Growth Hormone-Releasing Hormone Antagonist MZ-4-71 Inhibits in vivo Proliferation of Caki-i Renal Adenocarcinoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 1997-05, Vol.94 (11), p.5810-5813
• Main Authors: Jungwirth, Andreas, Schally, Andrew V., Pinski, Jacek, Groot, Kate, Armatis, Patricia, Halmos, Gabor
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Biological Sciences; Cancer; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Division - drug effects; Cell growth; Cell lines; Cell Membrane - metabolism; Cellular biology; DNA, Neoplasm - biosynthesis; Growth Hormone - metabolism; Growth Hormone-Releasing Hormone - antagonists & inhibitors; Hormone Antagonists - therapeutic use; Hormone Antagonists - toxicity; Hormones; Humans; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor II - metabolism; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; Liver; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Nude; Receptor, IGF Type 1 - analysis; Receptors; Renal cell carcinoma; Sermorelin - analogs & derivatives; Sermorelin - therapeutic use; Sermorelin - toxicity; Thymidine - metabolism; Transplantation, Heterologous; Tumor burden; Tumor cell line; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.11.5810

In view of evidence that growth hormone (GH) and insulin-like growth factors (IGF) may play a role in the development of renal cell carcinoma (RCC), we investigated the effects of growth hormone-releasing hormone (GH-RH) antagonist MZ-4-71 on the proliferation of the human renal adenocarcinoma cell line Caki-I in vitro and in vivo. Male nude mice bearing xenografts of human Caki-I RCC were treated for 4 weeks with MZ-4-71 injected s.c. twice daily at a dose of 20 μ g per animal. Tumor growth, serum, liver, and tumor IGF levels and IGF-I receptor concentrations in Caki-I cell membranes were measured. After 4 weeks of therapy, the final volume of Caki-I tumors in nude mice treated with MZ-4-71 was significantly (P < 0.01) decreased to 52.6 ± 12.3 mm3 as compared with controls that measured 504.2 ± 104.1 mm3. Treatment with GH-RH antagonist also significantly reduced tumor weight, serum levels of GH and IGF-I, liver concentrations of IGF-I, and tumor levels of IGF-I and IGF-II. High-affinity binding sites for IGF-I were detected in the cell membranes of Caki-I tumors. IGF-I and IGF-II stimulated the proliferation of Caki-I cells in tissue cultures. Antagonist MZ-4-71 could inhibit in vitro growth of Caki-I cells, but only at high concentrations. Our findings demonstrate that GH-RH antagonist MZ-4-71 can significantly inhibit the growth of Caki-I RCC. MZ-4-71 may exert its suppressive effect on tumor growth through a reduction in GH release from the pituitary and the subsequent decrease in the production of IGF-I in the liver and IGF-I and II by the tumors. The efficacy of MZ-4-71 suggests that this compound could be considered for the therapy of recurrent or metastatic RCC.