Rekasi Z, Varga J L, Schally A V, Halmos G, Armatis P, Groot K, Czompoly T
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70112, USA.
Endocrinology. 2000 Jun;141(6):2120-8. doi: 10.1210/endo.141.6.7511.
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 ofVPAC-R-negative MiaPaCa-2 cells, it can be concluded that their antiproliferative effect is exerted through a mechanism independent of VPAC-R.
生长激素释放激素（GHRH）和血管活性肠肽（VIP）的拮抗剂在体外和体内均能抑制多种肿瘤的增殖，但迄今为止尚未见有关它们抗肿瘤作用及作用机制比较的报道。我们最近合成并鉴定了一系列类似物，其中一些主要是GHRH拮抗剂（JV-1-36、JV-1-38和JV-1-42），而另一些对VIP受体（VPAC-R；JV-1-50、JV-1-51、JV-1-52和JV-1-53）具有更高的选择性。LNCaP人前列腺癌细胞表达VPAC-R，通过逆转录聚合酶链反应（RT-PCR）确定其主要亚型为1型。我们的研究表明，GHRH拮抗剂能显著抑制体外培养的VPAC-R阳性LNCaP细胞的增殖（P<0.001）以及VPAC-R阴性的MiaPaCa-2人胰腺癌细胞的增殖（P<0.05至P<0.001）。LNCaP细胞的生长抑制伴随着前列腺特异性抗原（PSA）分泌的相应减少（P<0.001）。在灌注系统中，类似物对VIP和GHRH诱导的PSA分泌速率的抑制活性与其对LNCaP细胞膜的VPAC-R结合亲和力密切相关。对VPAC-R更具选择性的拮抗剂对诱导的PSA释放的抑制作用比GHRH拮抗剂更强，但对培养中的细胞增殖和PSA分泌的影响较小或无影响。总体而言，我们的研究结果表明，类似物对癌细胞的抗增殖活性与其VPAC-R拮抗效力无关。由于GHRH拮抗剂比VPAC-R拮抗剂更有效地抑制LNCaP细胞的增殖，并且还能抑制VPAC-R阴性的MiaPaCa-2细胞的生长，因此可以得出结论，它们的抗增殖作用是通过独立于VPAC-R的机制发挥的。
