Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Hasegawa Y
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Cancer Res. 2000 Dec 15;60(24):6921-6.
Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A128 in the promoter and UGT1A16, UGT1A127, UGT1A129, and UGT1A17 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A128 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A128 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A127 encountered severe toxicity. No statistical association of UGT1A16 with the occurrence of severe toxicity was observed. None had UGT1A129 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.
伊立替康意外地会导致严重的白细胞减少或腹泻毒性。伊立替康经代谢形成活性物质SN - 38，后者进一步由尿苷二磷酸葡萄糖醛酸基转移酶（UGT）1A1酶进行结合反应并解毒。UGT1A1的基因多态性会通过改变SN - 38的生物利用度来影响伊立替康毒性的个体间差异。在这项病例对照研究中，我们对临床记录进行回顾性分析并测定UGT1A1多态性，以调查携带UGT1A1变异基因型的患者是否更易发生伊立替康所致的严重毒性。所有患者此前均在日本的大学医院、癌症中心或大型城市医院接受过伊立替康抗癌治疗。我们确定了26例发生严重毒性的患者和92例未发生严重毒性的患者。研究了多种变异基因型（启动子区的UGT1A128以及编码区的UGT1A16、UGT1A127、UGT1A129和UGT1A17）与4级白细胞减少（<或=0.9×10⁹/升）和/或3级（水样便持续5天或更长时间）或4级（出血性或脱水）腹泻严重毒性之间的关系。在26例发生严重毒性的患者中，UGT1A128基因型纯合子有4例（15%），杂合子有8例（31%）；而在92例未发生严重毒性的患者中，纯合子有3例（3%），杂合子有10例（11%）。多变量分析表明，UGT1A128基因型杂合子或纯合子是伊立替康所致严重毒性的显著危险因素（P<0.001；比值比，7.23；95%置信区间，2.52 - 22.3）。所有3例UGT1A127基因型杂合子患者均发生了严重毒性。未观察到UGT1A16与严重毒性发生之间存在统计学关联。无人携带UGT1A129或UGT1A1*7。我们认为，测定UGT1A1基因型可能在临床上有助于预测癌症患者使用伊立替康时的严重毒性。本研究值得进行一项前瞻性试验，以证实伊立替康化疗前UGT1A1多态性基因诊断的有用性。
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