Abstract
We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB–IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (≥ 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P=0.002), poorly differentiated histology (P=0.015), and mixed type in Lauren's classification (P=0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs 57.2%, P=0.548) and overall survival (59.6% vs 59.3%, P=0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
American Joint Committee on Cancer (1997) AJCC cancer staging manual, 5th edn, pp. 71–76. Lippincott-Raven: Philadelphia
Boku N, Chin K, Hosokawa K, Ohtsu A, Tajiri H, Yoshida S, Yamao T, Kondo H, Shirao K, Shimada Y, Saito D, Hasebe T, Mukai K, Seki S, Saito H and Johnston PG (1998) Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis -platinum. Clin Cancer Res 4: 1469–1474
Carneiro F, Seixas M and Sobrinho-Simoes M (1995) New elements for an updated classification of the carcinomas of the stomach. Path Res Pract 191: 571–584
Cirera L, Balil A, Batiste-Alentorn E, Tusquets I, Cardona T, Arcusa A, Jolis L, Saigi E, Guasch I, Badia A and Boleda M (1999) Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol 17: 3810–3815
Earle CC and Maroun JA (1999) Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer 35: 1059–1064
Fuchs CS and Mayer RJ (1995) Gastric carcinoma. N Engl J Med 333: 32–41
Hermans J, Bonenkamp JJ, Boon MC, Bunt AMG, Ohyama S, Sasako M and Van de Velde CJH (1993) Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 11: 1441–1447
Japanese Research Society for Gastric Cancer (1981) The general rules for the gastric cancer study in surgery and pathology. Jpn J Surg 11: 127–139
Johnston PG, Drake JC, Trepel J and Allegra CJ (1992) Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res 52: 4306–4312
Johnston PG, Fisher ER, Rockette HE, Fisher B, Wolmark N, Drake JC, Chabner BA and Allegra CJ (1994) The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12: 2640–2647
Johnston PG, Lenz H-J, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV and Leichman L (1995) Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 55: 1407–1412
Kaplan EL and Meier P (1958) Non-parametric estimation from incomplete observations. J Am Statist Assoc 53: 457–481
Kelsen DP (1996) Adjuvant and neoadjuvant therapy for gastric cancer. Semin Oncol 23: 379–389
Kim IS, Suh I, Oh HC, Kim BS and Lee Y (1989) Incidence and survival of cancer in Kangwha County (1983–1987). Yonsei Med J 30: 256–268
Kim J-P, Kwon OJ, Oh ST and Yang HK (1992) Results of surgery on 6589 gastric cancer patients and immunochemosurgery as the best treatment of advanced gastric cancer. Ann Surg 216: 269–279
Kim S-Y, Park HC, Yoon C, Yoon HJ, Choi YM and Cho KS (1998) OK-432 and 5-fluorouracil, doxorubicin, and mitomycin C (FAM-P) versus FAM chemotherapy in patients with curatively resected gastric carcinoma: a randomized phase III trial. Cancer 83: 2054–2059
Krook JE, O'Connell MJ, Wieand HS, Beart RW Jr, Leigh JE, Kugler JW, Foley JF, Pfeifle DM and Twito DI (1991) A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer 67: 2454–2458
Kuniyasu T, Nakamura T, Tabuchi Y and Kuroda Y (1998) Immunohistochemical evaluation of thymidylate synthase in gastric carcinoma using a new polyclonal antibody: the clinical role of thymidylate synthase as a prognostic indicator and its therapeutic usefulness. Cancer 83: 1300–1306
Lenz H-J, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Cohen H, Laine L, Crookes P, Silberman H, Baranda J, Garcia Y, Li J and Leichman L (1996) Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 14: 176–182
Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, Fiorentino M, Santos JGD, Labianca R, Rougier P and Gignoux M (1995) Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol 13: 2757–2763
Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, Eyre HJ, Solanki D, Cruz AB Jr, Gagliano R, Estes NC, Tangen CM and Rivkin S (1995) Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: a Southwest Oncology Group study. Ann Surg Oncol 2: 488–494
Nakazato H, Koike A, Saji S, Ogawa N and Sakamoto J (1994) Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet 343: 1122–1126
Noguchi Y, Imada T, Matsumoto A, Coit DG and Brennan MF (1989) Radical surgery for gastric cancer: a review of the Japanese experience. Cancer 64: 2053–2062
Pestalozzi BC, Peterson HF, Gelber RD, Goldhirsch A, Gusterson BA, Trihia H, Lindtner J, Cortes-Funes H, Simmoncini E, Byrne MJ, Golouh R, Rudenstam CM, Castinglione-Gertsch M, Allegra CJ and Johnston PG (1997) Prognostic importance of thymidylate synthase expression in early breast cancer. J Clin Oncol 15: 1923–1931
Pinedo HM and Peters GFJ (1988) Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6: 1653–1664
Setälä LP, Kosma V-M, Marin S, Lipponen PK, Eskelinen MJ, Syrjänen KJ and Alhava EM (1996) Prognostic factors in gastric cancer: the value of vascular invasion, mitotic rate and lymphoplasmacytic infiltration. Br J Cancer 74: 766–772
Shiu MH, Perrotti M and Brennan MF (1989) Adenocarcinoma of the stomach: a multivariate analysis of clinical, pathologic and treatment factors. Hepatogastroenterology 36: 7–12
Stelzner S and Emmrich P (1997) The mixed type in Lauren's classification of gastric carcinoma: histologic description and biologic behavior. Gen Diagn Pathol 143: 39–48
Suda Y, Kuwashima Y, Tanaka Y, Uchida K and Akazawa S (1999) Immunohistochemical detection of thymidylate synthase in advanced gastric cancer: a prognostic indicator in patients undergoing gastrectomy followed by adjuvant chemotherapy with 5-fluoropyrimidines. Anticancer Res 19: 805–810
Washtien WL (1984) Increased levels of thymidylate synthetase in cells exposed to 5-fluorouracil. Mol Pharmacol 25: 171–177
Wils J (1996) The treatment of advanced gastric cancer. Semin Oncol 23: 397–406
Yeh K-H, Shun C-T, Chen C-L, Lin J-T, Lee W-J, Lee P-H, Chen Y-C and Cheng A-L (1998) High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy. Cancer 82: 1626–1631
Yu CC-W, Levison DA, Dunn JA, Ward LC, Demonakou M, Allum WH and Hallisey MT (1995) Pathological prognostic factors in the second British Stomach Cancer Group trial of adjuvant therapy in resectable gastric cancer. Br J Cancer 71: 1106–1110
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Choi, JH., Lim, HY., Nam, D. et al. Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. Br J Cancer 84, 186–192 (2001). https://doi.org/10.1054/bjoc.2000.1553
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1553
Keywords
This article is cited by
-
STAT3 mediates RCP-induced cancer cell invasion through the NF-κB/Slug/MT1-MMP signaling cascade
Archives of Pharmacal Research (2022)
-
ERCC1 predicts outcome in patients with gastric cancer treated with adjuvant cisplatin-based chemotherapy
Cancer Chemotherapy and Pharmacology (2013)
-
Long-term outcome of continuous 5-fluorouracil/cisplatin-based chemotherapy followed by chemoradiation in patients with resected gastric cancer
Medical Oncology (2012)
-
Expression of thymidylate synthase determines the response of gastric cancer patients undergoing gastrectomy to 5-fluorouracil-based adjuvant chemotherapy
Langenbeck's Archives of Surgery (2010)
-
ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen
British Journal of Cancer (2008)