Powerful Inhibition of Human Renal Cell Carcinomas with Antagonists of Growth Hormone-Releasing Hormone (ghrh): A Preclinical Study.

Abstract BACKGROUND: Advances in targeted medical thereapy has demonstrated improved clinical outcomes for patients with metastatic renal cell carcinoma (RCC), however, a complete response is rare and current therapy has various adverse effects that are unfortunately not as rare. Early antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit experimental RCC cell line, Caki-1, in vitro and in vivo. GHRH itself acts as an autocrine/paracrine growth factor in human cancers, including RCC. Herein, we investigate the effects of novel and highly potent new antagonists of GHRH on the growth of three RCC cell lines with different primary tumor sites. METHODS: The expression of GHRH receptor in all three cell lines was evaluated by ligand competition studies. The in vitro influence of GHRH antagonists designated MIA-602, MIA-604, MIA-606 and MIA-690 on cell viability was assessed by MTS assay in ACHN, A498, and 786-0 human RCC cells. GHRH antagonists were given at a dose of 5μg daily in these three nude-mice xenograft models in vivo. Cell cycle parameters were analyzed by laser flow cytometry. RESULTS: Ligand competition studies revealed specific, high affinity binding sites for GHRH receptor in all three RCC cell lines. GHRH antagonists inhibited the proliferation of all three RCC cells in a dose dependent manner. GHRH antagonists caused significant inhibition of tumor growth of ACHN, A498, and 786-0 RCCs ranging from 53-75% after 35 days of treatment (p<0.001). Treatment of ACHN and A498 cells with 10μM MIA-602 and MIA-690 (5 and 10μM) led to a significant increase in number of cells with subG1 DNA content, suggesting apoptosis. CONCLUSIONS: The effectiveness of the new and novel GHRH antagonists in inhibiting growth of experimental RCC models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists is mainly due to direct suppressive effects exerted through GHRH receptors. Further biochemical and histological evaluation is warranted to explore the mechanisms of action of GHRH antagonists in RCC. Citation Format: Ferenc G. Rick, Andrew Abi-Chaker, Luca Szalontay, Norman L. Block, Gabor Halmos, Mehrdad Nadji, Andrew V. Schally. Powerful inhibition of human renal cell carcinomas with antagonists of growth hormone-releasing hormone (GHRH): a preclinical study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 91. doi:10.1158/1538-7445.AM2013-91