基因变异在UDP-glucuronosyltransferase 1 a1基因预测伊立替康的严重中性粒细胞减少的风险。
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陈Innocenti F, Undevia SD,艾耶L, PX, Das, Kocherginsky M, Karrison T, Janisch L,拉米雷斯J,鲁丁厘米,Vokes EE, Ratain乔丹
基因变异在UDP-glucuronosyltransferase 1 a1基因预测伊立替康的严重中性粒细胞减少的风险。
肿瘤防治杂志。2004年4月15日,22 (8):1382 - 8。Epub 2004年3月8日。
- PubMed ID
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15007088 (在PubMed]
- 文摘
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目的:严重毒性通常观察到癌症患者接受伊立替康。UDP-glucuronosyltransferase 1 a1 (UGT1A1)催化活性代谢物的glucuronidation SN-38。本研究前瞻性评估之间的联系的流行严重的毒性和UGT1A1基因变异。病人和方法:六十六例癌症晚期疾病患者耐火材料和其他治疗收到伊立替康350毫克/米(2)每3周。毒性和药代动力学数据测量周期期间1。UGT1A1变体(-3279 g > T, -3156 g > A,发起人TA indel, 211 g > A, 686 c >)基因分型。结果:4级嗜中性白血球减少症的患病率为9.5%。4级中性粒细胞减少患者更常见的助教indel 7/7基因型(3 6例;50%)与6/7(3 24例;29岁患者的12.5%)和6/6 (0; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51). CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.
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