Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil.
The identification of genetic factors associated with either responsiveness or resistance to 5-fluorouracil (5-FU) chemotherapy, as well as genetic factors predisposing patients to the development of severe 5-FU-associated toxicity, is increasingly being recognised as an important field of study. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Although the role of tumoral levels as a prognostic factor for clinical responsiviness has not been firmly established, there is ample evidence that a deficiency of DPD is associated with severe toxicity after the administration of 5-FU. Patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia. In addition, the onset of toxicity occurred twice as fast compared with patients with a normal DPD activity. To date, 39 different mutations and polymorphisms have been identified in DPYD. The IVS14+1G>A mutation proved to be the most common one and was detected in 24-28% of all patients suffering from severe 5-FU toxicity. Thus, a deficiency of DPD appears to be an important pharmacogenetic syndrome.
van Kuilenburg
André B P
AB
Academic Medical Center, University of Amsterdam, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands. a.b.vanKuilenburg@amc.uva.nl
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005472:Fluorouracil / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil