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| |  AACR: DPYD Methylation May Cause 5-FU Toxicity By Paula Moyer ANAHEIM, CA -- April 25, 2005 -- Methylation of the regulatory elements of the dihydropyrimidine dehydrogenase promoter should be considered as a potential molecular mechanism of 5-fluorouracil (5-FU) toxicity, research suggests. Investigators presented these findings here on April 19th at the 96th annual meeting of the American Association for Cancer Research. Dihydropyrimidine dehydrogenase -- or DPD or DPYD -- is the rate limiting enzyme involved in the catabolism of pyrimidines like thymidine and uracil. It is also the main enzyme involved in the degradation of structurally related compounds like 5-FU, a widely used anticancer drug. Patients with DPD deficiency are known to have greater risk of 5-FU toxicity, said principal investigator Adam M. Lee, a doctoral student in clinical pharmacology at the University of Alabama in Birmingham. The investigators noted that methylation had not been investigated in the search for the underlying pathogenesis of DPD deficiency, and therefore, they decided to see if it played a role in this condition. Dr. Lee and colleagues conducted their study to better understand the underlying pathogenesis of DPD deficiency and to help develop a treatment targeting DPD deficiency in affected individuals who need to undergo chemotherapy with 5-FU. They selected five healthy volunteers with no evidence of DPD deficiency, four DPD-deficient individuals who were otherwise healthy, and two DPD-deficient patients with cancer and a history of 5-FU toxicity. Among the cancer patients, one had no known genotypic abnormality in the DPYD gene. The investigators assessed the participants' methylation status with denaturing high performance liquid chromatography (DHPLC), a method that can distinguish methylated and unmethylated samples. Analysis of the samples detected no evidence of methylation in the volunteers who were not DPD-deficient. Methylation, as well as no mutations in the DPYD gene, was observed in all four of the volunteers with DPD deficiency. Among the patients with DPD deficiency and 5-FU toxicity, the patient who had no evidence of methylation had a DPYD 2A mutation, the most common mutation linked to DPD deficiency. An area-under-the-curve (AUC) calculation showed that the methylation ranged from 12% to 25% in the DPD-deficient volunteers and was 19% in the DPD-deficient patients. The findings show that DPYD promoter downregulation may be a cause of DPD deficiency in patients with 5-FU toxicity, the investigators reported.
[Presentation title: Methylation of the DPYD Promoter Downregulates the Expression of Dihydropyrimidine Dehydrogenase (DPD) Enzyme: Potential Importance in DPD Deficient Cancer Patients. Abstract LB-212]
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