Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jan;84(2):186–192. doi: 10.1054/bjoc.2000.1553

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

J-H Choi 1, H-Y Lim 1, D K Nam 1, H S Kim 1, D Y Cho 1, J W Yi 1, H C Kim 1, Y K Cho 2, M W Kim 2, H J Joo 3, K B Lee 3, K B Kim 4
PMCID: PMC2363711  PMID: 11161374

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

Keywords: gastric cancer, thymidylate synthase, adjuvant chemotherapy, drug resistance, prognosis

Full Text

The Full Text of this article is available as a PDF (336.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boku N., Chin K., Hosokawa K., Ohtsu A., Tajiri H., Yoshida S., Yamao T., Kondo H., Shirao K., Shimada Y. Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. Clin Cancer Res. 1998 Jun;4(6):1469–1474. [PubMed] [Google Scholar]
  2. Carneiro F., Seixas M., Sobrinho-Simões M. New elements for an updated classification of the carcinomas of the stomach. Pathol Res Pract. 1995 Jul;191(6):571–584. doi: 10.1016/S0344-0338(11)80878-2. [DOI] [PubMed] [Google Scholar]
  3. Cirera L., Balil A., Batiste-Alentorn E., Tusquets I., Cardona T., Arcusa A., Jolis L., Saigí E., Guasch I., Badia A. Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 1999 Dec;17(12):3810–3815. doi: 10.1200/JCO.1999.17.12.3810. [DOI] [PubMed] [Google Scholar]
  4. Earle C. C., Maroun J. A. Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer. 1999 Jul;35(7):1059–1064. doi: 10.1016/s0959-8049(99)00076-3. [DOI] [PubMed] [Google Scholar]
  5. Fuchs C. S., Mayer R. J. Gastric carcinoma. N Engl J Med. 1995 Jul 6;333(1):32–41. doi: 10.1056/NEJM199507063330107. [DOI] [PubMed] [Google Scholar]
  6. Hermans J., Bonenkamp J. J., Boon M. C., Bunt A. M., Ohyama S., Sasako M., Van de Velde C. J. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol. 1993 Aug;11(8):1441–1447. doi: 10.1200/JCO.1993.11.8.1441. [DOI] [PubMed] [Google Scholar]
  7. Johnston P. G., Drake J. C., Trepel J., Allegra C. J. Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and -resistant human cancer cell lines. Cancer Res. 1992 Aug 15;52(16):4306–4312. [PubMed] [Google Scholar]
  8. Johnston P. G., Fisher E. R., Rockette H. E., Fisher B., Wolmark N., Drake J. C., Chabner B. A., Allegra C. J. The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol. 1994 Dec;12(12):2640–2647. doi: 10.1200/JCO.1994.12.12.2640. [DOI] [PubMed] [Google Scholar]
  9. Johnston P. G., Lenz H. J., Leichman C. G., Danenberg K. D., Allegra C. J., Danenberg P. V., Leichman L. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 1995 Apr 1;55(7):1407–1412. [PubMed] [Google Scholar]
  10. Kelsen D. P. Adjuvant and neoadjuvant therapy for gastric cancer. Semin Oncol. 1996 Jun;23(3):379–389. [PubMed] [Google Scholar]
  11. Kim I. S., Suh I., Oh H. C., Kim B. S., Lee Y. Incidence and survival of cancer in Kangwha County (1983-1987). Yonsei Med J. 1989 Sep;30(3):256–268. doi: 10.3349/ymj.1989.30.3.256. [DOI] [PubMed] [Google Scholar]
  12. Kim J. P., Kwon O. J., Oh S. T., Yang H. K. Results of surgery on 6589 gastric cancer patients and immunochemosurgery as the best treatment of advanced gastric cancer. Ann Surg. 1992 Sep;216(3):269–279. doi: 10.1097/00000658-199209000-00006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kim S. Y., Park H. C., Yoon C., Yoon H. J., Choi Y. M., Cho K. S. 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. 1998 Nov 15;83(10):2054–2059. doi: 10.1002/(sici)1097-0142(19981115)83:10<2054::aid-cncr2>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  14. Krook J. E., O'Connell M. J., Wieand H. S., Beart R. W., Jr, Leigh J. E., Kugler J. W., Foley J. F., Pfeifle D. M., Twito D. I. A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer. 1991 May 15;67(10):2454–2458. doi: 10.1002/1097-0142(19910515)67:10<2454::aid-cncr2820671010>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  15. Kuniyasu T., Nakamura T., Tabuchi Y., Kuroda Y. 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. 1998 Oct 1;83(7):1300–1306. doi: 10.1002/(sici)1097-0142(19981001)83:7<1300::aid-cncr5>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  16. Lenz H. J., Leichman C. G., Danenberg K. D., Danenberg P. V., Groshen S., Cohen H., Laine L., Crookes P., Silberman H., Baranda J. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol. 1996 Jan;14(1):176–182. doi: 10.1200/JCO.1996.14.1.176. [DOI] [PubMed] [Google Scholar]
  17. Lise M., Nitti D., Marchet A., Sahmoud T., Buyse M., Duez N., Fiorentino M., Dos Santos J. G., Labianca R., Rougier P. 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. 1995 Nov;13(11):2757–2763. doi: 10.1200/JCO.1995.13.11.2757. [DOI] [PubMed] [Google Scholar]
  18. Macdonald J. S., Fleming T. R., Peterson R. F., Berenberg J. L., McClure S., Chapman R. A., Eyre H. J., Solanki D., Cruz A. B., Jr, Gagliano R. 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. 1995 Nov;2(6):488–494. doi: 10.1007/BF02307081. [DOI] [PubMed] [Google Scholar]
  19. Nakazato H., Koike A., Saji S., Ogawa N., Sakamoto J. Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet. 1994 May 7;343(8906):1122–1126. doi: 10.1016/s0140-6736(94)90233-x. [DOI] [PubMed] [Google Scholar]
  20. Noguchi Y., Imada T., Matsumoto A., Coit D. G., Brennan M. F. Radical surgery for gastric cancer. A review of the Japanese experience. Cancer. 1989 Nov 15;64(10):2053–2062. doi: 10.1002/1097-0142(19891115)64:10<2053::aid-cncr2820641014>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  21. Pestalozzi B. C., Peterson H. F., Gelber R. D., Goldhirsch A., Gusterson B. A., Trihia H., Lindtner J., Cortés-Funes H., Simmoncini E., Byrne M. J. Prognostic importance of thymidylate synthase expression in early breast cancer. J Clin Oncol. 1997 May;15(5):1923–1931. doi: 10.1200/JCO.1997.15.5.1923. [DOI] [PubMed] [Google Scholar]
  22. Pinedo H. M., Peters G. F. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988 Oct;6(10):1653–1664. doi: 10.1200/JCO.1988.6.10.1653. [DOI] [PubMed] [Google Scholar]
  23. Setälä L. P., Kosma V. M., Marin S., Lipponen P. K., Eskelinen M. J., Syrjänen K. J., Alhava E. M. Prognostic factors in gastric cancer: the value of vascular invasion, mitotic rate and lymphoplasmacytic infiltration. Br J Cancer. 1996 Sep;74(5):766–772. doi: 10.1038/bjc.1996.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shiu M. H., Perrotti M., Brennan M. F. Adenocarcinoma of the stomach: a multivariate analysis of clinical, pathologic and treatment factors. Hepatogastroenterology. 1989 Feb;36(1):7–12. [PubMed] [Google Scholar]
  25. Stelzner S., Emmrich P. The mixed type in Laurén's classification of gastric carcinoma. Histologic description and biologic behavior. Gen Diagn Pathol. 1997 Jul;143(1):39–48. [PubMed] [Google Scholar]
  26. Suda Y., Kuwashima Y., Tanaka Y., Uchida K., Akazawa S. 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. 1999 Jan-Feb;19(1B):805–810. [PubMed] [Google Scholar]
  27. Washtien W. L. Increased levels of thymidylate synthetase in cells exposed to 5-fluorouracil. Mol Pharmacol. 1984 Jan;25(1):171–177. [PubMed] [Google Scholar]
  28. Wils J. The treatment of advanced gastric cancer. Semin Oncol. 1996 Jun;23(3):397–406. [PubMed] [Google Scholar]
  29. Yeh K. H., Shun C. T., Chen C. L., Lin J. T., Lee W. J., Lee P. H., Chen Y. C., Cheng A. L. High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy. Cancer. 1998 May 1;82(9):1626–1631. doi: 10.1002/(sici)1097-0142(19980501)82:9<1626::aid-cncr5>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  30. Yu C. C., Levison D. A., Dunn J. A., Ward L. C., Demonakou M., Allum W. H., Hallisey M. T. Pathological prognostic factors in the second British Stomach Cancer Group trial of adjuvant therapy in resectable gastric cancer. Br J Cancer. 1995 May;71(5):1106–1110. doi: 10.1038/bjc.1995.214. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES