Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
Int J Oncol. 2015 Mar;46(3):989-98. doi: 10.3892/ijo.2015.2815. Epub 2015 Jan 7.
Although cytotoxic chemotherapy is essential in epidermal growth factor receptor (EGFR)‑mutated non‑small cell lung cancer (NSCLC), it is unclear which regimen is most effective. We retrospectively compared the efficacy of standard platinum‑based chemotherapy with that of combination chemotherapy using vinorelbine (VNR) plus dihydropyrimidine dehydrogenase‑inhibitory fluoropyrimidine (DIF) in EGFR‑mutated lung adenocarcinomas, and we investigated a potential mechanism by which the combination chemotherapy of VNR + DIF was favorable in the treatment of EGFR‑mutated lung adenocarcinoma in vitro. In our retrospective analysis, the response rate and disease control rate afforded by the VNR + DIF treatment tended to be better than those by platinum‑based chemotherapy, and the progression‑free survival of the 24 VNR + DIF‑treated patients was significantly longer than that of the 15 platinum‑based chemotherapy patients. In EGFR‑mutated PC9 cells, VNR induced EGFR dephosphorylation at a clinically achievable concentration. 1BR3‑LR cells, a line of fibroblast cells transfected with a mutant EGFR construct, were completely resistant to gefitinib in the medium containing 10% fetal bovine serum (FBS), whereas the sensitivity of these cells to gefitinib was increased in 0.5% FBS‑containing medium. Similarly, the sensitivity of 1BR3‑LR cells to VNR was increased when they were cultured in low‑serum condition. In addition, sodium orthovanadate (Na3VO4) inhibited the EGFR dephosphorylation induced by VNR or gefitinib and suppressed the cell growth inhibition by these agents in PC9 cells. VNR and gefitinib showed synergistic cell growth inhibition in combination with 5‑fluorouracil (5‑FU) in PC9 cells. We propose that the EGFR dephosphorylation induced by VNR is related to cell growth inhibitory activity of VNR, and that this is one of the mechanisms of the synergistic effect of VNR + 5‑FU in EGFR‑mutated lung cancer cells. In conclusion, the combination chemotherapy of VNR + DIF may be a promising treatment for NSCLC patients with EGFR mutations.
虽然细胞毒性化疗在表皮生长因子受体 (EGFR) 突变型非小细胞肺癌 (NSCLC) 中必不可少，但哪种方案最有效尚不清楚。我们回顾性比较了标准铂类化疗与长春瑞滨 (VNR) 联合二氢嘧啶脱氢酶抑制剂氟嘧啶 (DIF) 联合化疗在 EGFR 突变型肺腺癌中的疗效，并探讨了 VNR + DIF 联合化疗在体外治疗 EGFR 突变型肺腺癌中的潜在机制。在我们的回顾性分析中，VNR + DIF 治疗的缓解率和疾病控制率倾向于优于铂类化疗，并且 24 例接受 VNR + DIF 治疗的患者的无进展生存期明显长于 15 例接受铂类化疗的患者。在 EGFR 突变的 PC9 细胞中，VNR 在临床可达到的浓度下诱导 EGFR 去磷酸化。转染突变型 EGFR 构建体的成纤维细胞系 1BR3-LR 细胞在含有 10%胎牛血清 (FBS) 的培养基中对吉非替尼完全耐药，而当这些细胞在含有 0.5%FBS 的培养基中时，它们对吉非替尼的敏感性增加。同样，在低血清条件下培养时，1BR3-LR 细胞对 VNR 的敏感性增加。此外，正钒酸钠 (Na3VO4) 抑制 VNR 或吉非替尼诱导的 EGFR 去磷酸化，并抑制这些药物在 PC9 细胞中的细胞生长抑制作用。VNR 和吉非替尼与 5-氟尿嘧啶 (5-FU) 联合在 PC9 细胞中表现出协同的细胞生长抑制作用。我们提出，VNR 诱导的 EGFR 去磷酸化与 VNR 的细胞生长抑制活性有关，这是 VNR + 5-FU 在 EGFR 突变型肺癌细胞中协同作用的机制之一。总之，VNR + DIF 联合化疗可能是治疗 EGFR 突变型 NSCLC 患者的一种有前途的方法。
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