title: Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice.
abstract: In this study, combination therapies using the oral fluoropyrimidine tegafur-gimeracil-oteracil (S-1) with several targeted agents or antibodies, were evaluated. First, the effects of tyrosine kinase inhibitors (erlotinib hydrochloride, sorafenib tosilate and sunitinib malate) against human non-small cell lung cancer (NSCLC), breast cancer and colorectal cancer were evaluated in vivo. The effects of the combination of S-1 and targeted antibodies (bevacizumab and cetuximab) against human colorectal cancers was also evaluated in vivo. S-1 and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, showed a significant inhibition of growth in human NSCLC (Lu-99 and PC-9 cell lines). The antitumor activity of the combination of S-1 and erlotinib against Lu-99 and PC-9 cancer cell lines was significantly superior to either monotherapy (P<0.05). Combination therapy using the multi-tyrosine kinase inhibitors, sorafenib or sunitinib, with S-1 against breast cancer (MX-1 cell line) and NSCLC (NCI-H460 cell line) was significantly superior to either monotherapy (P<0.01). The combination of the anti-vascular endothelial growth factor antibody bevacizumab or the anti-EGFR antibody, cetuximab, with S-1 against human colorectal cancer [Col-1, KM20C (bevacizumab) and DLD-1 (cetuximab) cell lines] and a 5-fluorouracil (5-FU)-resistant cell line (KM12C/5-FU) was significantly superior to either monotherapy (p<0.01). In particular, the growth of the Col-1 cells was completely inhibited by the combination of S-1 and bevacizumab. No toxic mortalities and no significant difference in the body weight changes of the animals treated with S-1 combined with the targeted agents or with the mono-therapies were observed; therefore, the treatments appeared to be well-tolerated. Our preclinical findings indicate that the combination therapies of S-1 and targeted agents are promising treatment options.
authors.affiliation: Oncology Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194;
authors.forename: Mamoru
authors.initials: M
authors.lastname: Nukatsuka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Saito
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakagawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Sayaka
authors.initials: S
authors.lastname: Tsukioka
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kiniwa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobunai
authors.forename: Teiji
authors.initials: T
authors.lastname: Takechi