Zhang Peilin, Gao Wei Yi, Turner Steven, Ducatman Barbara S
Department of Pathology & Cancer Center, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, WV 26506-9203, USA.
Mol Cancer. 2003 Jan 3;2:1. doi: 10.1186/1476-4598-2-1.
Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer.
We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2-3 microM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 microM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor alpha, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR alpha phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-alpha expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-alpha.
These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.
格列卫（又名STI571、伊马替尼）是美国食品药品监督管理局（FDA）最近批准用于治疗慢性粒细胞白血病的抗肿瘤药物。格列卫特异性结合BCR-ABL酪氨酸激酶并抑制酪氨酸激酶活性。它与另外两个重要的膜酪氨酸激酶受体c-kit和血小板衍生生长因子（PDGF）受体发生交叉反应。我们试图研究格列卫在非小细胞肺癌治疗中是否具有潜在作用。
我们已经表明，单独使用格列卫可以剂量依赖性方式抑制A549肺癌细胞生长，格列卫抑制A549细胞生长的最佳浓度在2 - 3微摩尔（IC50）范围内。我们还表明，A549细胞对顺铂治疗耐药（IC50为64微摩尔）。将格列卫添加到用顺铂处理的A549细胞中会产生协同细胞杀伤作用，这表明格列卫可以增强顺铂对A549细胞的作用。我们还表明，A549肺癌细胞表达血小板衍生生长因子受体α，格列卫对A549细胞的抑制作用可能是通过抑制PDGFRα磷酸化介导的。我们进一步通过组织微阵列和免疫组织化学检测了33例肺癌患者的肿瘤标本，以观察PDGFR-α表达的频率。我们发现，18例鳞状细胞癌中有16例（89%）、11例腺癌中有11例（100%）以及4例小细胞肺癌中有4例（100%）表达PDGFR-α。
这些结果表明格列卫作为非小细胞肺癌辅助治疗药物具有潜在作用。
