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DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity

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Abstract

Purpose

5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities.

Methods

Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0–G1).

Results

Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association.

Conclusions

Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity.

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Acknowledgments

This work was supported in part by the grants from Italian Association for Research on Cancer (AIRC); Ministry of University and Research (MIUR) 60 % and Research Projects of National Interest (PRIN); Veneto Institute of Oncology, IOV-IRCCS 5 ‰.

Conflict of interest

No conflicts of interest were disclosed.

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Authors and Affiliations

  1. Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Via Gattamelata 64, 35128, Padova, Italy

    Enrica Rumiato, Elisa Boldrin, Alberto Amadori & Daniela Saggioro

  2. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

    Alberto Amadori

Authors
  1. Enrica Rumiato
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  2. Elisa Boldrin
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  3. Alberto Amadori
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  4. Daniela Saggioro
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Corresponding author

Correspondence to Daniela Saggioro.

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Rumiato, E., Boldrin, E., Amadori, A. et al. DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity. Cancer Chemother Pharmacol 72, 483–488 (2013). https://doi.org/10.1007/s00280-013-2210-1

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  • DOI: https://doi.org/10.1007/s00280-013-2210-1

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