Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköpings Universitet, Linköping, Sweden.
Pharmacogenomics J. 2012 Apr;12(2):111-8. doi: 10.1038/tpj.2010.79. Epub 2010 Oct 12.
Overexpression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P=0.03 and P=0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P=0.02), and tended to be more susceptible to etoposide and daunorubicin (P=0.07-0.09), but not to cytarabine. No significant difference in allele frequencies was found between patients and healthy volunteers (n=400).
ABCB1 基因编码的多药转运蛋白 P-糖蛋白的过度表达是急性髓系白血病（AML）中一个具有临床相关性的问题。ABCB1 中的多态性可能与癌症风险和治疗反应有关。因此，我们研究了 ABCB1 中的 G1199A、C1236T、G2677T/A 和 C3435T 多态性对 100 例核型正常的初发 AML 患者的癌症易感性、体外细胞毒性和总生存期的影响。1236C/C 或 2677G/G 基因型的患者比其他基因型的患者生存更差（P=0.03 和 P=0.02）。这两种基因型在多变量分析中都是生存的重要因素，与年龄、NPM1 和 FLT3 突变状态有关。体外细胞毒性研究表明，1236T/T 和 2677T/T 患者的白血病细胞对米托蒽醌的敏感性显著增加（P=0.02），且对依托泊苷和柔红霉素的敏感性增加（P=0.07-0.09），但对阿糖胞苷的敏感性无差异。在患者和健康志愿者（n=400）之间，等位基因频率没有发现显著差异。
