Seitz Stephan, Hohla Florian, Schally Andrew V, Moder Angelika, Engel Joerg B, Horn Felicitas, Varga Josef, Zarandi Marta, Ortmann Olaf, Köster Frank, Buchholz Stefan
Veterans Affairs Medical Center Miami, FL 33125, USA.
Oncol Rep. 2008 Nov;20(5):1289-94.
GHRH antagonists have been shown to inhibit growth of various human cancer cell lines xenografted into nude mice including estrogen receptor negative human breast cancers. Previous observations also suggest that GHRH locally produced in diverse neoplasms including breast cancer might directly affect proliferation of tumor cells. In the present study we demonstrate that a novel highly potent GHRH antagonist JMR-132 strongly inhibits the proliferation of both estrogen receptor negative SKBR 3 and estrogen receptor positive ZR 75 human breast cancer cell lines in vitro. The proliferation in vitro of ZR 75 and SKBR 3 was increased after direct stimulation with GHRH(1-29)NH2. The GHRH antagonist JMR-132 had a significant antiproliferative activity in the absence of GHRH and nullified the proliferative effect of GHRH in these cell lines. SKBR 3 and ZR 75 expressed the GHRH ligand as well as the pituitary type of GHRH-receptor, which likely appears to mediate the antiproliferative mechanisms in these cell lines. These in vitro results suggest that JMR-132 is a potent inhibitor of breast cancer growth, independent of the estrogen receptor status. Further investigations on the combination treatment with endocrine agents affecting the estrogen pathway and GRHR antagonists are needed in order to improve the treatment of breast cancer.
生长激素释放激素（GHRH）拮抗剂已被证明可抑制移植到裸鼠体内的各种人类癌细胞系的生长，包括雌激素受体阴性的人类乳腺癌细胞系。先前的观察结果还表明，在包括乳腺癌在内的多种肿瘤中局部产生的GHRH可能直接影响肿瘤细胞的增殖。在本研究中，我们证明了一种新型高效的GHRH拮抗剂JMR-132在体外能强烈抑制雌激素受体阴性的SKBR 3和雌激素受体阳性的ZR 75人乳腺癌细胞系的增殖。用GHRH(1-29)NH2直接刺激后，ZR 75和SKBR 3的体外增殖增加。GHRH拮抗剂JMR-132在没有GHRH的情况下具有显著的抗增殖活性，并消除了GHRH在这些细胞系中的增殖作用。SKBR 3和ZR 75表达GHRH配体以及垂体型GHRH受体，这可能介导了这些细胞系中的抗增殖机制。这些体外结果表明，JMR-132是一种强效的乳腺癌生长抑制剂，与雌激素受体状态无关。为了改善乳腺癌的治疗，需要进一步研究影响雌激素途径的内分泌药物与GHRH拮抗剂的联合治疗。
