Mutationen im Dihydropyrimidindehydrogenase-Gen als Ursache von 5-Fluororuracil-Intoleranz

Zusammenfassung

Bei Krebspatienten, die schwere Nebenwirkungen unter der Chemotherapie mit 5-Fluorouracil (5-FU) entwickeln, wird eine verminderte Aktivität des Enzyms Dihydropyrimidindehydrogenase (DPD) vermutet. Bisher sind über 20 Mutationen im entsprechenden DPD-Gen (DPYD) bekannt, die für eine herabgesetzte Enzymfunktion verantwortlich sein sollen. Bei den meisten dieser genetischen Alterationen besteht jedoch noch kein klarer Zusammenhang zwischen Genotyp und Phänotyp. Wir führen derzeit eine Populationsstudie an einem deutschen Kollektiv durch, um die Häufigkeit genetischer Veränderungen der DPD in der Bevölkerung zu evaluieren und um neue, therapierelevante Mutationen zu finden. Ziel ist es, ein effizientes und sensitives Screening zu entwickeln, um Tumorpatienten mit Mutationen im DPYD-Gen, die mit 5-FU-Intoleranz assoziiert sein könnten, zu identifizieren. Dazu haben wir den gesamten kodierenden Abschnitt des DPYD-Gens mit Hilfe der denaturierenden HPLC (DHPLC) analysiert. Die DHPLC-Technik erwies sich als geeignetes Mittel, um große Probenmengen innerhalb eines adäquaten Zeitraums und Kostenrahmens zu untersuchen. Unsere Studie soll die Grundlage für die weitere Erforschung der molekularen Basis der DPD-Defizienz an einem ausgewählten Patientenkollektiv bilden.

Abstract

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.

Schlüsselwörter

DPD - 5-Fluorouracil - DHPLC-Analyse - Chemotherapie - Pharmakogenetik

Key words

DPD - 5-Fluorouracil - DHPLC-Analysis - Chemotherapy - Pharmacogenetics

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