Gregers J, Gréen H, Christensen I J, Dalhoff K, Schroeder H, Carlsen N, Rosthoej S, Lausen B, Schmiegelow K, Peterson C
1] Clinical Pharmacology, Faculty of Health Sciences, Division of Drug Research, Department of Medical and Health Sciences, Linköpings Universitet, Linköping, Sweden [2] Laboratory of Molecular Medicine, Department of Clinical Immunology 7631, Rigshospitalet, University Hospital in Copenhagen, Copenhagen, Denmark.
1] Clinical Pharmacology, Faculty of Health Sciences, Division of Drug Research, Department of Medical and Health Sciences, Linköpings Universitet, Linköping, Sweden [2] Science for Life Laboratory, Division of Gene Technology, School of Biotechnology, KTH Royal Institute of Technology, Solna, Sweden [3] Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
Pharmacogenomics J. 2015 Aug;15(4):372-9. doi: 10.1038/tpj.2014.81. Epub 2015 Jan 13.
The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.
由ABCB1基因编码的膜转运蛋白P-糖蛋白会影响抗癌药物的药代动力学。我们推测ABCB1的变异会影响儿童急性淋巴细胞白血病（ALL）的治疗结果和毒性。我们研究了522名丹麦ALL患儿，占所有符合条件患儿的93%。与1199GG基因型的患者相比，1199GA基因型患者的复发风险增加了2.9倍（P = 0.001）；与3435CC基因型的患者相比，3435CT或3435TT基因型的患者复发风险分别降低了61%和40%（总体P = 0.02）。在阿霉素、长春新碱和泼尼松诱导治疗期间，3435TT基因型的患者骨髓毒性程度比3435CT/3435CC基因型的患者更显著（P = 0.01/P < 0.0001）。我们观察到，与3435CT/TT基因型的患者相比，3435CC基因型的患者在接受大剂量甲氨蝶呤治疗后肝脏毒性更大（P = 0.03）。总之，ABCB1基因多态性与ALL治疗的疗效和毒性之间存在统计学上的显著关联，ABCB1 1199G>A可能是儿童ALL治疗结果的一个新的潜在预测标志物。
