title: Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase.
abstract: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors.
authors.affiliation: Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okabe
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Sayaka
authors.initials: S
authors.lastname: Tsukioka
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwasa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Erina
authors.initials: E
authors.lastname: Hatashita
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D015342:DNA Probes; D015536:Down-Regulation / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000494:pharmacology*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000378:metabolism*
chemical_list: D015342:DNA Probes; D011799:Quinazolines; D013940:Thymidylate Synthase; D066246:ErbB Receptors; D000077156:Gefitinib; D005472:Fluorouracil