Antagonists of growth hormone-releasing hormone and vasoactive intestinal peptide inhibit tumor proliferation by different mechanisms: Evidence from in vitro studies on human prostatic and pancreatic cancer

Antagonists of GH-releasing hormone (GHRH) and vasoactive intestinal peptid e (VIP) inhibit the proliferation of various tumors in vitro and in vivo, b ut a comparison of their antitumor effects and mechanisms of action has not been reported to date. We recently synthesized and characterized a series of analogs, some of which are primarily GHRH antagonists (JV-1-36, JV-1-38, and JV-1-42), whereas others are more selective for VIP receptors (VPAC-R; JV-1-50, JV-1-51, JV-1-52, and JV-1-53). LNCaP human prostatic cancer cell s express VPAC-R, with predominant subtype 1 determined by RT-PCR. Our stud ies show that GHRH antagonists significantly inhibit the proliferation of b oth VPAC-R positive LNCaP cells (P < 0.001) and VPAC-R negative MiaPaCa-5 h uman pancreatic cancer cells cultured in vitro (P < 0.05 to P < 0.001). Gro wth inhibition of LNCaP cells is accompanied by a proportional reduction in prostate-specific antigen (PSA) secretion (P < 0.001). In a superfusion sy stem, the inhibitory activities of the analogs on the rate of VIP and GHRH- induced FSA secretion correlate well with their VPAC-R binding affinities t o LNCaP cell membranes. Antagonists more selective for VPAC-R display a str onger inhibition of inducible PSA release than GHRH antagonists, but have s maller effects or no effects on proliferation and PSA secretion in culture. Collectively, our findings demonstrate that the antiproliferative activity of the analogs on cancer cells is not correlated to their VPAC-R antagonis tic potencies. Because GHRH antagonists inhibit the proliferation of LNCaP cells more powerfully than VPAC-R antagonists and also suppress the growth of VPAC-R-negative MiaPaCa-2 cells, it can be concluded that their antiprol iferative effect is exerted through a mechanism independent of VPAC-R.