Drugs & Aging

, Volume 25, Issue 6, pp 531–539 | Cite as

Glutathione S-Transferase P1 Ile105Val Polymorphism is Associated with Haematological Toxicity in Elderly Rectal Cancer Patients Receiving Preoperative Chemoradiotherapy

  • Marco Agostini
  • Lara Maria Pasetto
  • Salvatore Pucciarelli
  • Salvatore Terrazzino
  • Alessandro Ambrosi
  • Chiara Bedin
  • Francesca Galdi
  • Maria Luisa Friso
  • Claudia Mescoli
  • Emanuele Urso
  • Alberta Leon
  • Mario Lise
  • Donato Nitti
Original Research Article

Abstract

Background: Increasing evidence suggests that common gene polymorphisms may influence the toxicity of various cytotoxic agents used in the treatment of cancer.

Objective: To evaluate the predictive value of acute toxicity of methylenetetrahydrofolate reductase 677T polymorphism, glutathione S-transferase P1 (GSTP1) substitution of isoleucine with valine at codon 105 (Ile105Val) polymorphism and the tandem repeat polymorphism in the thymidylate synthase gene promoter in elderly patients with rectal cancer receiving preoperative chemoradiotherapy (CRT).

Method: From 1994 to 2002, 166 Caucasian patients underwent surgery following CRT for mid-low rectal cancer at a single institution, 42 (male-to-female ratio, 25:17) of whom were aged ≥65 years (median age 70 years, range 65–79). The pre-treatment clinical stage was tumour (T) stage 3–4 in 38 patients and node (N)-positive in 29 patients. Patients received external-beam radiotherapy with conventional fractionation and fluorouracil-based chemotherapy. Blood samples were used to extract and amplify DNA. Gene polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. Acute toxicity to preoperative therapy was reported according to the National Cancer Institute Common Toxicity Criteria, version 2. Univariate and multivariate analyses were performed using one-way analysis of variance and linear regression, respectively.

Results: Haematological toxicity (grade 1–2) was observed in 15 of 40 patients for whom toxicity data were available and gastrointestinal toxicity (grade 1–4) in 24 of these same 40 patients. At univariate analysis, female sex (p = 0.036) and GSTP1 Ile105Val (p = 0.0376) were associated with haematological toxicity. At multivariate analysis, GSTP1 Ile105Val polymorphism (p = 0.041) was the only factor found to be associated with haematological toxicity. Patients carrying the Val/Val genotype in the GSTP1 gene had a lower risk of haematological toxicity (odds ratio = 0.322, 95% CI 0.101, 0.957) than patients with the Ile/Ile genotype.

Conclusion: GSTP1 Ile105Val polymorphism is a promising marker of potential haematological toxicity in elderly patients with rectal cancer receiving preoperative CRT.

Notes

Acknowledgements

This study, conducted in Padova (Italy), was partially supported by grants from the Italian Ministry of Health (Programma speciale ex. art.12, 2004), AIRC (Associazione Italiana Ricerca Cancro). The authors have no conflicts of interest that are directly relevant to the content of this study. The authors are grateful to Miss Marta Briarava for collecting and managing clinical and research data, and to Antonette Leon for her assistance with the English language.

References

  1. 1.
    EUCAN. Cancer incidence, mortality and prevalence in the European Union: 1998 estimates [online]. Available from URL: http://www-dep.iarc.fr/eucan/eucan.htm [Accessed 2008 Apr 1]
  2. 2.
    Grobovsky L, Kaplon M, Krozser-Hamati A, et al. Features of cancer in frail elderly patients (pts) (85 years of age) [abstract no. 2469]. Proc Am Soc Clin Oncol 2000; 19: 139Google Scholar
  3. 3.
    Pucciarelli S, Friso ML, Toppan P, et al. Preoperative combined radiotherapy and chemotherapy for middle and lower rectal cancer: preliminary results. Ann Surg Oncol 2000; 7(1): 38–44PubMedCrossRefGoogle Scholar
  4. 4.
    The Advanced Colorectal Meta-Analysis Project. Modulation of fluorouracil with leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992; 10: 896–903Google Scholar
  5. 5.
    O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. New Engl J Med 1994; 331: 502–7PubMedCrossRefGoogle Scholar
  6. 6.
    Sobrero A, Guglielmi A, Cirillo M, et al. 5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer. Br J Cancer 2001; 84(8): 1023–8PubMedCrossRefGoogle Scholar
  7. 7.
    Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345(15): 1091–7PubMedCrossRefGoogle Scholar
  8. 8.
    The Advanced Colorectal Cancer Meta-Analysis Project. Metaanalysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 1994; 12: 960–9Google Scholar
  9. 9.
    The Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301–8Google Scholar
  10. 10.
    Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9: 1053–71PubMedCrossRefGoogle Scholar
  11. 11.
    Hessman O, Bergkvist L, Strom S. Colorectal cancer in patients over 75 years of age: determinants of outcome. Eur J Surg Oncol 1997; 23(1): 13–9PubMedCrossRefGoogle Scholar
  12. 12.
    Koperna T, Kisser M, Schulz F. Hepatic resection in the elderly. World J Surg 1998; 22(4): 406–12PubMedCrossRefGoogle Scholar
  13. 13.
    Balducci L, Yates G. General guidelines for the management of older patients with cancer. Oncology 2000; 14: 221–7PubMedGoogle Scholar
  14. 14.
    Relling MV, Dervieux T. Pharmacogenetics and cancer therapy. Nat Rev Cancer 2001; 1: 99–108PubMedCrossRefGoogle Scholar
  15. 15.
    Ulrich CM, Robien K, McLeod HL. Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nat Rev Cancer 2003; 3: 912–20PubMedCrossRefGoogle Scholar
  16. 16.
    Nagasubramanian R, Innocenti F, Ratain MJ, et al. Pharmacogenetics in cancer treatment. Ann Rev Med 2003; 54: 437–52PubMedCrossRefGoogle Scholar
  17. 17.
    Jakobsen A, Nielsen JN, Gyldenkerne N, et al. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol 2005; 23: 1365–9PubMedCrossRefGoogle Scholar
  18. 18.
    Chiusolo P, Reddiconto G, Casorelli I, et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 2002; 13(12): 1915–8PubMedCrossRefGoogle Scholar
  19. 19.
    Stoehlmacher J, Park DJ, Zhang W, et al. Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 2002; 94: 936–42PubMedCrossRefGoogle Scholar
  20. 20.
    Edvardsen H, Kristensen VN, Grenaker Alnaes GI, et al. Germline glutathione S-transferase variants in breast cancer: relation to diagnosis and cutaneous long-term adverse effects after two fractionation patterns of radiotherapy. Int J Radiat Oncol Biol Phys 2007; 67(4): 1163–71PubMedCrossRefGoogle Scholar
  21. 21.
    Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. An improved reference for grading the acute effects of cancer treatment: impact on RT. Int J Radiat Oncol Biol Phys 2000; 47: 13–47PubMedCrossRefGoogle Scholar
  22. 22.
    Van Triest B, Peters GJ. Thymidylate synthase: a target for combination therapy and determinant of chemotherapeutic response in colorectal cancer. Oncology 1999; 57: 179–94PubMedCrossRefGoogle Scholar
  23. 23.
    Agostini M, Pucciarelli S, Calandra P, et al. Genetic heterogeneity of variable number tandem repeats in thymidylate synthase gene in colorectal cancer patients. Int J Biol Markers 2004; 19(4): 332–6PubMedGoogle Scholar
  24. 24.
    Terrazzino S, Agostini M, Pucciarelli S, et al. A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation. Pharmacogenet Genomics 2006; 16(11): 817–24PubMedCrossRefGoogle Scholar
  25. 25.
    Harries LW, Stubbins MJ, Forman D, et al. Identification of genetic polymorphisms at the glutathione S-transferase P1 locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis 1997; 18: 641–4PubMedCrossRefGoogle Scholar
  26. 26.
    Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5FU chemotherapy. Pharmacogenomics J 2001; 1(1): 65–70PubMedCrossRefGoogle Scholar
  27. 27.
    Cohen V, Panet-Raymond V, Sabbaghian N, et al. Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 2003; 9: 1611–5PubMedGoogle Scholar
  28. 28.
    Mannervik B, Alin P, Guthenberg C, et al. Identification of three classes of cytosolic glutathione transferase common to several mammalian species: correlation between structural data and enzymatic properties. Proc Natl Acad Sci U S A 1985; 82: 7202–6PubMedCrossRefGoogle Scholar
  29. 29.
    Moscow JA, Fairchild CR, Madden MJ, et al. Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res 1989; 49: 1422–8PubMedGoogle Scholar
  30. 30.
    Ban N, Takahashi Y, Takayama T, et al. Transfection of glutathione S-transferase (GST)-P1 antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide. Cancer Res 1996; 56: 3577–82PubMedGoogle Scholar
  31. 31.
    O’Brien M, Kruh GD, Tew KD. The influence of coordinate overexpression of glutathione phase II detoxification gene products on drug resistance. J Pharmacol Exp Ther 2000; 294: 480–7PubMedGoogle Scholar
  32. 32.
    Tsuchida S, Sato K. Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 1992; 27: 337–84PubMedCrossRefGoogle Scholar
  33. 33.
    Watson MA, Stewart RK, Smith GB, et al. Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 1998; 19: 275–80PubMedCrossRefGoogle Scholar
  34. 34.
    Srivastava SK, Singhal SS, Hu X, et al. Differential catalytic efficiency of allelic variants of human glutathione S-transferase P1 in catalyzing the glutathione conjugation of thiotepa. Arch Biochem Biophys 1999; 366: 89–94PubMedCrossRefGoogle Scholar
  35. 35.
    Sweeney C, McClure GY, Fares MY, et al. Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism. Cancer Res 2000; 60: 5621–4PubMedGoogle Scholar
  36. 36.
    Mandola MV, Stoehlmacher J, Muller-Weeks S, et al. A novel single nucleotide polymorphism within the 50 tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003; 63(11): 2898–904PubMedGoogle Scholar
  37. 37.
    Dotor E, Cuatrecases M, Martinez-Iniesta M. Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 2006; 24(10): 1603–11PubMedCrossRefGoogle Scholar
  38. 38.
    Toffoli G, Russo A, Innocenti F, et al. Effect of methylenetetrahydrofolate reductase 677C—>T polymorphism on toxicity and homocysteine plasma level after chronic methotrexate treatment of ovarian cancer patients. Int J Cancer 2003; 103: 294–9PubMedCrossRefGoogle Scholar
  39. 39.
    Pasetto LM, Friso ML, Pucciarelli S, et al. Rectal cancer neoadjuvant treatment in elderly patients. Anticancer Res 2006; 26: 3913–24PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Marco Agostini
    • 1
  • Lara Maria Pasetto
    • 2
  • Salvatore Pucciarelli
    • 1
  • Salvatore Terrazzino
    • 3
    • 4
  • Alessandro Ambrosi
    • 1
    • 5
  • Chiara Bedin
    • 1
  • Francesca Galdi
    • 1
  • Maria Luisa Friso
    • 6
  • Claudia Mescoli
    • 7
  • Emanuele Urso
    • 1
  • Alberta Leon
    • 3
  • Mario Lise
    • 1
    • 8
  • Donato Nitti
    • 1
  1. 1.Clinica Chirurgica II, Department of Oncological and Surgical SciencesUniversity of PadovaPadovaItaly
  2. 2.Oncologia Medica 2Istituto Oncologico Veneto IRCCSPadovaItaly
  3. 3.Research & Innovation LaboratoriesPadovaItaly
  4. 4.Studio Nutrizione & BenessereComoItaly
  5. 5.Istituto Oncologico Veneto IRCCSPadovaItaly
  6. 6.Radioterapia, Istituto Oncologico Veneto IRCCSPadovaItaly
  7. 7.Anatomia PatologicaIstituto Oncologico Veneto IRCCSPadovaItaly
  8. 8.Chirurgia Oncologica I, Centro di Riferimento OncologicoIRCCSAvianoItaly

Personalised recommendations