Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of U-87MG Human Glioblastoma in Nude Mice

Abstract

Antagonists of growth hormone-releasing hormone(GH-RH) inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF) -I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1-36 at the dose of 20 µmg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GHRH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1-36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1-36 at 1 MM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-136 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.