Antagonists of growth hormone-releasing hormone (GH-RH) inhibit IGF-II production and growth of HT-29 human colon cancers

Insulin-like growth factors (IGFs) I and II are implicated in progression o f various tumours including colorectal carcinomas. To interfere with the pr oduction of IGFs, we treated male nude mice bearing xenografts of HT-29 hum an colon cancer with various potent growth hormone-releasing hormone (GH-RH ) antagonists. Twice daily injections of antagonist MZ-4-71, 10 mu g intrap eritoneally or 5 mu g subcutaneously (s.c.) resulted in a significant 43-45 % inhibition of tumour growth. Longer acting GH-RH antagonists. MZ-5-156 an d JV-1-36 given once daily at doses of 20 mu g s.c. produced a 43-58% decre ase in volume and weight of cancers. Histological analyses of HT-29 cancers demonstrated that both a decreased cell proliferation and an increased apo ptosis contributed to tumour inhibition. GH-RH antagonists did not change s erum IGF-I or IGF-II levels, but significantly decreased IGF-II concentrati on and reduced mRNA expression for IGF-II in tumours. In vitro studies show ed that HT-29 cells produced and secreted IGF-Il into the medium, and addit ion of MZ-5-156 dose-dependently decreased IGF-II production by about 40% a s well as proliferation of HT-29 cells. Our studies demonstrate that GH-RH antagonists inhibit growth of HT-29 human colon cancers in vivo and in vitr o. The effect of GH-RH antagonists may be mediated through a reduced produc tion and secretion of IGF-II by cancer cells. (C) 2000 Cancer Research Camp aign.