Skip to main content

Advertisement

Log in

TS mRNA levels can predict pemetrexed and raltitrexed sensitivity in colorectal cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of the study is to analyze the relationship between tumor thymidylate synthase (TS) mRNA expression levels and raltitrexed/pemetrexed/5-FU sensitivity.

Patients and methods

We collected freshly removed colorectal tumor specimens from 50 patients. Chemosensitivities to anticancer drugs were evaluated by histoculture drug response assay. We adopted quantitative reverse transcription polymerase chain reaction for TS mRNA detection and immunohistochemical staining for assessing TS expression in tumor tissues.

Results

There is a significant relationship between TS mRNA expression levels and in vitro chemosensitivity of freshly removed colorectal tumor specimens to pemetrexed (P < 0.001)/raltitrexed (P = 0.004)/5-FU (P = 0.007).

Conclusions

TS mRNA expression levels can predict pemetrexed and raltitrexed sensitivity in colorectal cancer.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Landis SH, Murray T, Bolden S, Wingo PA (1999) Cancer statistics, 1999. CA Cancer J Clin 49:8–31

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  3. Ping Z, Min D, Wanqing C, Ni L (2010) Cancer trends in China. Jpn J Clin Oncol 40(4):281–285

    Article  Google Scholar 

  4. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz AM, Benson AB (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544

    Article  CAS  PubMed  Google Scholar 

  5. Chin L, Andersen JN, Futreal PA (2011) Cancer genomics: from discovery science to personalized medicine. Nat Med 17(3):297–303

    Article  CAS  PubMed  Google Scholar 

  6. Rosell R, Moran T, Viteri S, Carcereny E, Gasco A, Quiroga V, Wei J, Camps C, Massuti B (2010) Optimization of genetics to create therapies for metastatic (stage IV) non-small-cell lung cancer. Expert Opin Pharmacother 11:1683–1693

    Article  CAS  PubMed  Google Scholar 

  7. Adjei AA (2000) Pemetrexed: a multitargeted antifolate agent with promising activity in solid tumors. Ann Oncol 11:1335–1341

    Article  CAS  PubMed  Google Scholar 

  8. Raymond E, Louvet C, Tournigand C, Coudray AM, Faivre S, De Gramont A, Gespach C (2002) Pemetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells. Int J Oncol 21(2):361–367

    CAS  PubMed  Google Scholar 

  9. Cunningham D, Zalcberg JR, Rath U, Oliver I, Cutsem EV, Svensson C, Seitz JF, Harper P, Kerr D, Perez-Manga G (1996) Final results of a randomised trial comparing ‘Tomudex’ (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. “Tomudex” Colorectal Cancer Study Group. Ann Oncol 7:961–965

    Article  CAS  PubMed  Google Scholar 

  10. Cunningham D (1997) Efficacy and tolerability of a new inhibitor of thymidylate synthase: ‘Tomudex’ (raltitrexed). Tumori 83(Suppl 1):S70–S71

    CAS  PubMed  Google Scholar 

  11. Cocconi G, Cunningham D, Van CE, Francois E, Gustavsson B, Hazel GV, Kerr D, Possinger K, Hietschold SM (1998) Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943–2952

    CAS  PubMed  Google Scholar 

  12. Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, Bianco AR, El-Serafi M, Bedenne L, Paillot B, Minik E, Sanches E, Welchm J, Collette L, Praet M, Wils J (2008) Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer 44:2204–2211

    Article  CAS  PubMed  Google Scholar 

  13. Giovannetti E, Backus HH, Wouters D, Ferreira CG, van Houten VM, Brakenhoff RH, Poupon MF, Azzarello A, Pinedo HM, Peters GJ (2007) Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer 96:769–775

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Di Gennaro E, Bruzzese F, Pepe S, Leone A, Delrio P, Subbarayan PR, Avallone A, Budillon A (2009) Modulation of thymidylate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or raltitrexed. Cancer Biol Ther 8:782–791

    Article  PubMed  Google Scholar 

  15. Furukawa T, Kubota T, Hoffman RM (1995) Clinical applications of the histoculture drug response assay. Clin Cancer Res 1:305–311

    CAS  PubMed  Google Scholar 

  16. Yoshimasu T, Oura S, Hirai I, Tamaki T, Kokawa Y, Hata K, Ohta F, Nakamura R, Kawago M, Tanino H, Okamura Y, Furukawa T (2007) Data acquisition for the histoculture drug response assay in lung cancer. J Thorac Cardiovasc Surg 133:303–308

    Article  CAS  PubMed  Google Scholar 

  17. Lee SW, Kim YM, Kim MB, Kim DY, Kim JH, Nam JH, Kim YT (2009) Chemosensitivity of uterine cervical cancer demonstrated by the histoculture drug response assay. Tohoku J Exp Med 219(4):277–282

    Article  CAS  PubMed  Google Scholar 

  18. Hanauske AR, Eismann U, Oberschmidt O, Pospisil H, Hoffmann S, Hanauske-Abel H, Ma D, Chen V, Paoletti P, Niyikiza C (2007) In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression. Invest New Drugs 25:417–423

    Article  CAS  PubMed  Google Scholar 

  19. Shen J, Wang H, Wei J, Yu LX, Xie L, Qian XP, Zou ZY, Liu BR, Guan WX (2012) Thymidylate synthase mRNA levels in plasma and tumor as potential predictive biomarkers for raltitrexed sensitivity in gastric cancer. Int J Cancer 131:E938–E945

    Article  CAS  PubMed  Google Scholar 

  20. Hothorn T, Zeileis A (2008) Generalized maximally selected statistics. Biometrics 64:1263–1269

    Article  PubMed  Google Scholar 

  21. Livak KJ, Schmittgen TD (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 03:1101–1108

    Article  Google Scholar 

  22. Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra CJ, Danenberg PV, 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

    CAS  PubMed  Google Scholar 

  23. Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ, Levin B (1995) bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res 55:237–241

    CAS  PubMed  Google Scholar 

  24. Seitz JF, Bennouna J, Paillot B, Gamelin E, Francois E, Conroy T, Raoul JL, Becouarn Y, Bertheault-Cvitkovic F, Ychou M, Nasca S, Fandi A, Barthelemy P, Douillard JY (2002) Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non-pretreated metastatic colorectal cancer patients. Ann Oncol 13(7):1072–1079

    Article  PubMed  Google Scholar 

  25. Santini D, Massacesi C, D’Angelillo RM, Marcucci F, Campisi C, Vincenzi B, Pilone A, Bianco V, Bonsignori M, Tonini G (2004) Raltitrexed plus weekly oxaliplatin as first-line chemotherapy in metastatic colorectal cancer. Med Oncol 21(1):59–66

    Article  CAS  PubMed  Google Scholar 

  26. Atkins JN, Jacobs SA, Wieand HS, Smith RE, John WJ, Colangelo LH, Vogel VG, Kuebler JP, Cescon TP, Miller BJ, Geyer CE Jr, Wolmark N (2005) Pemetrexed/oxaliplatin for first-line treatment of patients with advanced colorectal cancer: a phase II trial of the National Surgical Adjuvant Breast and Bowel Project Foundation Research Program. Clin Colorectal Cancer 5(3):181–187

    Article  PubMed  Google Scholar 

  27. Aschele C, Debernardis D, Casazza S, Antonelli G, Tunesi G, Baldo C, Lionetto R, Maley F, Sobrero A (1999) Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J Clin Oncol 17(6):1760

    CAS  PubMed  Google Scholar 

  28. Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S, Tsao-Wei DD, Lenz HJ, Leichman GC, 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(4):1322–1327

    CAS  PubMed  Google Scholar 

  29. Edler D, Hallström 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(4):1378–1384

    CAS  PubMed  Google Scholar 

  30. Van Triest B, Pinedo HM, Blaauwgeers JL, Van Diest PJ, Schoenmakers PS, Voorn DA, Smid K, Hoekman K, Hoitsma HFW, Peters GJ (2000) Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer. Clin Cancer Res 6(3):1063–1072

    PubMed  Google Scholar 

  31. Chattopadhyay Shrikanta, Moran Richard G, David Goldman I (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther 6:404–417

    Article  CAS  PubMed  Google Scholar 

  32. Chu E, Callender MA, Farrell MP (2003) Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol 52(Suppl 1):S80–S89

    Article  CAS  PubMed  Google Scholar 

  33. Ozasa H, Oguri T, Uemura T, Miyazaki M, Maeno K, Sato S, Ueda R (2010) Significance of thymidylate synthase for resistance to pemetrexed in lung cancer. Cancer Sci 101:161–166

    Article  CAS  PubMed  Google Scholar 

  34. Woods B, Paracha N, Scotta DA, Thatcher N (2012) Raltitrexed plus cisplatin is cost-effective compared with pemetrexed plus cisplatin in patients with malignant pleural mesothelioma. Lung Cancer 75:261–267

    Article  PubMed  Google Scholar 

  35. Chen CY, Chang YL, Shih JY, Lin JW, Chen KY, Yang CH, Yu CJ, Yang PC (2011) Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: the association with treatment efficacy of pemetrexed. Lung Cancer 74:132–138

    Article  PubMed  Google Scholar 

  36. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2640

    Article  CAS  PubMed  Google Scholar 

  37. Surmont VF, Meerbeeck JPV (2011) Raltitrexed in mesothelioma. Expert Rev Anticancer Ther 11(10):1481–1490

    Article  CAS  PubMed  Google Scholar 

  38. Hoffman RM (1993) To do tissue culture in two or three dimensions? That is the question. Stem Cells 11:105–111

    Article  CAS  PubMed  Google Scholar 

  39. Miller BE, Miller FR, Heppner GH (2005) Assessing tumor drug sensitivity by a new in vitro assay which preserves tumor heterogeneity and subpopulation interactions. J Cell Physiol Suppl 3:105–116

    Google Scholar 

  40. Yuan SQ, Zhi ZW, Liang YJ, Fu LW, Chen G, Qiu HB, Zhang LY (2009) Correlation of chemosensitivity tested using histoculture drug response assay to expression of multidrug resistance genes and proteins in colorectal cancer tissues. Chin J Cancer 28(9):932–993

    Article  CAS  Google Scholar 

  41. Pathak KA, Juvekar AS, Radhakrishnan DK, Deshpande MS, Pai VR, Chaturvedi P, Pai PS, Chaukar DA, D’Cruz AK, Parikh PM (2007) In vitro chemosensitivity profile of oral squamous cell cancer and its correlation with clinical response to chemotherapy. Indian J Cancer 44:142–146

    Article  CAS  PubMed  Google Scholar 

  42. Yoon YS, Kim CW, Roh SA, Cho DH, Kim GP, Hong YS, Kim TW, Kim MB, Kim JC (2012) Applicability of histoculture drug response assays in colorectal cancer chemotherapy. Anticancer Res 8:3581–3586

    Google Scholar 

  43. Ohie S, Udagawa Y, Aoki D, Nozawa S (2005) Histoculture drug response assay to monitor chemoresponse. Methods Mol Med 110:79–86

    CAS  PubMed  Google Scholar 

  44. Garcia V, Garcia JM, Pena C, Silva J, Dominguez G, Lorenzo Y, Diaz R, Espinosa P, de Sola JG, Cantos B, Bonilla F (2008) Free circulating mRNA in plasma from breast cancer patients and clinical outcome. Cancer Lett 263:312–320

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by Drum Tower Hospital (Nanjing, China), the National Natural Science Foundation of China (Grant Number: 81172094; Grant sponsor: Natural Science), the Foundation of Jiangsu Province (Grant Numbers: BK2011095, WS005).

Conflict of interest

The authors declare no conflict of interests.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wenxian Guan or Xiaoping Qian.

Additional information

Qun Zhang and Jie Shen have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Q., Shen, J., Wang, H. et al. TS mRNA levels can predict pemetrexed and raltitrexed sensitivity in colorectal cancer. Cancer Chemother Pharmacol 73, 325–333 (2014). https://doi.org/10.1007/s00280-013-2354-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-013-2354-z

Keywords

Navigation