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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA040004-04A1
Application #
3179436
Study Section
(SSS)
Project Start
1985-09-01
Project End
1992-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
4
Fiscal Year
1989
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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