Skip to main content

Advertisement

SpringerLink
Log in

Prognostic and Predictive Value of Thymidylate Synthase Expression in Colon Cancer

  • Original Paper
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Thymidylate synthase (TS) is an enzyme responsible for DNA synthesis. Its competitive inhibition constitutes the major mechanism of the antitumor effect of 5-fluorouracil (5-FU) therapy, which significantly improves the survival rate of colon cancer patients. The aim of our study was to examine the clinical importance of TS expression in colon cancer patients and to correlate its expression with various clinicopathological parameters, tumor proliferative capacity, cell cycle-related molecules’ expression and patients’ survival. Of the 71 colon cancer patients studied, 51 (71.8%) tested positive for TS, with the positive result being statistically significantly correlated with patients’ gender (P = 0.012), tumor histological grade (P = 0.032), vascular invasion (P = 0.017) and the expression of cyclin E, pRb and p16 (P = 0.042, P = 0.001 and P = 0.001, respectively). The overall 5-year survival rate was 40% for TS-positive patients and 68.6% for TS-negative ones (P = 0.0134); in patients aged >70 years, this was 30 and 77.8%, respectively (P = 0.0008). In a multivariate analysis of survival, TS expression proved to be of prognostic significance (P = 0.0174). Our findings support evidence for the clinical importance of TS expression in colon cancer patients and define it as an independent prognostic risk factor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Johnston PG, Allegra CJ (1995) Colorectal cancer biology: clinical implications. Semin Oncol 22:418–432

    PubMed  CAS  Google Scholar 

  2. Johnston PG, Benson AB III, Catalano P, Rao MS, O’Dwyer PJ, Allegra CJ (2003) Thymidylate synthase protein expression in primary colorectal cancer: lack of correlation with outcome and response to fluorouracil in metastatic disease sites. J Clin Oncol 21:815–819

    Article  PubMed  CAS  Google Scholar 

  3. Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN, Song K, Jones J, Rockette H (1999) Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: result from four National surgical adjuvant breast and bowel project adjuvant studies C-01, C-02, C-03, & C-04). J Clin Oncol 17:1349–1355

    PubMed  CAS  Google Scholar 

  4. Popat S, Matakidou A, Houlston R (2004) Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 22:529–536

    Article  PubMed  CAS  Google Scholar 

  5. Danenberg PV, Heidelberger C, Mulkins MA, Peterson AR (1981) The incorporation of 5-fluoro-2′-deoxyuridine into DNA of mammalian tumor cells. Biochem Biophys Res Commun 102:654–658

    Article  PubMed  CAS  Google Scholar 

  6. Carreras CW, Santi DV (1995) The catalytic mechanism and structure of thymidylate synthase. Annu Rev Biochem 64:721–762

    Article  PubMed  CAS  Google Scholar 

  7. Johnston PG, Drake JC, Trepel J, Allegra CL (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

    PubMed  CAS  Google Scholar 

  8. Drake JC, Allegra CJ, Moran RG, Johnston PG (1996) Resistance to Tomudex (ZD1694): multifactorial in human breast and colon carcinoma cell lines. Biochem Pharmacol 51:1349–1355

    Article  PubMed  CAS  Google Scholar 

  9. Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JA, Dimitrov NV, Glass AG, Fisher ER, Fisher B (1999) Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 17:3553–3559

    PubMed  CAS  Google Scholar 

  10. Haller DG, Catalano PJ, Macdonald JS, Mayer RJ (1998) Fluorouracil, leucovorin and levamisole adjuvant therapy for colon cancer: five-year final report of INT-0089. Proc Am Soc Clin Oncol 17:256a

    Google Scholar 

  11. Chu E, Callender MA, Farrell MP, Schmitz JC (2003) Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol 52:S80–S89

    Article  PubMed  CAS  Google Scholar 

  12. Tomiak A, Vincent M, Earle CC, Johnston PG, Kocha W, Taylor M, Maroun J, Eidus L, Whiston F, Stitt L (2001) Thymidylate synthase expression in stage II and III colon cancer: a retrospective review. Am J Clin Oncol 24:597–602

    Article  PubMed  CAS  Google Scholar 

  13. Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S, Tsao-Wei DD, Lenz HJ, Leichman CG, Leichman L, Diasio RB, Danenberg PV (2000) Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6:1322–1327

    PubMed  CAS  Google Scholar 

  14. Paradiso A, Simone G, Petroni S, Leone B, Vallejo C, Lacava J, Romero A, Machiavelli M, De Lena M, Allegra CJ, Johnston PG (2000) Thymidylate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br J Cancer 82:560–567

    Article  PubMed  CAS  Google Scholar 

  15. Sakamoto J, Hamashima H, Susuki H, Ito K, Mai M, Saji S, Fukushima M, Matsushita Y, Nakazato H (2003) Thymidylate synthase expression as a predictor of the prognosis of curatively resected colon carcinoma in patients registered in an adjuvant immunochemotherapy clinical trial. Oncl Rep 10:1081–1090

    Google Scholar 

  16. Edler D, Hallstrom M, Johnston PG, Magnusson I, Ragnhammar P, Blomgren H (2000) Thymidylate synthase expression: an independent prognostic factor for local recurrence, distant metastasis, disease-free and overall survival in rectal cancer. Clin Cancer Res 6:1378–1384

    PubMed  CAS  Google Scholar 

  17. Edler D, Kressner U, Ragnhammar P, Johnston PG, Magnusson I, Glimelius B, Påhlman L, Lindmark G, Blomgren H (2000) Immunohistochemically detected thymidylate synthase in colorectal cancer: an independent prognostic factor of survival. Clin Cancer Res 6:488–492

    PubMed  CAS  Google Scholar 

  18. Lenz HJ, Danenberg KD, Leichman CG, Florentine B, Johnston PG, Groshen S, Zhou L, Xiong YP, Danenberg PV, Leichman LP (1998) p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site. Clin Cancer Res 4:1227–1234

    PubMed  CAS  Google Scholar 

  19. Sakamoto J, Fukushima M, Hamashima H (1999) Thymidylate synthase expression predict prognosis of curatively resected colorectal carcinoma patients registered in an adjuvant immunochemotherapy clinical trial. Proc ASCO 18:268a

    Google Scholar 

  20. Sanguedolce R, Vultaggio G, Sanguedolce F, Modica G, Li Volsi F, Diana G, Guereio G, Bellanca L, Rausa L (1998) The role of thymidylate synthase levels in the prognosis and the treatment of patients with colorectal cancer. Anticancer Res 18:1515–1520

    PubMed  CAS  Google Scholar 

  21. Goldberg RM, Sargent D, Mahoney MR (1998) Limited prognostic importance of immunohistochemical parameters (IHP) [thymidylate synthase (TS), KI-67, and P53] in 465 patients with Dukes’ B2 and C colon cancer enrolled on North Central Cancer Treatment Group (NCCTG) trials. Proc ASCO 18:267a

    Google Scholar 

  22. Elwell A, Xiong YP, Chang M (1997) p53, p21 and thymidylate synthase protein expression: associations with recurrence in stage II and III rectal cancer. Proc ASCO 16:258a

    Google Scholar 

  23. Johnston PG, Fisher ER, Rockette HE, Fisher B, Wolmark N, Drake JC, Chabner BA, 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

    PubMed  CAS  Google Scholar 

  24. Edler D, Blomgren H, Allegra CJ, Johnston PG, Lagerstedt U, Magnusson I, Ragnhammar P (1997) Immunohistochemical determination of thymidylate synthase in colorectal cancer-methodological studies. Eur J Cancer 33:2278–2281

    Article  PubMed  CAS  Google Scholar 

  25. Lichtenstein E (1997) Behavioral research contributions and needs in cancer prevention and control: Tobacco use prevention and cessation. Prev Med 26:S57–S63

    Article  PubMed  CAS  Google Scholar 

  26. Sherr CJ (1994) G1 phase progression: cycling on cue. Cell 79:551–555

    Article  PubMed  CAS  Google Scholar 

  27. Meyerson M, Harlow E (1994) Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 14:2077–2086

    PubMed  CAS  Google Scholar 

  28. Dulic V, Lees E et al (1992) Association of human cyclin E with a periodic G1-S phase protein kinase. Science 257:1958–1961

    Article  PubMed  CAS  Google Scholar 

  29. Elledge SJ, Richman R, Hall FL, Williams RT, Lodgson N, Harper JW (1992) Cdk2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before Cdc2 in the cell cycle. Proc Natl Acad Sci USA 89:2907–2911

    Article  PubMed  CAS  Google Scholar 

  30. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M (1995) Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 15:2612–2624

    PubMed  CAS  Google Scholar 

  31. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704

    Article  PubMed  CAS  Google Scholar 

  32. Longley DB, Ferguson PR, Boyer J, Latif T, Lynch M, Maxwell P, Harkin DP, Johnston PG (2001) Characterization of a thymidylate synthase (TS)-inducible cell line. Clin Cancer Res 7:3533–3539

    PubMed  CAS  Google Scholar 

  33. Yin MB, Guo B, Panadero A, Frank C, Wrzosek C, Slocum HK, Rustum YM (1999) Cyclin E-Cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. Exp Cell Res 247:189–199

    Article  PubMed  CAS  Google Scholar 

  34. Kamoshida S, Matsuoka H, Shiogama K, Matsuyama A, Shimomura R, Inada K, Maruta M, Tsutsumi Y (2004) Immunohistochemical analysis of thymidylate synthase, p16INK4a, cyclin-dependent kinase 4 and cyclin D1 in colorectal cancers receiving preoperative chemotherapy: Significance of p16INK4a-mediated cellular arrest as an indicator of chemosensitivity to 5-fluorouracil. Pathol Int 54:564–575

    Article  PubMed  CAS  Google Scholar 

  35. Kamoshida S, Matsuoka H, Ishikawa T, Maeda K, Shimomura R, Inada K, Tsutsumi Y (2004) Immunohistochemical evaluation of thymidylate synthase (TS) and p16INK4a in advanced colorectal cancer: implication of TS expression in 5-FU-based adjuvant chemotherapy. Jpn J Clin Oncol 34:594–601

    Article  PubMed  Google Scholar 

  36. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman R, Lowe S (2002) A senescence program controlled by p53 and p16INK4A contributes to the outcome of cancer therapy. Cell 109:335–346

    Article  PubMed  CAS  Google Scholar 

  37. Omura K, Uno Y, Kawakami K, Kanehira E, Tawaraya K, Tsukayama M, Hiranuma C, Watanabe Y (2000) Expression of thymidylate synthase in human gastric and colorectal adenocarcinomas is upregulated by p16/INK4. Hepatogastroenterology 47:742–745

    PubMed  CAS  Google Scholar 

  38. Backus HHJ, van Groeningen CJ, Vos W, Dukers DF, Bloemena E, Wouters D, Pinedo HM, Reters GJ (2002) Differential expression of cell cycle and apoptosis related proteins in colorectal mucosa, primary colon tumours, and liver metastases. J Clin Pathol 55:206–211

    PubMed  CAS  Google Scholar 

  39. Backus HH, van Riel JM, van Groeningen CJ, Vos W, Dukers DF, Bloemena E, Wouters D, Pinedo HM, Reters GJ (2001) Rb, mcl-1 and p53 expression correlate with clinical outcome in patients with liver metastases from colorectal cancer. Ann Oncol 12:779–785

    Article  PubMed  CAS  Google Scholar 

  40. Hayes DF, Bast RC, Desch CE, Fritsche H, Kemeny NE Jr., Jessup JM, Locker GY, Macdonald JS, Mennel RG, Norton L, Ravdin P, Taube S, Winn RJ (1996) Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 88:1456–1466

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Second Department of Propedeutic Surgery, Medical School, University of Athens, 17, Ag. Thoma Str., Athens, 11527, Greece

    Gerasimos Tsourouflis, Anastasia Sampani, Alkiviadis Kostakis & Gregory Kouraklis

  2. Department of Forensic Medicine and Toxicology, Medical School, University of Athens, 75 Mikras Asias Str., Athens, 11527, Greece

    Stamatios E. Theocharis & Athina Giagini

Authors
  1. Gerasimos Tsourouflis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stamatios E. Theocharis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anastasia Sampani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Athina Giagini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alkiviadis Kostakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory Kouraklis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stamatios E. Theocharis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsourouflis, G., Theocharis, S.E., Sampani, A. et al. Prognostic and Predictive Value of Thymidylate Synthase Expression in Colon Cancer. Dig Dis Sci 53, 1289–1296 (2008). https://doi.org/10.1007/s10620-007-0008-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-007-0008-x

Keywords

Search

Navigation