[Pharmacogenetics in oncology: 5-fluorouracil and the dihydropyrimidine dehydrogenase].

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5-fluorouracil (5-FU) forms the basis for the chemotherapy of advanced colorectal cancer and of other solid tumours. About 9% of patients suffer from serious, sometimes even life-threatening adverse effects of a 5-FU therapy, such as haemotoxicity, which cannot be reliably predicted by conventional clinical and pharmacokinetic criteria. The systemic exposure to 5-FU is fundamentally determined by the genetically polymorphic enzyme dihydropyrimidine dehydrogenase (DPD). This deficiency is closely related to 5-FU-induced toxicity and a variety of non-synonymous variants has been detected in affected patients. The exon14-skipping mutation is the gene defect most frequently associated with serious 5-FU-related adverse effects and it has been reported ten times more often in affected individuals than in the general population. The 2846A>T polymorphism, which leads to an amino acid substitution, appears to be of comparable importance. While the causative role of premature stop codons - presumably resulting from spontaneous mutations - is very likely, the pathophysiological relevance of various other amino acid changes is still unclear. Patients who harbour a high-risk genotype should not be treated with 5-FU if therapeutic alternatives are available. The present data indicate that complete genotyping of the encoding DPYD gene is desirable, in the interest of drug safety, before treatment is started, although only a small number of patients would actually benefit. A method for the quantification of the DPD activity in vivo would have the advantage of reflecting all genetic and non-genetic influences.' However, no such method is currently available for routine use. Prospective genotyping for the exon 14-skipping and the 2846A>T-polymorphisms may result in a reduction of serious, 5-FU-induced, toxic events of about 25%. Cost-effective screening methods should enable the future implementation of DPYD genotyping in clinical routine.

Author-supplied keywords

  • Amino Acid Substitution
  • Amino Acid Substitution: genetics
  • Antimetabolites, Antineoplastic
  • Antimetabolites, Antineoplastic: adverse effects
  • Antimetabolites, Antineoplastic: metabolism
  • Antimetabolites, Antineoplastic: therapeutic use
  • Dihydrouracil Dehydrogenase (NADP)
  • Dihydrouracil Dehydrogenase (NADP): deficiency
  • Dihydrouracil Dehydrogenase (NADP): genetics
  • Dihydrouracil Dehydrogenase (NADP): metabolism
  • Exons
  • Exons: genetics
  • Fluorouracil
  • Fluorouracil: adverse effects
  • Fluorouracil: metabolism
  • Fluorouracil: therapeutic use
  • Genotype
  • Humans
  • Mutation
  • Neoplasms
  • Neoplasms: drug therapy
  • Neoplasms: genetics
  • Polymorphism, Genetic

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