycin C and Cisplatinum; 3) controlled delivery systems based on the microcapsule (pLGA) or implant formulations of new LH-RH antagonists of X-R1-R2-D-Trp-Ser-Tyr-R6-Leu-Arg-Pro-R10-NH2 class; 4) combinations of LH-RH antagonists with somatostatin analogs, antiestrogens, and chemotherapeutic agents; 5) continued synthesis of various LH-RH analogs containing cytostatic radicals such as Melphalan, Aziridine, Mitomycin C and their evaluation in models of breast and ovarian cancer as targeted hormonal carriers for chemotherapeutic agents; 6) in vitro evaluation of direct effects of LH-RH analogs, somatostatin analogs and cytostatic effect of peptides with antineoplastic radicals on human breast cancer lines; 7) measurements of membrane receptors for LH-RH, somatostatin, prolactin and growth factors such as EGF and IGF-1 in tumor tissue in the course of the treatment as well as blood and tissue levels of EGF and IGF-1; 8) the microcapsules of D-Trp-6-LH-RH and of an LH-RH antagonist given alone or in combination with chemotherapy will be also investigated in various models of ovarian and uterine tumors; 9) detailed histological evaluations will be performed to correlate morphological changes with tumor regression. The aim of this project will be to improve the response to LH-RH agonists in mammary cancer by combined therapy with other agents, especially somatostatin analogs, evaluate the usefulness of the LH-RH antagonists and analogs with cytostatic radicals for the inhibition of this tumor, and investigate the possible application of LH-RH agonists and antagonists for the treatment of ovarian cancer and neoplasms of the female genital tract.