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

• Published in: Molecular cancer therapeutics Vol. 7; no. 3; pp. 599 - 606
• Main Authors: Okabe, Takafumi, Okamoto, Isamu, Tsukioka, Sayaka, Uchida, Junji, Iwasa, Tsutomu, Yoshida, Takeshi, Hatashita, Erina, Yamada, Yuki, Satoh, Taroh, Tamura, Kenji, Fukuoka, Masahiro, Nakagawa, Kazuhiko
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-03-2008
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Base Sequence; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; DNA Probes; Down-Regulation - drug effects; epidermal growth factor receptor; Fluorouracil - analogs & derivatives; Fluorouracil - pharmacology; gefitinib; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; mutation; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Reverse Transcriptase Polymerase Chain Reaction; S-1; thymidylate synthase; Thymidylate Synthase - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-07-0567

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.
[Mol Cancer Ther 2008;7(3):599–606]