Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Nanjing, 211166, China.
Invest New Drugs. 2021 Apr;39(2):458-468. doi: 10.1007/s10637-020-01003-3. Epub 2021 Jan 21.
Chemotherapy is usually the subsequent treatment for non-small cell lung cancer patients with acquired radioresistance after long-term fractionated radiotherapy. However, few studies have focused on the selection of chemotherapeutic drugs to treat lung adenocarcinoma patients with radioresistance. Our study compared the sensitivity changes of lung adenocarcinoma cells to conventional chemotherapeutic drugs under radioresistant circumstances by using three lung adenocarcinoma cell models, which were irradiated with fractionated X-rays at a total dose of 60 Gy. The results showed that the toxicities of paclitaxel, docetaxel and SN-38 were increased in radioresistant cells. The IC values of docetaxel and SN-38 decreased 0 ~ 3 times and 3 ~ 36 times in radioresistant cells, respectively. Notably, the A549 radioresistant cells were approximately 36 times more sensitive to SN-38 than the parental cells. Further results revealed that the downregulation of the efflux transporter BCRP by long-term fractionated irradiation was an important factor contributing to the increased cytotoxicity of SN-38. In addition, the reported miRNAs and transcriptional factors that regulate BCRP did not participate in the downregulation. In conclusion, these results presented important data on the sensitivity changes of lung adenocarcinoma cells to chemotherapeutic drugs after acquiring radioresistance and suggested that irinotecan (the prodrug of SN-38) might be a promising drug candidate for lung adenocarcinoma patients with acquired radioresistance.
化疗通常是经过长期分割放疗后获得放射抵抗的非小细胞肺癌患者的后续治疗。然而，很少有研究关注选择化疗药物来治疗具有放射抵抗的肺腺癌患者。我们的研究通过使用三个经分割 X 射线照射总剂量为 60Gy 的肺腺癌细胞模型，比较了肺腺癌细胞在放射抵抗情况下对常规化疗药物的敏感性变化。结果表明，紫杉醇、多西紫杉醇和 SN-38 的毒性在放射抵抗细胞中增加。在放射抵抗细胞中，多西紫杉醇和 SN-38 的 IC 值分别降低了 03 倍和 336 倍。值得注意的是，A549 放射抵抗细胞对 SN-38 的敏感性比亲本细胞高约 36 倍。进一步的结果表明，长期分割照射下调外排转运蛋白 BCRP 是 SN-38 细胞毒性增加的一个重要因素。此外，报道的调节 BCRP 的 miRNA 和转录因子没有参与下调。总之，这些结果提供了关于肺腺癌细胞获得放射抵抗后对化疗药物敏感性变化的重要数据，并表明伊立替康（SN-38 的前药）可能是具有放射抵抗的肺腺癌患者的一种有前途的药物候选物。
