Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil

In humans, 80-90% of an administered dose of 5-fluorouracil (5-FU) is degra ded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate- limiting enzyme in pyrimidine catabolism. Cancer patients with decreased DP D activity are at increased risk for severe toxicity including diarrhea, st omatitis, mucositis, myelosuppression, neurotoxicity, and, in some cases, d eath. We now report the first known cancer patient who developed life-threa tening complications after treatment with topical 5-FU and was shown subseq uently to have profound DPD deficiency, RT-PCR and genomic PCR methodologie s were used to identify a G to A mutation in the GT 5' splicing recognition sequence of intron 14, resulting in a 165-bp deletion (corresponding to ex on 14) in this patient's DPD mRNA, Immunoprecipitation and Western blot ana lysis were then used to demonstrate that the aberrant DPD mRNA is translate d into a nonfunctional DPD protein that is ubiquitinated, We conclude that the presence of this metabolic defect combined with topical 5-FU (a drug de monstrating a narrow therapeutic index) results in the unusual presentation of life-threatening toxicity after treatment with a topical drug. These da ta further suggest that degradation by the ubiquitin-proteosome-mediated sy stem plays a role in the elimination of the DPD protein.