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Inhibition of Growth of Experimental Human Endometrial Cancer by an Antagonist of Growth Hormone-Releasing Hormone

Endocrine, Polypeptide, and Cancer Institute (J.B.E., G.K., A.V.S., G.L.T., K.G., A.H., P.A., M.Z., J.L.V., G.H.), Veterans Affairs Medical Center; and Section of Experimental Medicine (J.B.E., G.K., A.V.S., G.L.T., K.G., A.H., P.A., M.Z., J.L.V., G.H.), Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. Andrew V. Schally, Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, Louisiana 70112-1262. E-mail: aschally{at}tulane.edu.

Antagonists of GHRH are being developed for the treatment of various cancers. In this study we investigated in vivo and in vitro the effects of the GHRH antagonist MZ-J-7-118 and its mechanism of action in HEC-1A human endometrial cancer. Treatment of nude mice bearing HEC-1A xenografts with 10 µg/d MZ-J-7-118 for 6 wk significantly inhibited the volume of HEC-1A tumors by 43%, tumor weight by 40% compared with controls and prolonged the tumor doubling time from 18.7 ± 1.4 to 25.4 ± 3.8 d. Administration of 20 µg MZ-J-7-118, sc, twice a day significantly (P < 0.05) decreased HEC-1A growth, as evidenced by a 57.9% decrease in tumor volume, a 50.7% reduction in tumor weight, and the extension of tumor doubling time from 17.5 ± 2.8 to 36.4 ± 6.5 d. Therapy with GHRH antagonists significantly decreased serum IGF-I levels in experiment 1, and significantly increased tumoral IGF-I levels in experiment 2 in treated mice. Levels of IGF-II and vascular endothelial growth factor-A in tumors were not changed. Specific high affinity binding sites for GHRH were found on HEC-1A tumor membranes using ligand competition assays with ¹²⁵I-labeled GHRH antagonist JV-1-42. MZ-J-7-118 displaced radiolabeled JV-1-42 with an IC₅₀ of 0.13 ± 0.04 nM. The expression of mRNA for GHRH and splice variants of the GHRH receptor in HEC-1A tumors was demonstrated by real-time RT-PCR analysis. HEC-1A cells cultured in vitro secreted GHRH into the medium. The GHRH antagonist MZ-J-7-118 inhibited the growth of HEC-1A cells in vitro. Our results indicate that GHRH antagonists can reduce the growth of human endometrial cancer and could be used as an alternative adjuvant therapy for the management of endometrial cancer.

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