Inhibition of growth, production of insulin-like growth factor-II (IGF-II), and expression of IGF-II mRNA of human cancer cell lines by antagonistic analogs of growth hormone-releasing hormone in vitro

Antagonistic analogs of growth hormone-releasing hormone (GHRH) suppress gr owth of various tumors in in vivo. This effect is exerted in part through i nhibition of the GHRH-GH-insulin-like growth factor (IGF)-I axis. Neverthel ess, because autocrine/paracrine control of proliferation by IGF-II also is a major factor in many tumors, the interference with this growth-stimulati ng pathway would offer another approach to tumor control. We thus investiga ted whether GHRH antagonists MZ-4-14 and MZ-5-156 also act an the tumor cel ls directly by blocking the production of IGF-II, An increase in the IGF-II concentration in the media during culture was found in 13 of 26 human canc er cell lines tested. Reverse transcription-PCR studies on 8 of these cell lines showed that they also expressed IGF-II mRNA, Intagonists of GHRH sign ificantly inhibited the rate of proliferation of mammary (MDA-MB-468 and ZR -75-1), prostatic (PC-3 and DU-145), and pancreatic (MiaPaCa-2, Sw-1990, an d Capan-2) cancer cell lines as shown by colorimetric and [3(H)] thymidine incorporation tests and reduced the expression of IGF-Il mRNA in the cells and the concentration of IGF-II secreted into the culture medium. Growth an d IGF-II production of lung (H-23 and H-69) and ovarian (OV-1063) cancer ce lls that express mRNA for IGF-II and excrete large quantities of IGF-II als o was marginally suppressed by the antagonists. These Findings suggest that antagonistic analogs of GHRH can inhibit growth of certain tumors not only by inhibiting the GHRH-GH-IGF-I asis, but also by reducing the IGF-II prod uction and by interfering with the autocrine regulatory pathway.