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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 Cancers¹

Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center (Z.R., J.L.V., A.V.S., G.H., P.A., K.G., T.C.), and Department of Medicine, Tulane University School of Medicine (Z.R., J.L.V., A.V.S., G.H., T.C.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. Andrew V. Schally (151), Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, Louisiana 70112-1262.

Antagonists of GH-releasing hormone (GHRH) and vasoactive intestinal peptide (VIP) inhibit the proliferation of various tumors in vitro and in vivo, but 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 cells express VPAC-R, with predominant subtype 1 determined by RT-PCR. Our studies show that GHRH antagonists significantly inhibit the proliferation of both VPAC-R positive LNCaP cells (P < 0.001) and VPAC-R negative MiaPaCa-2 human pancreatic cancer cells cultured in vitro (P < 0.05 to P < 0.001). Growth inhibition of LNCaP cells is accompanied by a proportional reduction in prostate-specific antigen (PSA) secretion (P < 0.001). In a superfusion system, the inhibitory activities of the analogs on the rate of VIP and GHRH-induced PSA secretion correlate well with their VPAC-R binding affinities to LNCaP cell membranes. Antagonists more selective for VPAC-R display a stronger inhibition of inducible PSA release than GHRH antagonists, but have smaller 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 antagonistic 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 antiproliferative effect is exerted through a mechanism independent of VPAC-R.

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