Koppán M, Halmos G, Arencibia J M, Lamharzi N, Schally A V
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.
Cancer. 1998 Oct 1;83(7):1335-43. doi: 10.1002/(sici)1097-0142(19981001)83:7<1335::aid-cncr10>3.0.co;2-5.
Antagonists of bombesin/gastrin-releasing peptide (BN/GRP) have been developed to block the autocrine stimulatory effect of BN/GRP on tumors such as small cell lung carcinoma (SCLC). Although several studies have addressed the intracellular events that follow the formation of the receptor-ligand complex, the mechanism of action of BN/GRP antagonists remains unclear.
In this study the authors investigated the effect of synthetic BN/GRP antagonists RC-3095 and RC-3940-II on tumor growth and the expression of epidermal growth factor receptors (EGF-R) in H-69 SCLC. Athymic nude mice xenografted with H-69 SCLC were treated subcutaneously for 5 weeks with RC-3095 and RC-3940-II at the dose of 10 microg/animal/day.
RC-3095 decreased tumor volume by approximately 50% (P < 0.05) and RC-3940-II by 70-60% (P < 0.01). Tumor burden also was significantly decreased in the groups treated with RC-3095 and RC-3940-II. Receptor analyses demonstrated high affinity binding sites for BN/GRP and EGF on the untreated H-69 SCLC tumors. After treatment with RC-3095 and RC-3940-II, the concentration of receptors for BN/GRP was decreased by 29.0% and 36.5%, respectively (both, P < 0.01) compared with controls, and EGF-R levels were reduced by 62.3% and 63.0%, respectively (both, P < 0.01). Reverse transcriptase-polymerase chain reaction and Southern blot analyses revealed that the levels of mRNA for EGF-R in tumors were lowered by 31% (P < 0.05) and 43% (P < 0.01), respectively, after treatment with RC-3095 and RC-3940-II.
This study indicates that the inhibition of growth of H-69 SCLC by BN/GRP antagonists RC-3095 and RC-3940-II is accompanied by a marked decrease in the levels and mRNA expression of EGF-R.
已研发出蛙皮素/胃泌素释放肽（BN/GRP）拮抗剂，以阻断BN/GRP对诸如小细胞肺癌（SCLC）等肿瘤的自分泌刺激作用。尽管多项研究探讨了受体-配体复合物形成后发生的细胞内事件，但BN/GRP拮抗剂的作用机制仍不清楚。
在本研究中，作者调查了合成的BN/GRP拮抗剂RC-3095和RC-3940-II对H-69 SCLC肿瘤生长及表皮生长因子受体（EGF-R）表达的影响。将接种有H-69 SCLC的无胸腺裸鼠皮下注射RC-3095和RC-3940-II，剂量为10微克/动物/天，持续5周。
RC-3095使肿瘤体积减少约50%（P<0.05），RC-3940-II使其减少70%-60%（P<0.01）。在接受RC-3095和RC-3940-II治疗的组中，肿瘤负荷也显著降低。受体分析表明，未治疗的H-69 SCLC肿瘤上存在BN/GRP和EGF的高亲和力结合位点。用RC-3095和RC-3940-II治疗后，与对照组相比，BN/GRP受体浓度分别降低了29.0%和36.5%（均P<0.01），EGF-R水平分别降低了62.3%和63.0%（均P<0.01）。逆转录聚合酶链反应和Southern印迹分析显示，用RC-3095和RC-3940-II治疗后，肿瘤中EGF-R的mRNA水平分别降低了31%（P<0.05）和43%（P<0.01）。
本研究表明，BN/GRP拮抗剂RC-3095和RC-3940-II对H-69 SCLC生长的抑制伴随着EGF-R水平及其mRNA表达的显著降低。
