RRC ID 67813
Author Izumi H, Touge H, Igishi T, Makino H, Nishii-Ito S, Takata M, Nakazaki H, Ueda Y, Matsumoto S, Kodani M, Kurai J, Takeda K, Sakamoto T, Yanai M, Tanaka N, Nirodi CS, Shimizu E.
Title Favorable effect of the combination of vinorelbine and dihydropyrimidine dehydrogenase‑inhibitory fluoropyrimidine in EGFR‑mutated lung adenocarcinoma: retrospective and in vitro studies.
Journal Int J Oncol
Abstract 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.
Volume 46(3)
Pages 989-98
Published 2015-3-1
DOI 10.3892/ijo.2015.2815
PMID 25573239
PMC PMC4324589
MeSH Adenocarcinoma / drug therapy* Adenocarcinoma / genetics* Adenocarcinoma / mortality Adenocarcinoma / pathology Adenocarcinoma of Lung Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols / pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor / drug effects Dihydrouracil Dehydrogenase (NADP) / antagonists & inhibitors Drug Combinations ErbB Receptors / genetics* ErbB Receptors / metabolism Female Fluorouracil / administration & dosage Gefitinib Humans Kaplan-Meier Estimate Lung Neoplasms / drug therapy* Lung Neoplasms / genetics* Lung Neoplasms / mortality Lung Neoplasms / pathology Male Middle Aged Mutation Oxonic Acid / administration & dosage Quinazolines / pharmacology Retrospective Studies Tegafur / administration & dosage Treatment Outcome Vinblastine / administration & dosage Vinblastine / analogs & derivatives Vinblastine / pharmacology Vinorelbine
IF 3.899
Human and Animal Cells PC-9(RCB4455)