Insulin-like growth factor-I receptor signaling blockade combined with radiation
Insulin-like growth factor-I receptor signaling blockade combined with radiation
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DOI：
10.1158/0008-5472.can-06-2000
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Harari, Paul M.
中科院分区：
文献类型：
--
作者：
Allen, Gregory W.;Saba, Corey;Harari, Paul M.
胰岛素样生长因子-I受体(IGF-IR)信号转导与细胞增殖、细胞凋亡、肿瘤发生、转移和对细胞毒性癌症治疗的抵抗有关。因此，靶向阻断IGF-IR信号与细胞毒治疗相结合，可能会比单独使用传统治疗产生更好的抗癌效果。在这项研究中，一种全人抗IGF-IR单抗A12(ImClone Systems，Inc.，New York，NY)作为放射治疗的辅助手段进行了检测。IGF-IR在不同的细胞系中都有表达，而A12靶向阻断IGF-IR则抑制IGF-IR的磷酸化和下游效应因子Akt和丝裂原激活蛋白激酶的激活。A12以剂量依赖的方式抑制锚定依赖的增殖和异种移植瘤生长，特别是对非小细胞肺癌细胞系。A12可抑制在锚定依赖条件下生长的H2 6和H460细胞的克隆辐射存活，表现出对IGF-IR阻断的辐射剂量增强效应。辐射后，A12可抑制A549和H460细胞的非锚定集落形成。在H460异种移植模型中，联合使用A12和放射治疗比单独使用任何一种方法都能显著增强抗肿瘤效果。这些作用可能是通过促进细胞培养中观察到的辐射诱导的双链DNA损伤和凋亡来实现的。综上所述，这些结果验证了IGF-IR信号转导阻断作为一种有前景的策略来提高人类肿瘤的放射治疗效果，为未来的临床试验奠定了基础。
Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Post-radiation, anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiationi-nduced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.