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 degraded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate-limiting enzyme in pyrimidine catabolism. Cancer patients with decreased DPD activity are at increased risk for severe toxicity including diarrhea, stomatitis, mucositis, myelosuppression, neurotoxicity, and, in some cases, death. We now report the first known cancer patient who developed life-threatening complications after treatment with topical 5-FU and was shown subsequently to have profound DPD deficiency. RT-PCR and genomic PCR methodologies 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 exon 14) in this patient's DPD mRNA. Immunoprecipitation and Western blot analysis were then used to demonstrate that the aberrant DPD mRNA is translated into a nonfunctional DPD protein that is ubiquitinated. We conclude that the presence of this metabolic defect combined with topical 5-FU (a drug demonstrating a narrow therapeutic index) results in the unusual presentation of life-threatening toxicity after treatment with a topical drug. These data further suggest that degradation by the ubiquitin-proteosome-mediated system plays a role in the elimination of the DPD protein.
Johnson
M R
MR
Department of Pharmacology and Toxicology and Comprehensive Cancer Center, University of Alabama at Birmingham, 35294, USA.
Hageboutros
A
A
Wang
K
K
High
L
L
Smith
J B
JB
Diasio
R B
RB
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D015153:Blotting, Western; D002280:Basal Cell Carcinoma / Q000188:drug therapy*; D004252:DNA Mutational Analysis; D003967:Diarrhea / Q000139:chemically induced; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy*; D014498:Uracil / Q000097:blood / Q000652:urine
D000964:Antimetabolites, Antineoplastic; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil