title: [Pharmacogenetics in oncology: 5-fluorouracil and the dihydropyrimidine dehydrogenase].
abstract: 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.
authors.affiliation: Institut für Pharmakologie, Klinikum der Universität zu Köln.
authors.forename: A
authors.initials: A
authors.lastname: Lazar
authors.forename: A
authors.initials: A
authors.lastname: Jetter
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005472:Fluorouracil / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil