Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity

Citation
M. Kouwaki et al., Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity, CLIN CANC R, 4(12), 1998, pp. 2999-3004
Citations number
27
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
4
Issue
12
Year of publication
1998
Pages
2999 - 3004
Database
ISI
SICI code
1078-0432(199812)4:12<2999:IONMIT>2.0.ZU;2-L
Abstract
5-Fluorouracil (5-FU) is used widely in the treatment of several common neo plasms. Dihydropyrimidine dehydro genase (DPD) is the initial and rate-limi ting enzyme in the catabolism of 5-FU, Several recent studies have describe d a pharmacogenetic disorder in which cancer patients with decreased DPD ac tivity develop life-threatening toxicity following exposure to 5-FU. We rep orted recently the first Japanese case of decreased DPD activity accompanie d by severe 5-FU toxicity. The present study describes the results of molec ular analysis of this patient and her family, in which three novel mutation s (Arg21Gln, Val335Leu, and Glu386Ter) of the gene coding for DPD were iden tified. We also revealed that Arg21Gln and Glu386Ter are on the same allele and that Val335Leu is on the other allele, on the basis of analysis of the family genome. Expression analysis in Escherichia coli showed that Val335L eu and Glu386Ter led to mutant DPD protein with significant loss of enzymat ic activity and no activity, respectively, The Arg21Gln mutation, however, resulted in no decrease in enzymatic activity compared with the wild type. The present data represent the first molecular genetic analysis of DPD defi ciency accompanied by severe 5-FU toxicity in a Japanese patient.