DOI QR코드

DOI QR Code

Relationship Between Antimetabolite Toxicity and Pharmacogenetics in Turkish Cancer Patients

  • Dogan, Mutlu (Dept of Medical Oncology, School of Medicine, Ankara University) ;
  • Karabulut, Halil G. (Dept of Medical Genetics, School of Medicine, Ankara University) ;
  • Tukun, Ajlan (Dept of Medical Genetics, School of Medicine, Ankara University) ;
  • Demirkazik, Ahmet (Dept of Medical Oncology, School of Medicine, Ankara University) ;
  • Utkan, Gungor (Dept of Medical Oncology, School of Medicine, Ankara University) ;
  • Yalcin, Bulent (Dept of Medical Oncology, School of Medicine, Ankara University) ;
  • Dincol, Dilek (Dept of Medical Oncology, School of Medicine, Ankara University) ;
  • Akbulut, Hakan (Dept of Medical Oncology, School of Medicine, Ankara University) ;
  • Icli, Fikri (Dept of Medical Oncology, School of Medicine, Ankara University)
  • 발행 : 2012.04.30

초록

Introduction: Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. Patients and Methods: Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5´UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. Results: Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. Conclusion: Pharmacogenetics might contribute to tailored therapy.

키워드

참고문헌

  1. Campalani E, Arenas M, Marinaki M, et al (2007). Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol, 127, 1860-7. https://doi.org/10.1038/sj.jid.5700808
  2. Dervieux T, Meshkin B, Neri B (2005). Pharmacogenetic testing: proofs of principle and pharmacoeconomic implications. Mutat Res, 573, 180-94. https://doi.org/10.1016/j.mrfmmm.2004.07.025
  3. Goyette P, Pai A, Milos R, et al (1998). Gene structure of human and mouse methylenetetrahydrofolate reductase. Mamm Genome, 9, 652-6. https://doi.org/10.1007/s003359900838
  4. Gross E, Busse B, Riemenschneider M, et al (2008). Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One, 3, e4003, 1-7.
  5. Kantar M, Kosova B, Cetingul N, et al (2009). Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma, 50, 912-7. https://doi.org/10.1080/10428190902893819
  6. Lopez-Cima MF, Gonzalez-Arriaga P, García-Castro L, et al (2007). Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain. BMC Cancer, 7, 162-73. https://doi.org/10.1186/1471-2407-7-162
  7. Magne N, Etienne-Grimaldi MC, Cals L, et al (2007). Dihydropryrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity. Br J lin Pharmacol, 64, 237-40. https://doi.org/10.1111/j.1365-2125.2007.02869.x
  8. Meta-Analysis Group in Cancer (1998). Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol, 16, 3537-41.
  9. Sliwinski T, Krupa R, Wisniewska-Jarosinska M et al (2009). Common polymorphisms in the XPD and hOGG1 genes are not associated with the risk of colorectal cancer in a Polish population. Tohoku J Exp Med, 218, 185-91. https://doi.org/10.1620/tjem.218.185
  10. Sreeja L, Syamala VS, Syamala V, et al (2008). Prognostic importance of DNA repair gene polymorphisms of XRCC1 Arg399Gln and XPD Lys751Gln in lung cancer patients from India. J Cancer Res Clin Oncol, 134, 645-52. https://doi.org/10.1007/s00432-007-0328-4
  11. Toffoli G, de Mattia E (2008). Pharmacogenetic relevance of MTHFR polymorphisms. Pharmacogenomics, 9, 1195-206. https://doi.org/10.2217/14622416.9.9.1195
  12. Van Kuilenburg AB, Haasjes J, Richel DJ, et al (2000). Clinical Implications of Dihydropyrimidine Dehydrogenase (DPD) Deficiency in Patients with Severe 5-Fluorouracil-associated Toxicity: Identification of New Mutations in the DPD Gene Clinical Cancer Research, 6, 4705-12.
  13. Van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH (2002). Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to dihydroprymidine dehydrogenase deficiency: high prevelance of the IVS14- 1G-A mutation. Int J Cancer, 101, 253-8. https://doi.org/10.1002/ijc.10599
  14. Van Kuilenburg AB (2004). Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer, 40, 939-50. https://doi.org/10.1016/j.ejca.2003.12.004
  15. Wang M, Gu D, Zhang Z, et al (2009). XPD polymorphisms, cigarette smoking, and bladder cancer risk: a meta-analysis. J Toxicol Environ Health A, 72, 698-05. https://doi.org/10.1080/15287390902841029

피인용 문헌

  1. Single Nucleotide Polymorphisms in the NER Pathway and Clinical Outcome of Patients with Bone Malignant Tumor vol.14, pp.3, 2013, https://doi.org/10.7314/APJCP.2013.14.3.2049
  2. Predictive Impact of Common Variations in DNA Repair Genes on Clinical Outcome of Osteosarcoma vol.14, pp.6, 2013, https://doi.org/10.7314/APJCP.2013.14.6.3677
  3. Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: An informative gene network analysis vol.12, pp.7, 2017, https://doi.org/10.1371/journal.pone.0180396
  4. Pharmacogenomics of genes involved in antifolate drug response and toxicity in osteosarcoma vol.13, pp.3, 2017, https://doi.org/10.1080/17425255.2017.1246532