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Common DPYD Mutation Associated with 5-Fluorouracil Toxicity Detected by PCR-mediated Site-directed Mutagenesis

^a Author for correspondence. Fax 33-2-40-679731; e-mail p-jezequel@gauducheau-nantes.fnclcc.fr.

Marie-Pierre Joalland¹
Gérard Milano²
Didier Lanoë¹
Gabriel Ricolleau¹
Etienne Marie-Christine²
Régine Deporte-Fety¹

¹ Département de Biologie Oncologique, Centre Régional, de Lutte Contre le Cancer, René Gauducheau, Boulevard Jacques Monod, 44805 Nantes-St. Herblain Cedex, France,
² Laboratoire d’Oncopharmacologie, Centre Régional, de Lutte Contre le Cancer, Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice Cedex, France

To the Editor:

The human dihydropyrimidine dehydrogenase gene (DPYD) encodes dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the first and rate-limiting enzyme in the three-step pathway of uracil and thymine catabolism. DPD is also the principal enzyme involved in detoxification of pyrimidine-based antimetabolic analogs, such as 5-fluorouracil (5-FU), a drug that is commonly used in the treatment of solid tumors (colon, breast, head, neck, ovary, and skin). Because >80% of the administered 5-FU is degraded by DPD (1), the DPD catalytic activity in cancer patients could affect the efficacy of 5-FU treatment. In cancer patients with very low DPD activity, toxic reactions (e.g., diarrhea, stomatitis, mucositis, myelosuppression, and neurotoxicity) were reported that in some cases were life-threatening and sometimes fatal (2). A frequency as high as 3% of putative heterozygotes for DPD deficiency was also estimated based on catalytic activities in population studies (3)(4). The identification and characterization of the human DPD cDNA (5) made possible the identification and molecular analysis of mutations that affect DPD expression and catalytic activity. The most . . . [Full Text of this Article]

Acknowledgments

References

The following articles in journals at HighWire Press have cited this article:

				M Steiner, M Seule, B Steiner, I Bauer, M Freund, C H Kohne, and P Schuff-Werner 5-Fluorouracil/irinotecan induced lethal toxicity as a result of a combined pharmacogenetic syndrome: report of a case J. Clin. Pathol., May 1, 2005; 58(5): 553 - 555. [Abstract] [Full Text] [PDF]

				A. B. P. van Kuilenburg, E. W. Muller, J. Haasjes, R. Meinsma, L. Zoetekouw, H. R. Waterham, F. Baas, D. J. Richel, and A. H. van Gennip Lethal Outcome of a Patient with a Complete Dihydropyrimidine Dehydrogenase (DPD) Deficiency after Administration of 5-Fluorouracil: Frequency of the Common IVS14+1G>A Mutation Causing DPD Deficiency Clin. Cancer Res., May 1, 2001; 7(5): 1149 - 1153. [Abstract] [Full Text]