Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil.
Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil.
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发表时间：
1999-08
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通讯作者：
Martin R. Johnson;Alexander Hageboutros;Kangsheng Wang;Lisa High;Jeffrey B. Smith;R. Diasio
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作者：
Martin R. Johnson;Alexander Hageboutros;Kangsheng Wang;Lisa High;Jeffrey B. Smith;R. Diasio
在人体中，80-90%的5-氟尿嘧啶（5-FU）给药剂量被二氢嘧啶脱氢酶（DPD; EC 1.3.1.2）降解，二氢嘧啶脱氢酶是嘧啶催化剂中的初始限速酶。DPD活性降低的癌症患者发生严重毒性的风险增加，包括腹泻、口腔炎、粘膜炎、骨髓抑制、神经毒性，以及在某些情况下死亡。我们现在报告的第一个已知的癌症患者谁开发的局部5-FU治疗后危及生命的并发症，随后被证明有深刻的DPD缺乏症。RT-PCR和基因组PCR方法用于鉴定内含子14的GT 5'剪接识别序列中的G到A突变，导致该患者的DPD mRNA中的165-bp缺失（对应于外显子14）。免疫沉淀和蛋白质印迹分析，然后被用来证明，异常DPD mRNA被翻译成一个非功能的DPD蛋白，是泛素化。我们得出结论，这种代谢缺陷的存在与局部5-FU（一种治疗指数较窄的药物）相结合，导致局部药物治疗后出现危及生命的毒性。这些数据进一步表明，降解的泛素-蛋白体介导的系统在DPD蛋白的消除中发挥作用。
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.