Measures to Predict DPD Deficiency in Patients Receiving 5-FU

The complexity of the genetic basis of DPD deficiency implies that the identification of patients at high risk of 5-FU toxicity is mostly based on phenotypic procedures. These methods are not suitable for general use and concomitant drags, dietary intake and other environmental factors could reduce their predictive power in cases of partial DPD deficit. 

DPD Biochemical Phenotype Measured in Peripheral Blood Mononuclear Cells (PBMC) 

DPD activity measured in PBMC is used as a surrogate for systemic DPD activity. DPD activity is normally distributed and highly variable among individuals (coefficient of variation of 33.9-46.6%) [43, 56-59]. DPD activity is undetectable in totally deficient patients. The majority of partially deficient patients had a DPD value 30% of the mean in the normal population, and this value is considered the cut-off for patients at higher risk of toxicity. Among patients experiencing severe toxicity after 5-FU, 36-59% of them were deficient in DPD activity [43, 53, 60]. This suggests the involvement of other determinants in the susceptibility to 5-FU toxicity. The concordance between liver and PBMC DPD activity is modest [61], and normal DPD activity in PBMC was found in one patient with very depressed liver DPD activity who died because of 5-FU toxicities [44]. 

In the majority of DPD defective patients experiencing severe 5-FU toxicity, abnormally high levels of natural pyrimidines are present in plasma and/or urine [62]. Moreover, endogenous dihydrouracil/uracil ratio in plasma has been proposed as a measure of 5-FU catabolic deficiency in cancer patients [63], and screening of cancer patients for these simple markers should be prospectively evaluated. 

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