title: Favorable effect of the combination of vinorelbine and dihydropyrimidine dehydrogenase‑inhibitory fluoropyrimidine in EGFR‑mutated lung adenocarcinoma: retrospective and in vitro studies.
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.
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Touge
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Igishi
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Makino
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Nishii-Ito
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Takata
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakazaki
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kodani
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kurai
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yanai
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors.forename: Chaitanya S
authors.initials: CS
authors.lastname: Nirodi
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, Yonago, Tottori 683‑8504, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors; D004338:Drug Combinations; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010094:Oxonic Acid / Q000008:administration & dosage; D011799:Quinazolines / Q000494:pharmacology; D012189:Retrospective Studies; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D004338:Drug Combinations; D011799:Quinazolines; C079198:S 1 (combination); D005641:Tegafur; D014747:Vinblastine; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); C512478:EGFR protein, human; D066246:ErbB Receptors; D000077235:Vinorelbine; D000077156:Gefitinib; D005472:Fluorouracil