Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, Florida, USA.
Cancer. 2012 Feb 1;118(3):670-80. doi: 10.1002/cncr.26291. Epub 2011 Jul 12.
Antagonists of growth hormone-releasing hormone (GHRH) inhibit the proliferation of various human cancer cell lines and experimental tumors by mechanisms that include direct action on GHRH receptors in cancer cells.
In this study, the effects of newly synthesized GHRH antagonists, MIA-313, MIA-602, MIA-604, and MIA-610, were investigated in 2 human ovarian epithelial adenocarcinoma cell lines, OVCAR-3 and SKOV-3, in vitro and in vivo. The expression of receptors for GHRH was demonstrated by Western blot analysis and ligand competition methods in the OVCAR-3 and SKOV-3 cell lines and in tumors from those cells grown in athymic nude mice. The effects of GHRH antagonists on the secretion of vascular endothelial growth factor (VEGF) by OVCAR-3 cells and on the vascularization of OVCAR-3 xenografts also were evaluated.
Both the pituitary and the splice variant type 1 (SV1) GHRH receptors were detected in the 2 cell lines and in tumor xenografts, and SV1 was expressed at higher levels. Cell viability assays revealed the antiproliferative effect of all GHRH antagonists that were. Maximal tumor growth inhibition was approximately 75% in both models. MIA-313 and MIA-602 decreased VEGF secretion of OVCAR-3 cells, as measured by enzyme-linked immunosorbent assay, and reduced tumor vascularization in a Matrigel plug assay, but caused no change in the expression of VEGF or VEGF receptor in the terminal ileum of mice with OVCAR-3 tumors.
Results from the current study indicated that a he novel approach based on GHRH antagonists may offer more effective therapeutic alternatives for patients with advanced ovarian cancer and who do not tolerate conventional anti-VEGF therapy.
生长激素释放激素（GHRH）拮抗剂通过包括直接作用于癌细胞中的 GHRH 受体在内的机制，抑制各种人类癌细胞系和实验肿瘤的增殖。
在这项研究中，研究了新合成的 GHRH 拮抗剂 MIA-313、MIA-602、MIA-604 和 MIA-610 在体外和体内对 2 个人卵巢上皮腺癌细胞系 OVCAR-3 和 SKOV-3 的影响。通过 Western blot 分析和配体竞争方法，在 OVCAR-3 和 SKOV-3 细胞系以及在从这些细胞在裸鼠中生长的肿瘤中证实了 GHRH 受体的表达。还评估了 GHRH 拮抗剂对 OVCAR-3 细胞血管内皮生长因子（VEGF）分泌的影响以及 OVCAR-3 异种移植物的血管生成的影响。
在 2 种细胞系和肿瘤异种移植物中均检测到垂体和剪接变体 1（SV1）GHRH 受体，并且 SV1 的表达水平更高。细胞活力测定显示所有 GHRH 拮抗剂均具有抗增殖作用。在两种模型中，最大肿瘤生长抑制率约为 75%。MIA-313 和 MIA-602 通过酶联免疫吸附试验降低了 OVCAR-3 细胞的 VEGF 分泌，并降低了 Matrigel 塞测定中的肿瘤血管生成，但在携带 OVCAR-3 肿瘤的小鼠的回肠末端未引起 VEGF 或 VEGF 受体的表达发生变化。
本研究结果表明，基于 GHRH 拮抗剂的新方法可能为不能耐受常规抗 VEGF 治疗的晚期卵巢癌患者提供更有效的治疗选择。
