Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization
Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization
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DOI：
10.1093/jnci/93.12.921
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发表时间：
2001-06-20
期刊：
影响因子：
--
通讯作者：
Schmidt-Ullrich, RK
中科院分区：
文献类型：
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作者：
Lammering, G;Hewit, TH;Schmidt-Ullrich, RK
背景：人类癌细胞暴露于电离辐射会激活表皮生长因子受体（EGFR），进而介导细胞保护反应，降低细胞对电离辐射的敏感性。显性失活 EGFR 突变体 EGFR-CD533 的过度表达通过阻止辐射诱导的受体及其下游效应器的激活来破坏细胞保护反应。为了研究EGFR-CD533基因治疗是否具有增加肿瘤细胞放射敏感性的潜力，我们将含有EGFR-CD533的腺病毒载体引入裸鼠的异种移植肿瘤中，并评估肿瘤对电离辐射的反应。方法：通过输注腺病毒载体 Ad-EGFR-CD533 或含有 β-半乳糖苷酶基因 Ad-LacZ 的对照载体，转导从人乳腺癌细胞系 MDA-MB-231 建立的异种移植肿瘤。然后将转导的肿瘤暴露于治疗剂量范围内的辐射，并通过检查免疫沉淀的 EGFR 的酪氨酸磷酸化来评估辐射诱导的 EGFR 激活。通过集落形成试验在体外测定放射增敏作用。所有统计检验都是双面的。结果：Ad-LacZ对MDA-MB-231肿瘤的转导效率为44%。肿瘤中 EGFR-CD533 的表达使辐射诱导的 EGFR 激活降低了 2.94 倍（95% 置信区间 [CI] = 2.23 至 4.14）。 Ad-EGFR-CD533 转导的肿瘤的放射敏感性在统计学上显着高于 Ad-LacZ 转导的肿瘤（46%；P < .001），剂量增强比为 1.85（95% CI = 1.54 至 2.51）。结论：用 Ad-EGFR-CD533 转导 MDA-MB-231 异种移植肿瘤可赋予显性阴性 EGFR 表型并诱导肿瘤放射增敏。因此，通过过度表达 EGFR-CD533 破坏 EGFR 功能可能有望成为一种增强肿瘤细胞对电离辐射敏感性的基因治疗方法。
Background: Exposure of human cancer cells to ionizing radiation activates the epidermal growth factor receptor (EGFR), which, in turn, mediates a cytoprotective response that reduces the cells' sensitivity to ionizing radiation. Overexpression of a dominant-negative EGFR mutant, EGFR-CD533, disrupts the cytoprotective response by preventing radiation-induced activation of the receptor and its downstream effecters. To investigate whether gene therapy with EGFR-CD533 has the potential to increase tumor cell radiosensitivity, we introduced an adenoviral vector containing EGFR-CD533 into xenograft tumors in nude mice and evaluated the tumor response to ionizing radiation. Methods: Xenograft tumors established from the human mammary carcinoma cell line MDA-MB-231 were transduced via infusion with the adenoviral vector Ad-EGFR-CD533 or a control vector containing the beta -galactosidase gene, Ad-LacZ. The transduced tumors were then exposed to radiation in the therapeutic dose range, and radiation-induced EGFR activation was assessed by examining the tyrosine phosphorylation of immunoprecipitated EGFR. Radiosensitization was determined in vitro by colony-formation assays. All statistical tests were two-sided. Results: The transduction efficiency of MDA-MB-231 tumors by Ad-LacZ was 44%. Expression of EGFR-CD533 in tumors reduced radiation-induced EGFR activation by 2.94-fold (95% confidence interval [CI] = 2.23 to 4.14). The radiosensitivity of Ad-EGFR-CD533-transduced tumors was statistically significantly higher (46%; P < .001) than that of Ad-LacZ-transduced tumors, yielding a dose-enhancement ratio of 1.85 (95% CI = 1.54 to 2.51). Conclusions: Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.