Favorable effect of the combination of vinorelbine and dihydropyrimidine dehydrogenase‑inhibitory fluoropyrimidine in EGFR‑mutated lung adenocarcinoma: retrospective and in vitro studies

Autor: Natsumi Tanaka, Masaaki Yanai, Hirofumi Nakazaki, Shizuka Nishii-Ito, Haruhiko Makino, Kenichi Takeda, Chaitanya S. Nirodi, Tadashi Igishi, Shingo Matsumoto, Hiroki Izumi, Yasuto Ueda, Tomohiro Sakamoto, Hirokazu Touge, Masahiro Kodani, Eiji Shimizu, Jun Kurai, Miyako Takata
Rok vydání: 2014
Předmět:
Oncology
Male
Cancer Research
Lung Neoplasms
dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine
medicine.medical_treatment
Kaplan-Meier Estimate
Carcinoma
Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
5-fluorouracil
Epidermal growth factor receptor
Aged
80 and over
biology
Combination chemotherapy
Gefitinib
Vinorelbine
Articles
Middle Aged
Vinblastine
ErbB Receptors
Drug Combinations
Treatment Outcome
Female
Fluorouracil
medicine.drug
Adult
medicine.medical_specialty
Adenocarcinoma of Lung
Adenocarcinoma
Internal medicine
Cell Line
Tumor
medicine
Dihydropyrimidine dehydrogenase
Humans
Lung cancer
Dihydrouracil Dehydrogenase (NADP)
Aged
Retrospective Studies
Tegafur
Chemotherapy
business.industry
medicine.disease
lung adenocarcinoma
Oxonic Acid
Mutation
Cancer research
biology.protein
Quinazolines
business
epidermal growth factor receptor
Zdroj: International Journal of Oncology
ISSN: 1791-2423
Popis: 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.
Databáze: OpenAIRE
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