Monitoring of Gefitinib Sensitivity with Radioiodinated PHY Based on EGFR Expression
Monitoring of Gefitinib Sensitivity with Radioiodinated PHY Based on EGFR Expression
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DOI：
10.1248/bpb.b13-00559
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发表时间：
2014-03-01
影响因子：
2
通讯作者：
Ohmomo, Yoshiro
中科院分区：
文献类型：
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作者：
Yoshimoto, Mitsuyoshi;Hirata, Masahiko;Ohmomo, Yoshiro
表皮生长因子受体（Epidermal growth factor receptor，埃格）在肿瘤细胞中特异性表达，是肿瘤诊断和治疗的重要靶点。EGFR-酪氨酸激酶（TK）抑制剂如吉非替尼和厄洛替尼广泛用于治疗非小细胞肺癌（NSCLC）。在这项研究中，我们调查了放射性碘标记的4-（3-碘苯氧基）-6，7-二乙氧基-喹唑啉（PRY），这是一个候选的EGFR-TK显像剂的单光子发射计算机断层扫描（SPECT）是否能够预测吉非替尼的敏感性。我们使用了四种NSCLC细胞系A549（野生型EGFR）、111650（突变型埃格; del E746_A750）、111975（突变型埃格; L 858 R，T790 M）和113255（突变型EGFR; L 858 R）和一种表皮样癌细胞系A431（野生型EGFR）。细胞增殖实验和Western blotting显示EGFR高表达的A431和143255对吉非替尼敏感性高。另一方面，A549、111650和111975对吉非替尼的敏感性要低得多。阻断研究显示，吉非替尼降低了荷A431小鼠中I-125-PHY的肿瘤摄取。此外，体内肿瘤对I-125-PHY的吸收与吉非替尼对细胞增殖的IC 50相关。在本研究中，肿瘤对I-125-PHY的摄取与吉非替尼的敏感性相关，这种摄取是基于埃格的表达水平，而不是突变状态。虽然突变状态是预测吉非替尼敏感性的最重要因素，但EGFR的丰富表达对于EGFR-TK抑制剂治疗至关重要。因此，放射性碘标记的PRY是一种潜在的成像剂，可以根据EGFR表达水平预测吉非替尼的敏感性，但需要对成像剂进行进一步修改以准确估计突变状态。
Epidermal growth factor receptor (EGER) is attractive target for tumor diagnosis and therapy, as it is specifically and abundantly expressed in tumor cells. EGFR-tyrosine kinase (TK) inhibitors such as gefitinib and erlotinib are widely used in the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated whether radioiodinated 4-(3-iodo-phenoxy)-6,7-diethoxy-quinazoline (PRY), which is a candidate EGFR-TK imaging agent for single photon emission computed tomography (SPECT) is able to predict gefitinib sensitivity. We used four NSCLC cell lines-A549 (wild-type EGFR), 111650 (mutant EGER; del E746_A750), 111975 (mutant EGER; L858R, T790M) and 113255 (mutant EGFR; L858R)-and one epidermoid carcinoma cell line, A431 (wild-type EGFR). Cell proliferation assay and Western blotting revealed that A431 and 143255 with high EGFR expression showed high sensitivity to gefitinib. On the other hand, A549, 111650 and 111975 showed much lower sensitivity to gefitinib. The blocking study revealed that gefitinib decreased tumor uptake in I-125-PHY in A431-bearing mice. Moreover, in vivo tumor uptake of I-125-PHY was correlated with the IC50 of gefitinib for cell proliferation. In the present study, tumor uptake of I-125-PHY was correlated with the gefitinib sensitivity and this uptake was based on expression levels of EGER, but not on mutation status. Although the mutation status is the most important factor for predicting gefitinib sensitivity, the abundant expression of EGFR is essential for therapy with EGFR-TK inhibitors. Therefore, radioiodinated PRY is a potential imaging agent to predict gefitinib sensitivity based on EGFR expression levels though further modifications of the imaging agent is needed to accurately estimate the mutation status.