A correlation of endocrine and anticancer effects of some antagonists of GHRH

Peptides. 2010 Oct;31(10):1839-46. doi: 10.1016/j.peptides.2010.07.006. Epub 2010 Jul 13.

Abstract

GHRH receptor antagonists inhibit growth and metastasis of a large number of experimental tumors expressing the pituitary GHRH receptor (pGHRH-R) and its major splice variant SV1. In this study, using Western blot, we demonstrated that DBTRG-05 and U-87MG human glioblastoma cell lines express pGHRH-R at levels 6-15 times higher than SV1. To reveal a correlation between the anticancer activity and the endocrine potency on inhibition of GH release, we compared the antitumor effect of GHRH antagonists JV-1-63 and MZJ-7-138 on growth of DBTRG-05 human glioblastomas grafted into athymic nude mice with their inhibitory potency on GH release. JV-1-63 strongly suppressed the stimulated GH secretion induced by clonidine in rats and inhibited the exogenous GHRH-induced GH surge by 88-99% in vivo and in vitro. MZJ-7-138 decreased the stimulated GH secretion by 58% in vitro and showed only a tendency to inhibit GH secretion in vivo. The strong inhibitor of GH release JV-1-63 reduced tumor growth of DBTRG-05 glioblastomas in nude mice by 46%, while the weak GH release suppressor MZJ-7-138 did not have an effect. Exposure of DBTRG-05 cells to the GHRH antagonists in vitro caused an upregulation of mRNA expression for pGHRH-R and a downregulation of SV1 expression, with JV-1-63 having significantly greater effects than MZJ-7-138. Our results demonstrate that a positive correlation exists between the endocrine potency and the antiproliferative efficacy of GHRH antagonists in tumors strongly expressing pGHRH-R.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Animals
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Glioblastoma / drug therapy
  • Growth Hormone / metabolism
  • Growth Hormone-Releasing Hormone / antagonists & inhibitors*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Pituitary Gland / drug effects*
  • Pituitary Gland / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, LHRH / genetics
  • Receptors, LHRH / metabolism*

Substances

  • Antineoplastic Agents
  • Protein Isoforms
  • Receptors, LHRH
  • Growth Hormone
  • Growth Hormone-Releasing Hormone