Kanashiro Celia A, Schally Andrew V, Cai R-Z, Halmos Gabor
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-1262, USA.
Anticancer Drugs. 2005 Feb;16(2):159-65. doi: 10.1097/00001813-200502000-00007.
We have investigated the antitumor effects and the mechanism of action of antagonists of bombesin/gastrin-releasing peptide (GRP), RC-3940-II and RC-3940-Et, on the growth of U-118MG human malignant glioma xenografted into nude mice. Tumors volume was measured weekly, and after 6 weeks of treatment with GRP antagonists the tumors were analyzed by Western blot assays for the expression of vascular endothelial growth factor (VEGF), protein kinase C (PKC)-alpha, the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bax. A radioreceptor assay was used to characterize the receptors for bombesin/GRP. Specific high-affinity receptors for bombesin were found in U-118MG tumors, and their growth was reduced by 52.5% by RC-3940-II and 72.6% by RC-3940-Et (both p<0.01). The tumor doubling time was prolonged by 4.6 and 12 days after treatment with RC-3940-II and RC-3940-Et, respectively, compared to controls (p<0.05). Both antagonists caused a significant (p<0.05) decrease of about 28% in the levels of VEGF protein and a reduction of approximately 35% in the expression of PKCalpha. The relative ratio of Bcl-2:Bax was also diminished by around 70% by both analogs, indicating a net apoptotic gain and the efficacy of treatment. Our results suggest that bombesin/GRP antagonists, RC-3940-II and RC-3940-Et, could be of value for the treatment of human glioblastomas.
我们研究了蛙皮素/胃泌素释放肽（GRP）拮抗剂RC - 3940 - II和RC - 3940 - Et对移植到裸鼠体内的U - 118MG人恶性胶质瘤生长的抗肿瘤作用及其作用机制。每周测量肿瘤体积，在用GRP拮抗剂治疗6周后，通过蛋白质印迹分析检测肿瘤中血管内皮生长因子（VEGF）、蛋白激酶C（PKC）-α、抗凋亡蛋白Bcl - 2和促凋亡蛋白Bax的表达。采用放射受体分析法对蛙皮素/GRP受体进行表征。在U - 118MG肿瘤中发现了特异性高亲和力的蛙皮素受体，RC - 3940 - II使其生长减少了52.5%，RC - 3940 - Et使其生长减少了72.6%（两者p<0.01）。与对照组相比，用RC - 3940 - II和RC - 3940 - Et治疗后，肿瘤倍增时间分别延长了4.6天和12天（p<0.05）。两种拮抗剂均使VEGF蛋白水平显著降低约28%（p<0.05），PKCα的表达降低约35%。两种类似物还使Bcl - 2:Bax的相对比例降低了约70%，表明有净凋亡增加及治疗效果。我们的结果表明，蛙皮素/GRP拮抗剂RC - 3940 - II和RC - 3940 - Et可能对治疗人类胶质母细胞瘤有价值。
