Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice

Nukatsuka,Mamoru; Saito,Hitoshi; Nakagawa,Fumio; Tsujimoto,Hiroaki; Sakamoto,Kazuki; Tsukioka,Sayaka; Uchida,Junji; Kiniwa,Mamoru; Kobunai,Takashi; Takechi,Teiji

doi:10.3892/etm.2012.484

Combination therapy using oral S-1 and targeted agents against human tumor xenografts in nude mice

Authors:
- Mamoru Nukatsuka
- Hitoshi Saito
- Fumio Nakagawa
- Hiroaki Tsujimoto
- Kazuki Sakamoto
- Sayaka Tsukioka
- Junji Uchida
- Mamoru Kiniwa
- Takashi Kobunai
- Teiji Takechi
View Affiliations

Affiliations: Oncology Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Okubo Tsukuba-Shi, Ibaraki 300-2611, Japan, Oncology Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan, Oncology Medical Affairs Division, Taiho Pharmaceutical Co., Ltd., Tokyo 101-0047, Japan
Published online on: February 13, 2012 https://doi.org/10.3892/etm.2012.484
Pages: 755-762

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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 monotherapies 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.

View Figures

View References

1.	Popov I, Milicević M and Radosević-Jelić LJ: The addition of bevacizumab to fluoropyrimidine, irinotecan and oxaliplatin-based therapy improves survival for patients with metastatic colorectal cancer (CRC): combined analysis of efficacy. Acta Chir Iugosl. 55:11–16. 2008. View Article : Google Scholar
2.	Meyerhardt JA, Stuart K, Fuchs CS, Zhu AX, Earle CC, Bhargava P, Blaszkowsky L, Enzinger P, Mayer RJ, Battu S, et al: Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer. Ann Oncol. 18:1185–1189. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Boccia RV, Cosgriff TM, Headley DL, Badarinath S and Dakhil SR: A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Clin Colorectal Cancer. 9:102–107. 2010. View Article : Google Scholar : PubMed/NCBI
4.	Townsley CA, Major P, Siu LL, Dancey J, Chen E, Pond GR, Nicklee T, Ho J, Hedley D, Tsao M, et al: Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer. 94:1136–43. 2006. View Article : Google Scholar : PubMed/NCBI
5.	Dal Lago L, D’Hondt V and Awada A: Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors. Oncologist. 13:845–858. 2008.PubMed/NCBI
6.	Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A, Saito H, Okabe H, Oyama K, Takeda S, et al: Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res. 56:2602–2606. 1996.
7.	Fukushima M, Satake H, Uchida J, Shimamoto Y, Kato T, Takechi T, Okabe H, Fujioka A, Nakano K, Ohshimo H, et al: Preclinical antitumor efficacy of S-1: A new oral formulation of 5-fluorouracil on human tumor xenografts. Int J Oncol. 13:693–698. 1998.PubMed/NCBI
8.	Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y and Taguchi T: Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer. 34:1715–1720. 1998. View Article : Google Scholar : PubMed/NCBI
9.	Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K and Taguchi T: Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma. Br J Cancer. 83:141–145. 2000.PubMed/NCBI
10.	Saeki T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, Morimoto K, Kimura M, Aoyama H, Ota J, et al: A phase II study of S-1 in patients with metastatic breast cancer - a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group. Breast Cancer. 11:194–202. 2002. View Article : Google Scholar : PubMed/NCBI
11.	Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, et al: Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol. 11:853–860. 2010. View Article : Google Scholar : PubMed/NCBI
12.	Nakashima K, Hironaka S, Boku N, Onozawa Y, Fukutomi A, Yamazaki K, Yasui H, Taku K, Kojima T and Machida N: Irinotecan plus cisplatin therapy and S-1 plus cisplatin therapy for advanced or recurrent gastric cancer in a single institution. Jpn J Clin Oncol. 38:810–815. 2008. View Article : Google Scholar : PubMed/NCBI
13.	Koizumi W, Tanabe S, Saigenji K, Ohtsu A, Boku N, Nagashima F, Shirao K, Matsumura Y and Gotoh M: Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer. 89:2207–2212. 2003. View Article : Google Scholar : PubMed/NCBI
14.	Narahara H, Fujitani K, Takiuchi H, Sugimoto N, Inoue K, Uedo N, Tsukuma H, Tsujinaka T, Furukawa H and Taguchi T: Phase II study of a combination of S-1 and paclitaxel in patients with unresectable or metastatic gastric cancer. Oncology. 74:37–41. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, Kamei T, Soma D, Miyato H, Yamashita H and Nagawa H: Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 21:67–70. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Okabe T, Okamoto I, Tsukioka S, Uchida J, Hatashita E, Yamada Y, Yoshida T, Nishio K, Fukuoka M, Jänne PA and Nakagawa K: Addition of S-1 to the epidermal growth factor receptor inhibitor gefitinib overcomes gefitinib resistance in non-small cell lung cancer cell lines with MET amplification. Clin Cancer Res. 15:907–913. 2009. View Article : Google Scholar
17.	Tanizaki J, Okamoto I, Takezawa K, Tsukioka S, Uchida J, Kiniwa M, Fukuoka M and Nakagawa K: Synergistic antitumor effect of S-1 and HER2-targeting agents in gastric cancer with HER2 amplification. Mol Cancer Ther. 9:1198–1207. 2010. View Article : Google Scholar : PubMed/NCBI
18.	Fukushima M, Fujioka A, Uchida J, Nakagawa F and Takechi T: Thymidylate synthase (TS) and ribonucleotide reductase (RNR) may be involved in acquired resistance to 5-fluorouracil (5-FU) in human cancer xenografts in vivo. Eur J Cancer. 37:1681–1687. 2001. View Article : Google Scholar : PubMed/NCBI
19.	Ikediobi ON, Davies H, Bignell G, Edkins S, Stevens C, O’Meara S, Santarius T, Avis T, Barthorpe S, Brackenbury L, et al: Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol Cancer Ther. 5:2606–2612. 2006. View Article : Google Scholar : PubMed/NCBI
20.	Higgins B, Kolinsky K, Smith M, Beck G, Rashed M, Adames V, Linn M, Wheeldon E, Gand L, Birnboeck H and Hoffmann G: Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models. Anticancer Drugs. 15:503–512. 2004. View Article : Google Scholar : PubMed/NCBI
21.	Arao T, Fukumoto H, Takeda M, Tamura T, Saijo N and Nishio K: Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474. Cancer Res. 64:9101–9104. 2004. View Article : Google Scholar : PubMed/NCBI
22.	Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW and Hicklin DJ: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res. 8:994–1003. 2002.
23.	Fox WD, Higgins B, Maiese KM, Drobnjak M, Cordon-Cardo C, Scher HI and Agus DB: Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res. 8:3226–3231. 2002.PubMed/NCBI
24.	Balin-Gauthier D, Delord JP, Rochaix P, Mallard V, Thomas F, Hennebelle I, Bugat R, Canal P and Allal C: In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. Cancer Chemother Pharmacol. 7:709–718. 2006. View Article : Google Scholar
25.	Bauer P, Röhmel J, Maurer W and Hothorn L: Testing strategies in multi-dose experiments including active control. Stat Med. 17:2133–2146. 1988. View Article : Google Scholar : PubMed/NCBI
26.	Malet-Martino M and Martino R: Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. Oncologist. 288–323. 2002. View Article : Google Scholar : PubMed/NCBI
27.	Peters GJ, van der Wilt CL, van Triest B, Codacci-Pisanelli G, Johnston PG, van Groeningen CJ and Pinedo HM: Thymidylate synthase and drug resistance. Eur J Cancer. 31A:1299–1305. 1995. View Article : Google Scholar : PubMed/NCBI
28.	Kadota K, Huang CL, Liu D, Yokomise H, Haba R and Wada H: Combined therapy with a thymidylate synthase-inhibiting vector and S-1 has effective antitumor activity against 5-FU-resistant tumors. Int J Oncol. 38:355–363. 2011.PubMed/NCBI
29.	Skvortsov S, Sarg B, Lindner H, Lukas P, Hilbe W, Zwierzina H and Skvortsova I: Cetuximab inhibits thymidylate synthase in colorectal cells expressing epidermal growth factor receptor. Proteomics Clin Appl. 2:908–914. 2008. View Article : Google Scholar : PubMed/NCBI
30.	Giovannetti E, Lemos C, Tekle C, Smid K, Nannizzi S, Rodriguez JA, Ricciardi S, Danesi R, Giaccone G and Peters GJ: Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol Pharmacol. 73:1290–1300. 2008. View Article : Google Scholar
31.	Takeuchi A, Shiota M, Tatsugami K, Yokomizo A, Eto M, Inokuchi J, Kuroiwa K, Kiyoshima K and Naito S: Sorafenib augments cytotoxic effect of S-1 in vitro and in vivo through TS suppression. Cancer Chemother Pharmacol. 68:1557–1564. 2011. View Article : Google Scholar : PubMed/NCBI
32.	Carloni S, Fabbri F, Brigliadori G, Ulivi P, Silvestrini R, Amadori D and Zoli W: Tyrosine kinase inhibitors gefitinib, lapatinib and sorafenib induce rapid functional alterations in breast cancer cells. Curr Cancer Drug Targets. 10:422–431. 2010. View Article : Google Scholar
33.	Kobunai T, Watanabe T and Fukusato T: Antitumor activity of S-1 in combination with cetuximab on human gastric cancer cell lines in vivo. Anticancer Res. 31:3691–3696. 2011.PubMed/NCBI
34.	Ooyama A, Takechi T, Toda E, Nagase H, Okayama Y, Kitazato K, Sugimoto Y, Oka T and Fukushima M: Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 97:510–522. 2006. View Article : Google Scholar
35.	Fukui Y, Oka T, Nagayama S, Danenberg PV, Danenberg KD and Fukushima M: Thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase mRNA and protein expression levels in solid tumors in large scale population analysis. Int J Mol Med. 22:709–716. 2008.
36.	Tang TC, Man S, Xu P, Francia G, Hashimoto K, Emmenegger U and Kerbel RS: Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia. 12:928–940. 2010.PubMed/NCBI
37.	Basaki Y, Chikahisa L, Aoyagi K, Miyadera K, Yonekura K, Hashimoto A, Okabe S, Wierzba K and Yamada Y: γ-hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis. 4:163–173. 2001.