Gréen Henrik, Söderkvist Peter, Rosenberg Per, Horvath György, Peterson Curt
Division of Clinical Pharmacology, Faculty of Health Sciences, Department of Medicine and Care, Linköping University, SE-581 85 Linköping, Sweden.
J Pharm Sci. 2008 Jun;97(6):2045-8. doi: 10.1002/jps.21169.
P-glycoprotein (P-gp), encoded by the ABCB1 gene, confers multi-drug resistance to a variety of antineoplastic agents, for example, paclitaxel. Recently, the G1199T/A polymorphism in the ABCB1 gene was shown to be important for the function of P-gp as well as for the resistance to several chemotherapeutic agents in vitro. We analyzed the allelic distribution of the G1199T/A and other polymorphisms in exons 11 and 12 of the ABCB1 gene in ovarian cancer patients treated with paclitaxel and carboplatin in order to evaluate their predictive value in vivo. The SNPs C1236T, G1199T/A, and A1308G were determined using Pyrosequencing in 51 patients with advanced ovarian cancer and correlated to the progression free survival. The G1199T/A SNP was found to affect the progression free survival. Although only two heterozygous (G/A) patients were found their mean progression free survival was only 2 months as compared to 19 months for the wild-type patients. This is in accordance with the higher resistance for the 1199A genetic variant found in vitro. Genotyping of the ABCB1 gene may be important for determining the tumor resistance to paclitaxel and provide useful information for individualized therapy.
由ABCB1基因编码的P-糖蛋白（P-gp）赋予对多种抗肿瘤药物（如紫杉醇）的多药耐药性。最近，ABCB1基因中的G1199T/A多态性被证明对P-gp的功能以及体外对几种化疗药物的耐药性很重要。我们分析了接受紫杉醇和卡铂治疗的卵巢癌患者中ABCB1基因第11和12外显子的G1199T/A及其他多态性的等位基因分布，以评估它们在体内的预测价值。使用焦磷酸测序法在51例晚期卵巢癌患者中测定了单核苷酸多态性（SNP）C1236T、G1199T/A和A1308G，并将其与无进展生存期相关联。发现G1199T/A SNP影响无进展生存期。虽然仅发现两名杂合子（G/A）患者，但他们的平均无进展生存期仅为2个月，而野生型患者为19个月。这与体外发现的1199A基因变体具有更高耐药性一致。ABCB1基因的基因分型对于确定肿瘤对紫杉醇的耐药性可能很重要，并可为个体化治疗提供有用信息。
