Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency
Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency
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二氢嘧啶脱氢酶缺乏症的药物遗传学和临床方面
DOI：
10.1258/000456303321016150
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发表时间：
2003
影响因子：
2.2
通讯作者：
A. H. Gennip
中科院分区：
文献类型：
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作者：
A. V. Kuilenburg;R. D. Abreu;A. H. Gennip
二氢嘧啶脱氢酶（DPD）是5-氟尿嘧啶（5 FU）催化转化的起始酶和限速酶。DPD的缺乏越来越被认为是一个重要的药物遗传学综合征的原因。DPD缺乏在非预期严重5 FU毒性病因学中的重要性已通过以下事实得到证实：在39- 59%的病例中，可在外周血单核（PBM）细胞中检测到DPD活性降低。DPD活性降低的患者中有55%发生IV级中性粒细胞减少，而DPD活性正常的患者中有13%发生IV级中性粒细胞减少（P = 0.01）。DPD活性低的患者出现毒性反应的时间明显早于DPD活性正常的患者（10.0 ± 7.6dvs19.1 ± 15.3d，P <0.05）。在重度5 FU相关毒性患者中，DPYD已发现11个突变，包括1个剪接位点突变（IVS 14 + 1G→A）、1个无义突变（E386 X）、4个错义突变（M166 V、V335 L、I560 S、D949 V）和5个多态性（C29 R、R21 Q、S534 N、I543 V、V732 I）。考虑到5 FU在癌症患者治疗中的普遍使用、低DPD活性患者的严重5 FU相关毒性以及IVS 14 + 1G→A突变的高患病率，在开始使用5 FU治疗之前，应常规进行PBM细胞中DPD活性的分析或IVS 14 + 1G→A突变的筛查。
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39-;59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P = 0·01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10·0 ± 7·6 versus 19·1 ± 15·3 days, P < 0·05). In patients suffering from severe 5FU-associated toxicity, 11 mutations have been identified in DPYD, including one splice-site mutation (IVS14 + 1G→A), one nonsense mutation (E386X), four missense mutations (M166V, V335L, I560S, D949V) and five polymorphisms (C29R, R21Q, S534N, I543V, V732I). Considering the common use of 5FU in the treatment of cancer patients, the severe 5FU-related toxicities in patients with a low DPD activity and the high prevalence of the IVS14 + 1G→A mutation, analysis of the DPD activity in PBM cells or screening for the IVS14 + 1G→A mutation should be routinely carried out prior to the start of treatment with 5FU.
DOI：
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发表时间：
1999-08
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Martin R. Johnson;Alexander Hageboutros;Kangsheng Wang;Lisa High;Jeffrey B. Smith;R. Diasio
通讯作者：
Martin R. Johnson;Alexander Hageboutros;Kangsheng Wang;Lisa High;Jeffrey B. Smith;R. Diasio
5-氟尿嘧啶改变小鼠骨髓细胞新合成 DNA 的二级结构。
影响因子：
11.2
作者：
Schuetz,JD;Collins,JM;Wallace,HJ;Diasio,RB
通讯作者：
Diasio,RB
5-氟尿嘧啶对完整骨髓细胞 DNA 链延长的影响。
DOI：
10.1016/0006-291x(85)91884-4
发表时间：
1985
影响因子：
3.1
作者：
Schuetz,JD;Diasio,RB
通讯作者：
Diasio,RB