Bajo A M, Schally A V, Groot K, Szepeshazi K
Endocrine Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
Br J Cancer. 2004 Jan 12;90(1):245-52. doi: 10.1038/sj.bjc.6601404.
The overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factors (IGFs) plays a role in the migration and proliferation of endothelial cells in many cancers. Consequently, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists on the expression of these angiogenic factors, the activities of matrix metalloproteinases (MMPs)-2 and -9, as well as the vascular density in MDA-MB-435 human oestrogen-independent breast cancers. Nude mice bearing orthotopic xenografts of MDA-MB-435 breast cancers were treated with bombesin/GRP antagonists for 6 weeks. Daily administration of 20 microg of RC-3095 or 10 microg of RC-3940-II significantly decreased the weight of MDA-MB-435 cancers by 44 and 53%, respectively. The inhibition of tumour growth was associated with a substantial reduction in the expression of mRNA and protein levels of basic fibroblast growth factor (bFGF), IGF-II and VEGF-A in the tumours. Both bombesin/GRP antagonists significantly decreased the vessel density of the tumours by about 37%, as shown by immunohistochemical detection of vessels on tumour slides. Gelatinolytic activities, detected by zymography, revealed a 33-46% reduction in MMP-9 activity after the treatment with either antagonist. In vitro studies revealed that MDA-MB-435 cells secrete bFGF, IGF-II and VEGF-A, and the secretion of these factors is inhibited by RC-3095 and RC-3940-II. This study demonstrates the antiangiogenic effect of bombesin/GRP antagonists RC-3095 and RC-3940-II, and underscores their possible therapeutic application for treatment of breast cancers.
血管内皮生长因子（VEGF）、成纤维细胞生长因子（FGF）和胰岛素样生长因子（IGF）等血管生成因子的过表达在许多癌症的内皮细胞迁移和增殖中发挥作用。因此，我们研究了蛙皮素/胃泌素释放肽（GRP）拮抗剂对这些血管生成因子表达、基质金属蛋白酶（MMP）-2和-9活性以及MDA-MB-435人雌激素非依赖性乳腺癌血管密度的影响。将携带MDA-MB-435乳腺癌原位异种移植的裸鼠用蛙皮素/GRP拮抗剂治疗6周。每天给予20μg的RC-3095或10μg的RC-3940-II可使MDA-MB-435癌的重量分别显著降低44%和53%。肿瘤生长的抑制与肿瘤中碱性成纤维细胞生长因子（bFGF）、IGF-II和VEGF-A的mRNA和蛋白质水平表达的大幅降低有关。如通过肿瘤切片上血管的免疫组织化学检测所示，两种蛙皮素/GRP拮抗剂均使肿瘤的血管密度显著降低约37%。通过酶谱法检测的明胶酶活性显示，用任何一种拮抗剂治疗后MMP-9活性降低33%-46%。体外研究表明，MDA-MB-435细胞分泌bFGF、IGF-II和VEGF-A，并且这些因子的分泌受到RC-3095和RC-3940-II的抑制。本研究证明了蛙皮素/GRP拮抗剂RC-3095和RC-3940-II的抗血管生成作用，并强调了它们在乳腺癌治疗中可能的治疗应用。
