医学
二氢嘧啶脱氢酶
内科学
突变
胃肠病学
癌症
氟尿嘧啶
遗传学
胸苷酸合酶
生物
基因
作者
André B. P. Kuilenburg,Rutger Meinsma,Lida Zoetekouw,Albert H. Gennip
出处
期刊:Pharmacogenetics
[Ovid Technologies (Wolters Kluwer)]
日期:2002-10-01
卷期号:12 (7): 555-558
被引量:161
标识
DOI:10.1097/00008571-200210000-00007
摘要
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU) and a DPD deficiency is increasingly being recognized as an important pharmacogenetic factor in the aetiology of severe 5FU-associated toxicity. In this study, we evaluated the DPD activity and the prevalence of the common splice site mutation IVS14 + 1G>A in tumour patients suffering from severe grade 3-4 toxicity after the administration of 5FU. DPD activity was measured with a radiochemical assay and screening for the presence of the IVS14 + 1G>A mutation was performed by restriction fragment length polymorphism. A decreased DPD activity could be detected in peripheral blood mononuclear cells in 60% of the cases. Furthermore, a high prevalence of the IVS14 + 1G>A mutation was noted as 28% of all patients were heterozygous or homozygous for this mutation. In patients with a low DPD activity, 42% were heterozygous and one patient (3%) was homozygous for the IVS14 + 1G>A mutation. In contrast, the IVS14 + 1G>A mutation could be detected in only one out of 24 (4%) patients with a normal DPD activity. Our study demonstrates that a DPD deficiency is the major determinant of 5FU-associated toxicity. The apparently high prevalence of the IVS14 + 1G>A mutation warrants genetic screening for this mutation in cancer patients before the administration of 5FU.
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