Insulin-like growth factor (IGF) binding protein-1 (BP-1) inhibits IGF-mediated proliferation of some breast cancer cell lines in vitro. Here we examined whether recombinant human wild-type IGFBP-1 (WT-BP-1) and IGFBP-1 conjugated with polyethylene glycol (PEG-BP-1) could inhibit breast cancer growth. Three breast cancer cell lines were usedMCF-7, MDA-MB-231 and MDA-MB-435A (ascites model). The cells were grown in agar with or without the BP-1 conjugates to investigate their effect on colony formation. Both WT-BP-1 and PEG-BP-1 inhibited anchorage-independent growth (AIG) of MCF-7 and MDA-MB-435A cells. AIG of MDA-MB-231 cells was not inhibited by PEG-BP-1, whereas WT-BP-1 significantly stimulated colony number. We also tested both forms of BP-1 in xenograft tumour models. Two solid breast tumour models were studied using MCF-7 and MDA-MB-231 cell lines, and one ascites model using the MDA-MB-435A cell line. PEG-BP-1 inhibited malignant ascites formation in the MDA-MB-435A model. Conversely, PEG-BP-1 did not significantly inhibit MCF-7 xenograft growth. However, the MDA-MB-231 tumour growth curves were significantly different by a constant amount, suggesting that PEG-BP-1 treatment inhibited early tumour growth of this cell line. In contrast, WT-BP-1 was ineffective in the MDA-MB-231 tumours. These data show that anti-IGF strategies can be used to inhibit breast cancer cell growth. Since PEG-BP-1 inhibited the in vivo, but not in vitro, growth of MDA-MB-231, we speculate that PEG-BP-1 may block host IGF functions required for optimal tumorigenesis. Because PEG-BP-1 has a prolonged serum half-life compared to WT-BP-1, we conclude that improvements in BP-1 pharmacological properties enhanced its antitumour effects in vivo.

译文

胰岛素样生长因子 (IGF) 结合蛋白-1 (BP-1) 在体外抑制IGF介导的某些乳腺癌细胞系的增殖。在这里,我们研究了重组人野生型IGFBP-1 (WT-BP-1) 和与聚乙二醇 (PEG-BP-1) 偶联的IGFBP-1是否可以抑制乳腺癌的生长。usedMCF-7,MDA-MB-231和MDA-MB-435A三种乳腺癌细胞系 (腹水模型)。将细胞在具有或不具有BP-1缀合物的琼脂中生长,以研究它们对集落形成的影响。WT-BP-1和PEG-BP-1均抑制MCF-7和MDA-MB-435A细胞的锚定非依赖性生长 (AIG)。MDA-MB-231细胞的AIG不受PEG-BP-1抑制,而WT-BP-1显着刺激了集落数。我们还在异种移植肿瘤模型中测试了两种形式的BP-1。使用MCF-7和MDA-MB-231细胞系研究了两个实体乳腺肿瘤模型,以及使用MDA-MB-435A细胞系研究了一个腹水模型。在MDA-MB-435A模型中,PEG-BP-1抑制了恶性腹水的形成。相反,PEG-BP-1没有显著抑制MCF-7异种移植生长。然而,MDA-MB-231的肿瘤生长曲线以恒定的量显着不同,表明PEG-BP-1治疗抑制了该细胞系的早期肿瘤生长。相反,WT-BP-1在MDA-MB-231肿瘤中无效。这些数据表明,抗IGF策略可用于抑制乳腺癌细胞的生长。由于PEG-BP-1抑制了MDA-MB-231的体内生长,而不是体外生长,因此我们推测PEG-BP-1可能会阻断最佳肿瘤发生所需的宿主IGF功能。由于与WT-BP-1相比,PEG-BP-1的血清半衰期延长,因此我们得出结论,BP-1药理特性的改善增强了其体内抗肿瘤作用。

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