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Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy

The Pharmacogenomics Journal volume 1, pages 65–70 (2001)Cite this article

Abstract

Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.

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Abbreviations

5-FU:

5-Fluorouracil

TS:

Thymidylate synthase

TP:

Thymidine phosphorylase

DPD:

Dihydropyrimidine dehydrogenase

References

  1. Midgley R, Kerr D . Colorectal cancer Lancet 1999 353: 391–399

    Article  CAS  Google Scholar 

  2. Moertel CG . Chemotherapy for colorectal cancer N Engl J Med 1994 330: 1136–1143

    Article  CAS  Google Scholar 

  3. Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Gerlach JH et al . Fluorinated pyrimidines: a new class of tumor inhibitory compounds Nature 1957 179: 663–666

    Article  CAS  Google Scholar 

  4. Danenberg P . Thymidylate synthase—a target enzyme in cancer chemotherapy Biochem Biophys Acta 1977 473: 73–92

    CAS  PubMed  Google Scholar 

  5. Horie N, Aiba H, Ogura K, Hojo H, Takeishi-K . Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase Cell Struct Funct 1995 20: 191–197

    Article  CAS  Google Scholar 

  6. Horie N, Chimoto M, Nozawa R, Takeishi K . Characterization of the regulatory sequences and nuclear factors that function in cooperation with the promoter of the human thymidylate synthase gene Biochem Biophys Acta 1993 1216: 409–416

    CAS  PubMed  Google Scholar 

  7. Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J, Groshen S . Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin J Clin Oncol 1997 15: 3223–3229

    Article  CAS  Google Scholar 

  8. Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen S, Gerlach JH et al . Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival J Clin Oncol 1995 14: 176–182

    Article  Google Scholar 

  9. Lenz HJ, Danenberg KD, Leichman CG, Florentine B, Johnston PG, Gerlach JH et al . p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site Clin Cancer Res 1998 4: 1227–1234

    CAS  PubMed  Google Scholar 

  10. Lenz HJ, Hayashi K, Salonga D, Danenberg KD, Danenberg PV, Gerlach JH et al . p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival Clin Cancer Res 1998 4: 1243–1250

    CAS  PubMed  Google Scholar 

  11. Kawakami K, Omura K, Kanehira E, Watanabe Y . Polymorphic tandem repeat in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers Anticancer Res 1999 19: 3249–3252

    CAS  Google Scholar 

  12. Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD . Searching expressed sequence tag database: discovery and confirmation of a common polymorphism in the Thymidylate synthase gene Cancer Epidemiol Biomarkers Prev 2000 9: 1381–1385

    CAS  Google Scholar 

  13. Pullarkat ST, Ingles SA, Xiong Y-P, Ingles SA, Sherrod A, Gerlach JH et al . Analysis of the thymidylate synthase gene polymorphism in the Latino population Proc AACR 1999 40: 4583

    Google Scholar 

  14. Marsh S, Collie-Duguid ESR, Li T, Liu X, McLeod HL . Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations Genomics 1999 58: 1–3

    Article  Google Scholar 

  15. Marsh S, Ameyaw MM, Githang’s J, Indalo A, Ofori-Adjei D, McLeod HL . Novel thymidylate synthase enhancer region alleles in African populations Hum Mut 2000 16: 528

    Article  CAS  Google Scholar 

  16. Metzger R, Danenberg K, Leichman CG, Salonga D, Schwartz EL, Gerlach JH et al . High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil Clin Cancer Res 1998 4: 2371–2376

    CAS  Google Scholar 

  17. Ishikawa Y, Kubota T, Otani Y, Watanabe M, Teramoto T, Gerlach JH et al . Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil Jpn J Cancer Res 2000 91: 105–112

    Article  CAS  Google Scholar 

  18. Kitchens ME, Forsthoefel AM, Barbour KW, Spencer HT, Berger FG . Mechanisms of acquired resistance to thymidylate synthase inhibitors: the role of enzyme stability Mol Pharmacol 1999 56: 1063–1070

    Article  CAS  Google Scholar 

  19. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidium thiocyabate-phenol-chloroform extraction Ann Biochem 1987 162: 156–159

    Article  CAS  Google Scholar 

  20. Takeishi K, Kaneda S, Ayusawa D, Shimizu K, Gotoh O, Seno T . Nucleotide sequence of a functional cDNA for thymidylate synthase Nucleic Acids Res 1987 13: 2035–2045

    Article  Google Scholar 

  21. Horikoshi T, Danenberg KD, Stadlbauer TH, Volkenandt M, Shea LC, Gerlach JH et al . Quantitation of thymidylate synthase, dihydrofolate reductase, and DT-diaphorase gene expression in human tumors using the polymerase chain reaction Cancer Res 1992 52: 108–116

    CAS  PubMed  Google Scholar 

  22. Zar JH . Biostatistical Analysis Prentice-Hall: Englewood Cliffs 1974

    Google Scholar 

  23. Kaplan EL, Meier P . Nonparametric estimation for incomplete observations J Am Stat Assoc 1958 53: 457–481

    Article  Google Scholar 

  24. Miller RG Jr . Survival Analysis John Wiley & Sons: New York 1981

    Google Scholar 

  25. Pike MC . Contribution to the discussion on the paper by R Peto and J Peto, ‘Asymptotically efficient rank invariant procedures’ J Royal Stat Soc 1972 Series A 135: 201–203

    Google Scholar 

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Acknowledgements

This work is funded by NIH grants R01 CA 82655, R01 CA74166 and P30 CA14089. JS is supported by Dr Mildred Scheel Stiftung, Bonn, Germany.

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Authors and Affiliations

  1. University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California

    S T Pullarkat, J Stoehlmacher, V Ghaderi, Y-P Xiong, S A Ingles, A Sherrod, D Tsao-Wei, S Groshen & H-J Lenz

  2. Department of Surgery, University of California San Francisco, San Francisco, CA, USA

    R Warren

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  1. S T Pullarkat
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  2. J Stoehlmacher
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  7. R Warren
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  10. H-J Lenz
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Correspondence to H-J Lenz.

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Pullarkat, S., Stoehlmacher, J., Ghaderi, V. et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1, 65–70 (2001). https://doi.org/10.1038/sj.tpj.6500012

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  • DOI: https://doi.org/10.1038/sj.tpj.6500012

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