[Mutations in the dihydropyrimidine dehydrogenase gene and their role in 5-fluororuracil intolerance]

Cancer patients developing severe side effects upon chemotherapy with 5-fluorouracil (5-FU) are assumed to display reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD). Meanwhile over 20 different mutations are known in the dihydropyrimidine dehydrogenase gene (DPYD) which could be associated with a loss of enzyme function. For most of these genetic alterations, however, clear genotype-phenotype relations are still lacking. We are conducting a population study using a German cohort to determine the frequency of DPD defects in the German population and to detect new toxicity-associated mutations. Our aim is to develop a sensitive and efficient screening of tumor patients to identify patients with mutations in the DPYD gene which might be related to 5-FU-toxicity. For this purpose we analysed the whole coding region of DPYD by the technique of denaturing HPLC (DHPLC). The DHPLC analysis turned out to be a reliable method for the investigation of large samples in an acceptable cost and time range. To further elucidate the molecular basis of the DPD deficiency syndrome we will continue to analyse a patient panel receiving 5-FU.