Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.
Pharmacogenomics J. 2011 Feb;11(1):61-71. doi: 10.1038/tpj.2010.10. Epub 2010 Feb 23.
Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1()28/()28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1()28/()28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).
伊立替康和 5-氟尿嘧啶（5-FU）用于治疗转移性结直肠癌。伊立替康的活性代谢物被 UDP-葡萄糖醛酸基转移酶 1A1（UGT1A1）灭活，而 Gilbert 综合征患者 UGT1A1 缺乏。伊立替康及其代谢产物由 ABCB1 编码的 P-糖蛋白转运。5-FU 通过抑制胸苷酸合成酶（TYMS）靶向叶酸代谢。亚甲基四氢叶酸还原酶（MTHFR）生成用于造血的活性叶酸。我们对北欧 VI 临床试验中 140 名接受伊立替康和 5-FU 治疗的瑞典和挪威结直肠癌患者进行了 UGT1A1、ABCB1、TYMS 和 MTHFR 选定变体的回顾性基因分型。我们发现，携带 ABCB1 3435 T/T 基因型的患者发生临床相关早期毒性的风险增加，比值比（OR）=3.79（95%置信区间（CI）=1.09-13.2），而携带 UGT1A1（*）28/28 基因型的患者，OR=4.43（95% CI=1.30-15.2）。UGT1A1（）28/*28 的患者中性粒细胞减少症的风险特别高，OR=6.87（95% CI=1.70-27.7）。在前两个周期发生毒性反应的患者总共接受的治疗周期更少（P<0.001），并且对治疗的反应更差（P<0.001）。ABCB1 中的遗传变异与早期毒性和对治疗的反应降低均相关。携带 ABCB1 1236T-2677T-3435T 单倍型的患者对治疗的反应更不频繁（43%对 67%，P=0.027），并且存活时间更短，OR=1.56（95% CI=1.01-2.45）。
