Impact of thymidylate synthase protein expression on efficacy of chemotherapy in advanced lung cancer patients

Nakagawa,Yoshiko; Shimizu,Tetsuo; Takahashi,Noriaki; Hashimoto,Shu

doi:10.3892/mco.2013.94

Impact of thymidylate synthase protein expression on efficacy of chemotherapy in advanced lung cancer patients

Authors:
- Yoshiko Nakagawa
- Tetsuo Shimizu
- Noriaki Takahashi
- Shu Hashimoto
View Affiliations

Affiliations: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
Published online on: March 19, 2013 https://doi.org/10.3892/mco.2013.94
Pages: 411-417

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

Advanced lung cancer is primarily treated with platinum combination chemotherapy, however, its prognosis remains poor. The aim of this study was to examine the correlation between the expression of thymidylate synthase (TS) in cancer tissues and the efficacy of chemotherapy in patients with advanced lung cancer in order to clarify the role of TS in the overall response. In total, 120 patients diagnosed with lung cancer between June 2004 and December 2010 at Nihon University Hospital, Tokyo, Japan, were included in this study. Cancer tissue specimens were obtained from the included patients by surgery or bronchofiberscopy prior to treatment. The expression of TS protein was evaluated using specimens immunostained with anti-TS antibody and H‑scoring. TS protein expression tended to be higher in smokers compared with non‑smokers. Overall survival (OS) (median value) was significantly prolonged in the low TS expression group compared with the high TS expression group. More favorable therapeutic effects were observed in the high TS expression group compared with the low TS expression group, when carboplatin + paclitaxel combined chemotherapy (CbPac therapy) was used. When the therapeutic effects were compared between CbPac therapy and carboplatin + pemetrexed combined chemotherapy (CbPem therapy) in the high TS expression group, prolongation of OS (median value) was observed with CbPac therapy. The present study suggests that TS protein expression is a critical factor in determining the efficacy of CbPac therapy in lung cancer. CbPac therapy is more effective when TS protein is highly expressed in lung cancer tissue.

View Figures

View References

1.	Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
2.	Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 304:1497–1500. 2004. View Article : Google Scholar : PubMed/NCBI
3.	Rosell R, Monzo M, Molina F, et al: K-ras genotypes and prognosis in non-small-cell lung cancer. Ann Oncol. 6:S15–S20. 1995. View Article : Google Scholar : PubMed/NCBI
4.	Takano T, Fukui T, Ohe Y, et al: EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol. 26:5589–5595. 2008. View Article : Google Scholar
5.	Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
6.	Ferguson PJ, Collins O, Dean NM, et al: Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells. Br J Pharmacol. 127:1777–1786. 1999. View Article : Google Scholar : PubMed/NCBI
7.	Flynn J, Berg RW, Wong T, et al: Therapeutic potential of antisense oligodeoxynucleotides to down-regulate thymidylate synthase in mesothelioma. Mol Cancer Ther. 5:1423–1433. 2006. View Article : Google Scholar : PubMed/NCBI
8.	Lin SB, Ts’o PO, Sun SK, et al: Inhibition of thymidylate synthase activity by antisense oligodeoxynucleotide and possible role in thymineless treatment. Mol Pharmacol. 60:474–479. 2001.PubMed/NCBI
9.	Hann N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 22:1589–1597. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Okamoto I, Yoshioka H, Morita S, et al: Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: result of a West Japan oncology group study. J Clin Oncol. 20:5240–5246. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Shirota Y, Stoehlmacher J, Brabender J, et al: ERCC1 and thymidylate synthase mRNA level predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol. 19:4298–4304. 2001.
12.	Nishimura R, Nagao K, Miyayama H, et al: Thymidylate synthase levels as a therapeutic and prognostic predictor in breast cancer. Anticancer Res. 19:5621–5626. 1999.PubMed/NCBI
13.	Takamura M, Nio Y, Yamasawa K, et al: Implication of thymidylate synthase in the outcome of patients with invasive ductal carcinoma of the pancreas and efficacy of adjuvant chemotherapy using 5-fluorouracil or its derivatives. Anticancer Drugs. 13:75–85. 2002. View Article : Google Scholar : PubMed/NCBI
14.	Zheng Z, Li X, Schell MJ, et al: Thymidylate synthase in situ protein expression and survival in stage I non small-cell lung cancer. Cancer. 112:2765–2773. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Chen CY, Chang YL, Shin JY, et al: Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer. 74:132–138. 2011. View Article : Google Scholar : PubMed/NCBI
16.	Non-small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated date on individual patients from 52 randomized clinical trials. BMJ. 311:899–909. 1995. View Article : Google Scholar : PubMed/NCBI
17.	Olaussen KA, Dunant A, Fouret P, et al IALT Bio Investigators: DNA repair by ERCC1 in non-small cell lung cancer and cisplatin-based adjuvant chemotherapy. N Eng J Med. 355:983–991. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Yin S, Bhattacharya R and Cabral F: Human mutations that confer paclitaxel resistance. Mol Cancer Ther. 9:327–335. 2010. View Article : Google Scholar
19.	Lenz HJ, Leichman CG, Danenberg KD, et al: Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol. 14:176–182. 1996.PubMed/NCBI
20.	Ceppi P, Volante M, Saviozzi S, et al: Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 107:1589–1596. 2006. View Article : Google Scholar : PubMed/NCBI
21.	Suzuki H, Takahashi T, Kuroishi T, et al: p53 mutations in non-small cell lung cancer in Japan: association between mutations and smoking. Cancer Res. 52:734–736. 1992.PubMed/NCBI
22.	Ahrendt SA, Decker PA, Alawi EA, et al: Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 92:1525–1530. 2001. View Article : Google Scholar : PubMed/NCBI
23.	Mitsudomi T, Oyama T, Nishida K, et al: Loss of heterozygosity at 3p in non-small cell lung cancer and its prognostic implication. Clin Cancer Res. 2:1185–1189. 1996.PubMed/NCBI
24.	Johnston PG, Fisher ER, Rocktte HE, et al: The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol. 12:2640–2647. 1994.PubMed/NCBI