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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA040004-01
Application #
3179434
Study Section
Reproductive Biology Study Section (REB)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Tulane University
Department
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Schally, A V; Comaru-Schally, A M; Nagy, A et al. (2001) Hypothalamic hormones and cancer. Front Neuroendocrinol 22:248-91
Srkalovic, G; Schally, A V; Wittliff, J L et al. (1998) Presence and characteristics of receptors for [D-Trp6]luteinizing hormone releasing hormone and epidermal growth factor in human ovarian cancer. Int J Oncol 12:489-98
Szepeshazi, K; Schally, A V; Halmos, G et al. (1996) Effect of a cytotoxic analog of LH-RH (T-98) on the growth of estrogen-dependent MXT mouse mammary cancers: correlations between growth characteristics and EGF receptor content of tumors. Breast Cancer Res Treat 40:129-39
Pinski, J; Schally, A V; Yano, T et al. (1995) Evaluation of the in vitro and in vivo activity of the L-, D,L- and D-Cit6 forms of the LH-RH antagonist Cetrorelix (SB-75). Int J Pept Protein Res 45:410-7
Shirahige, Y; Cai, R Z; Szepeshazi, K et al. (1994) Inhibitory effect of bombesin/gastrin-releasing peptide (GRP) antagonists RC-3950-II and RC-3095 on MCF-7 MIII human breast cancer xenografts in nude mice. Biomed Pharmacother 48:465-72
Yano, T; Pinski, J; Halmos, G et al. (1994) Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75. Proc Natl Acad Sci U S A 91:7090-4
Rekasi, Z; Szoke, B; Nagy, A et al. (1993) Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on the function of rat pituitary cells: tests in a long term superfusion system. Endocrinology 132:1991-2000
Pinski, J; Yano, T; Szepeshazi, K et al. (1993) Recovery of pituitary-gonadal function in male rats after long-term suppression induced by a single injection of microcapsules of LH-RH antagonist cetrorelix (SB-75). J Androl 14:164-9
Milovanovic, S R; Monje, E; Szepeshazi, K et al. (1993) Effect of treatment with LHRH analogs containing cytotoxic radicals on the binding characteristics of receptors for luteinizing-hormone-releasing hormone in MXT mouse mammary carcinoma. J Cancer Res Clin Oncol 119:273-8
Pinski, J; Yano, T; Janaky, T et al. (1993) Evaluation of biological activities of new LH-RH antagonists (T-series) in male and female rats. Int J Pept Protein Res 41:66-73

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