Analogs of luteinizing hormone-releasing hormone (LH-RH) given alone and in combination will be tested in rats bearing androgen- dependent Dunning R3327H adenocarcinomas, Dunning R-3327AT androgen-independent anaplastic prostate tumors, and other models of prostate cancers and in nude mice or nude rats with transplanted human prostate cancer cell lines e.g., LNCaP, DU-145, and PC-3. Our studies will include: (1) the investigation of prostate tumor growth inhibition induced by: (a) controlled delivery system based on the microcapsules of the agonist D-Trp-6-LH-RH in poly (D,L- lactide-co-glycolide) (pLGA) for once-a-month administration and a comparison of the effectiveness of microcapsules given alone and with various combinations, in inhibiting tumor growth; (b) combinations of D-Trp-6-LH-RH microcapsules with microcapsules of somatostatin superanalog D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH (RC-160); (c) New LH-RH antagonists such as (Ac-D-Nal (2), D-Phe (pC1)2, D-Tr3p, D-Cit6, D2-Ala10) LH-RH, (SB-30), or another related antagonist, administered as microcapsule formulations in pLGA; d) combinations of LH-RH antagonist microcapsules with somatostatin analog RC-160. Studies (1 alpha-d) will include long- term experiments in Dunning R3327H model to establish the duration of response. (2) continued synthesis of various agonists and antagonists of LH-RH containing cytotoxic radicals such as Melphalan, Aziridine and Mitomycin C, the evaluation of their binding to LH-RH receptors and testing of their effects in animal models of prostate cancer as targeted hormonal carriers for chemotherapeutic agents; (3) in vitro evaluation in rat and human prostate cancer cell lines of direct inhibitory effects of LH-RH agonists and antagonists, somatostatin analog RC-160 and antitumor effect of peptides with cytotoxic radicals; (4) Biochemical studies such as DNA synthesis and measurement of protein phosphorylation. (5) Determination of tumor membrane receptors for LH-RH, somatostatin and prolactin in animals treated with LH-RH and somatostatin analogs. Steroid (androgen) receptors will be also measured. (6) Determination of blood levels of IGF-1, tumor content of EGF, IGF-1, and the levels of receptors for EGF and IGF- 1. (7) Histological and histomorphometric evaluations to correlate morphological changes with tumor regression.
The aim of this project will be to: a) improve the response to LH-RH agonists in prostate cancer by combined therapy with somatostatin analog RC- 160; b) evaluate the usefulness of the new LH-RH antagonists and targeted LH-RH analogs with cytotoxic radicals for the inhibition of this tumor; c) elucidate the mechanism of action of these analogs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040003-05
Application #
3179430
Study Section
Special Emphasis Panel (SSS (C))
Project Start
1985-09-01
Project End
1994-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
5
Fiscal Year
1990
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
Schally, A V (1999) Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides 20:1247-62
Schally, A V (1999) LH-RH analogues: I. Their impact on reproductive medicine. Gynecol Endocrinol 13:401-9
Halmos, G; Wittliff, J L; Schally, A V (1995) Characterization of bombesin/gastrin-releasing peptide receptors in human breast cancer and their relationship to steroid receptor expression. Cancer Res 55:280-7
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
Yano, T; Pinski, J; Radulovic, S et al. (1994) Inhibition of human epithelial ovarian cancer cell growth in vitro by agonistic and antagonistic analogues of luteinizing hormone-releasing hormone. Proc Natl Acad Sci U S A 91:1701-5
Reile, H; Armatis, P E; Schally, A V (1994) Characterization of high-affinity receptors for bombesin/gastrin releasing peptide on the human prostate cancer cell lines PC-3 and DU-145: internalization of receptor bound 125I-(Tyr4) bombesin by tumor cells. Prostate 25:29-38
Szoke, B; Horvath, J; Halmos, G et al. (1994) LH-RH analogue carrying a cytotoxic radical is internalized by rat pituitary cells in vitro. Peptides 15:359-66
Pinski, J; Reile, H; Halmos, G et al. (1994) Inhibitory effects of analogs of luteinizing hormone-releasing hormone on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer. Int J Cancer 59:51-5
Pinski, J; Reile, H; Halmos, G et al. (1994) Inhibitory effects of somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer. Cancer Res 54:169-74

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