Abstract
BackgroundSevere toxicity to 5-fluorouracil (5-FU) based chemotherapy in gastrointestinal cancer has been associated with constitutional genetic alterations of the dihydropyrimidine dehydrogenase gene (DPYD).MethodsIn this study, we evaluated DPYD promoter methylation through quantitative methylation-specific PCR and screened DPYD for large intragenic rearrangements in peripheral blood from 45 patients with gastrointestinal cancers who developed severe 5-FU toxicity. DPYD promoter methylation was also assessed in tumor tissue from 29 patientsResultsTwo cases with the IVS14+1G > A exon 14 skipping mutation (c.1905+1G > A), and one case carrying the 1845 G > T missense mutation (c.1845G > T) in the DPYD gene were identified. However, DPYD promoter methylation and large DPYD intragenic rearrangements were absent in all cases analyzed.ConclusionsOur results indicate that DPYD promoter methylation and large intragenic rearrangements do not contribute significantly to the development of 5-FU severe toxicity in gastrointestinal cancer patients, supporting the need for additional studies on the mechanisms underlying genetic susceptibility to severe 5-FU toxicity.
Highlights
Severe toxicity to 5-fluorouracil (5-FU) based chemotherapy in gastrointestinal cancer has been associated with constitutional genetic alterations of the dihydropyrimidine dehydrogenase gene (DPYD)
DPYD promoter methylation was detected in the RKO cell line (Figure 2)
No intragenic rearrangements were found for DPYD in the peripheral blood samples of those patients
Summary
Severe toxicity to 5-fluorouracil (5-FU) based chemotherapy in gastrointestinal cancer has been associated with constitutional genetic alterations of the dihydropyrimidine dehydrogenase gene (DPYD). The fluoropyrimidine 5-fluorouracil (5-FU) is broadly used in the treatment of a wide range of gastrointestinal cancers[1]. The mechanism of 5-FU cytotoxicity has been ascribed to the inhibition of thymidylate synthase (TYMS) and misincorporation of fluoronucleotides into RNA and DNA [1,3]. The ratelimiting enzyme in 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to dihydrofluorouracil. The mechanism of 5-FU cytotoxicity may depend on genetic and clinical factors. In 5-FU bolus schedules, the incorporation of fluorouridine triphosphate into RNA appears to be the most important mechanism of action, whereas when the infusion time is prolonged, inhibition of TYMS becomes more important resulting in lower toxicity[7]
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