1] Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan [2] Center for Medical Genetics, School of Medicine, Keio University, Tokyo, Japan.
Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Keio University, Tokyo, Japan.
J Hum Genet. 2013 Dec;58(12):794-8. doi: 10.1038/jhg.2013.105. Epub 2013 Oct 3.
Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A16, UGT1A127 and UGT1A128) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A16, UGT1A127 and UGT1A128. Homozygosity for UGT1A16 or heterozygosity for UGT1A16/28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A16/6 and heterozygosity for UGT1A16/28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A16 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.
伊立替康是一种用于治疗多种肿瘤的关键化疗药物，包括宫颈癌和卵巢癌；然而，伊立替康会引起毒性，特别是在存在尿苷二磷酸葡萄糖醛酸基转移酶 1A1（UGT1A1）基因多态性的情况下，其与酶活性降低有关。在这里，我们研究了三种不同的 UGT1A1 变体（UGT1A16、UGT1A127 和 UGT1A128）的流行率及其与接受低剂量伊立替康治疗的妇科癌症患者伊立替康诱导的不良事件的关系，与接受其他类型实体瘤治疗的患者相比，这些患者接受的伊立替康剂量较低。我们筛选了 53 名接受伊立替康治疗的女性患者和 362 名未接受伊立替康治疗的女性患者的 UGT1A16、UGT1A127 和 UGT1A128。UGT1A16 纯合子或 UGT1A16/28 杂合子与严重绝对中性粒细胞减少或腹泻的高风险相关（比值比：16.03 和 31.33）。相比之下，血清胆红素水平与伊立替康毒性无关。UGT1A16/6 纯合子和 UGT1A16/28 杂合子与日本妇科癌症患者的绝对中性粒细胞计数和/或腹泻风险增加相关，尽管这些患者使用的伊立替康剂量较低。UGT1A16 和 UGT1A1*28 是妇科癌症患者低剂量伊立替康引起严重中性粒细胞减少和腹泻的潜在预测因子。
