Onoue Masahide, Terada Tomohiro, Kobayashi Masahiko, Katsura Toshiya, Matsumoto Shigemi, Yanagihara Kazuhiro, Nishimura Takafumi, Kanai Masashi, Teramukai Satoshi, Shimizu Akira, Fukushima Masanori, Inui Ken-ichi
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Int J Clin Oncol. 2009 Apr;14(2):136-42. doi: 10.1007/s10147-008-0821-z. Epub 2009 Apr 24.
Gene polymorphisms of the UDP-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) contribute to individual variations in adverse events among patients administered irinotecan, and the distribution of the polymorphisms shows large interethnic differences. Variation in the solute carrier organic anion-transporter family, member 1B1 (SLCO1B1) gene also has a significant effect on the disposition of irinotecan in Asian cancer patients. In the present study, we evaluated the association of genetic polymorphisms of UGT1A1 and SLCO1B1 with irinotecanrelated neutropenia in Japanese cancer patients.
One hundred and thirty-five consecutive patients treated with irinotecan were enrolled. Genotypes of UGT1A1 (*60, *28, *6, and *27) and SLCO1B1 (*1b, *5, and haplotype *15) were determined by direct sequencing. Severe neutropenia refers to events observed during the first cycle of irinotecan treatment.
Severe neutropenia was observed in 29 patients (22%). Six patients were homozygous and 48 heterozygous for UGT1A16. Only 1 patient was homozygous for UGT1A128. Homozygosity for UGT1A1*6 was associated with a high risk of severe neutropenia (odds ratio [OR], 7.78; 95% confidence interval [CI], 1.36 to 44.51). No significant association was found between severe neutropenia and other UGT1A1 polymorphisms or SLCO1B1 polymorphisms.
These findings suggest that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients.
尿苷二磷酸葡萄糖醛酸基转移酶1家族多肽A1（UGT1A1）的基因多态性导致接受伊立替康治疗的患者不良事件存在个体差异，且这些多态性的分布存在较大种族差异。溶质载体有机阴离子转运体家族成员1B1（SLCO1B1）基因的变异对亚洲癌症患者体内伊立替康的处置也有显著影响。在本研究中，我们评估了UGT1A1和SLCO1B1基因多态性与日本癌症患者伊立替康相关中性粒细胞减少的相关性。
纳入135例连续接受伊立替康治疗的患者。通过直接测序确定UGT1A1（*60、*28、6和27）和SLCO1B1（*1b、5和单倍型15）的基因型。严重中性粒细胞减少是指在伊立替康治疗的第一个周期中观察到的事件。
29例患者（22%）出现严重中性粒细胞减少。6例患者为UGT1A16纯合子，48例为杂合子。只有1例患者为UGT1A128纯合子。UGT1A1*6纯合子与严重中性粒细胞减少的高风险相关（比值比[OR]，7.78；95%置信区间[CI]，1.36至44.51）。未发现严重中性粒细胞减少与其他UGT1A1多态性或SLCO1B1多态性之间存在显著关联。
这些发现表明，UGT1A1*6多态性是日本癌症患者中伊立替康所致严重中性粒细胞减少的潜在预测指标。
