Zhu Andrew X, Puchalski Thomas A, Stanton Vincent P, Ryan David P, Clark Jeffrey W, Nesbitt Steven, Charlat Olga, Kelly Patrick, Kreconus Elaine, Chabner Bruce A, Supko Jeffrey G
Massachusetts General Hospital, Division of Hematology/Oncology, Harvard Medical School, Boston, MA, USA.
Clin Colorectal Cancer. 2004 Feb;3(4):225-34. doi: 10.3816/CCC.2004.n.003.
The causes of interpatient variation in severe toxicity resulting from treatment with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This study was undertaken to examine the contribution of commonly occurring polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV colorectal cancer were treated by bolus intravenous (I.V.) injection with 500 mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms in the DPYD gene. A well-characterized functional polymorphism in the 5' untranslated region of the thymidylate synthase (TS) gene was also analyzed. A cohort of 22 patients (15 male, 7 female) with a median age of 61 years was evaluated. Although there was no relationship between the area under the plasma concentration time curve (AUC) for the first dose of 5-FU and worst-grade toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC on week 4 was more than equal to 5 microgram/h/mL greater than the value for the first dose experienced grade 3/4 toxicity during subsequent treatment. Among the 8 polymorphisms in the DPYD gene, 7 were found to vary in the study population but none were significantly associated with the AUC of 5-FU. There was no relationship between the DPYD and TS genotypes examined and 5-FU toxicity. Extensive polymorphism in the DPYD gene was observed; however, no conclusive correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics or toxicity. Decreases in 5-FU clearance in certain patients may provide insight into the increased toxicity following repetitive cycles of treatment with weekly I.V. bolus 5-FU. The present study offers useful themes for undertaking larger prospective pharmacogenetic studies in the future.
对于每周使用5-氟尿嘧啶（5-FU）/亚叶酸（LV）治疗导致的患者间严重毒性差异的原因，目前了解甚少。本研究旨在探讨二氢嘧啶脱氢酶（DPYD）基因中常见多态性对5-FU药代动力学和毒性患者间变异性的影响。III/IV期结直肠癌患者通过静脉推注（I.V.）接受500mg/m²剂量的5-FU和LV治疗，每周一次。在第1周和第4周测定5-FU的药代动力学。针对DPYD基因中的8个多态性开发了基因分型检测方法。还分析了胸苷酸合成酶（TS）基因5'非翻译区一个特征明确的功能性多态性。评估了一组22例患者（15例男性，7例女性），中位年龄61岁。尽管在治疗的第一个周期中，首剂5-FU的血浆浓度-时间曲线下面积（AUC）与最差等级毒性之间没有关系，但在第4周AUC比首剂值高5μg/h/mL及以上的4例患者中，有3例在后续治疗中出现3/4级毒性。在DPYD基因的8个多态性中，有7个在研究人群中存在变异，但均与5-FU的AUC无显著关联。所检测的DPYD和TS基因型与5-FU毒性之间没有关系。观察到DPYD基因存在广泛多态性；然而，DPYD和TS基因型与5-FU药代动力学或毒性之间不存在明确的相关性。某些患者5-FU清除率的降低可能有助于解释每周静脉推注5-FU重复治疗周期后毒性增加的原因。本研究为未来开展更大规模的前瞻性药物遗传学研究提供了有益的思路。
