Antitumor effect of cetuximab in combination with S-1 in EGFR-amplified gastric cancer cells

Fukuda,Kazumasa; Saikawa,Yoshiro; Takahashi,Masashi; Takahashi,Tsunehiro; Wada,Norihito; Kawakubo,Hirohumi; Takeuchi,Hiroya; Kitagawa,Yuko

doi:10.3892/ijo.2011.1279

Antitumor effect of cetuximab in combination with S-1 in EGFR-amplified gastric cancer cells

Authors:
- Kazumasa Fukuda
- Yoshiro Saikawa
- Masashi Takahashi
- Tsunehiro Takahashi
- Norihito Wada
- Hirohumi Kawakubo
- Hiroya Takeuchi
- Yuko Kitagawa
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Affiliations: Department of Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan, Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Published online on: December 1, 2011 https://doi.org/10.3892/ijo.2011.1279
Pages: 975-982

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Abstract

Overexpression of human epidermal growth factor receptor (EGFR) has been detected in gastric cancer (GC) and is associated with poor outcomes. Combination treatment regimens with EGFR-targeting agents and cytotoxic agents are considered to be a potential therapeutic option for EGFR-overexpressing GC. Herein, we have investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the EGFR-targeting agent cetuximab in GC cells with or without EGFR overexpression. EGFR expression was determined by FACS and quantitative PCR in GC cells. Experimental 5-fluorouracil (5FU) was used instead of S-1 for in vitro experiments. The efficacy of 5FU or cetuximab monotherapy or combination 5FU/cetuximab therapy was examined in vitro and in vivo. Clinical specimens were examined for EGFR by immunohistochemistry (IHC). EGFR expression score was defined as strong membrane and cytoplasmic staining in at least 50-75% of cells. The combination of 5FU and cetuximab synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in GC cells with EGFR overexpression. Cetuximab also induced down-regulation of phosphorylation of EGFR and AKT, leading to diminished signaling. The antitumor effect of the combination of S-1 and cetuximab in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and EGFR-targeting therapy is a promising treatment option for GC with EGFR overexpression.

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1	Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
2	Mari E, Floriani I, Tinassi A, et al: Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomized trials. Ann Oncol. 11:837–843. 2000. View Article : Google Scholar : PubMed/NCBI
3	Panzini I, Gianni L, Fattori PP, et al: Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses. Tumori. 88:21–27. 2002.PubMed/NCBI
4	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. 2008. View Article : Google Scholar : PubMed/NCBI
5	Koizumi W, Kurihara M, Nakano S and Hasegawa K: Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology. 58:191–197. 2000. View Article : Google Scholar : PubMed/NCBI
6	Koizumi W, Narahara H, Hara T, et al: S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 9:215–221. 2008. View Article : Google Scholar : PubMed/NCBI
7	Sakuramoto S, Sasako M, Yamaguchi T, et al: Adjuvant chemotherapy for gastric cancer with S-1 an oral fluoropyrimidine. N Engl J Med. 357:1810–1820. 2007. View Article : Google Scholar : PubMed/NCBI
8	Boku N: Chemotherapy for metastatic disease: review from JCOG trials. Int J Clin Oncol. 13:196–200. 2008. View Article : Google Scholar : PubMed/NCBI
9	Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: Gastric cancer. Lancet. 374:477–490. 2009. View Article : Google Scholar
10	Wesolowski R, Lee C and Kim R: Is there a role for second-line chemotherapy in advanced gastric cancer? Lancet Oncol. 10:903–912. 2009. View Article : Google Scholar : PubMed/NCBI
11	Ferrara N and Kerbel RS: Angiogenesis as a therapeutic target. Nature. 438:967–974. 2005. View Article : Google Scholar : PubMed/NCBI
12	Iqbal S, Goldman B, Fenoglio-Preiser CM, Lenz HJ, Zhang W, Danenberg KD, Shibata SI and Blanke CD: Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol. May 20–2011.(Epub ahead of print).
13	Cappetta A, Lonardi S, Pastorelli D, Bergamo F, Lombardi G and Zagonel V: Advanced gastric cancer (GC) and cancer of the gastro-oesophageal junction (GEJ): focus on targeted therapies. Crit Rev Oncol Hematol. Jan 19–2011.(Epub ahead of print).
14	Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 351:337–345. 2004. View Article : Google Scholar : PubMed/NCBI
15	Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J and Mayer RJ: Phase II trial of cetuximabin patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 22:1201–1208. 2004. View Article : Google Scholar : PubMed/NCBI
16	Chou TC and Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 22:27–55. 1984. View Article : Google Scholar : PubMed/NCBI
17	Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI
18	Carpenter G and Cohen S: Epidermal growth factor. J Biol Chem. 265:7709–7712. 1999.
19	Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 354:567–578. 2006. View Article : Google Scholar : PubMed/NCBI
20	Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 359:1116–1127. 2008. View Article : Google Scholar : PubMed/NCBI
21	Hanna N, Lilenbaum R, Ansari R, et al: Phase II trial of cetuximab in patients with previously treated non-small cell lung cancer. J Clin Oncol. 24:5253–5258. 2006. View Article : Google Scholar : PubMed/NCBI
22	Lee JC, Wang ST, Chow NH and Yang HB: Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer. 38:1065–1071. 2002. View Article : Google Scholar : PubMed/NCBI
23	Porebska I, Harlozinska A and Bojarowski T: Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERBB2, ERBB3) in colorectal adenocarcinomas and adenomas. Tumor Biol. 21:105–115. 2002.PubMed/NCBI
24	Bancroft CC, Chen Z, Yeh J, et al: Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-κB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer. 99:538–548. 2002.
25	Raymond E, Fauvre S and Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 60(Suppl 1): S15–S23. 2000. View Article : Google Scholar : PubMed/NCBI
26	Baselga J, Norton L, Masui H, Pandiella A, Coplan K, Miller WH and Mendelsohn J: Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst. 85:1327–1333. 1993. View Article : Google Scholar : PubMed/NCBI
27	Bruns CJ, Harbison MT, Davis DW, et al: Epidermal growth factor receptor blockade with cetuximab plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res. 6:1936–1948. 2006.
28	Ciardiello F, Bianco R, Damiano V, et al: Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res. 4:909–916. 1999.PubMed/NCBI
29	Fan Z, Baselga J, Masui H and Mendelsohn J: Antitumor effect of anti-EGF receptor monoclonal antibodies plus cis-diamminedichloroplatinum (cis-ddp) on well established A431 cell xenografts. Cancer Res. 53:4637–4642. 1993.PubMed/NCBI
30	Huang SM, Bock JM and Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 59:1935–1940. 1999.PubMed/NCBI
31	Huang SM and Harari PM: Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res. 6:2166–2174. 2000.
32	Inoue K, Slaton JW, Perrotte P, et al: Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res. 6:4874–4884. 2000.
33	Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW and Hicklin DJ: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMCC225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res. 8:994–1003. 2002.
34	Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res. 7:1204–1213. 2001.PubMed/NCBI
35	Han SW, Oh DY, Im SA, Park SR, Lee KW, Bang YJ and Kim TY: Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br J Cancer. 100:298–304. 2009. View Article : Google Scholar : PubMed/NCBI