Tandia Mahamadou, Mhiri Asma, Paule Bernard, Saffroy Raphaël, Cailliez Valérie, Noé Gaëlle, Farinotti Robert, Bonhomme-Faivre Laurence
Laboratory of pharmacology, Service Pharmacie, Paul Brousse Hospital, AP-HP, 14 avenue Paul Vaillant-Couturier, 94800, Villejuif, France.
UPRES EA 4123 Faculty of Pharmaceutical Sciences, Université Paris XI, 5 rue Jean Baptiste Clémént, 92296, Chatenay-Malabry, cedex, France.
Cancer Chemother Pharmacol. 2017 Apr;79(4):759-766. doi: 10.1007/s00280-017-3268-y. Epub 2017 Mar 13.
We studied the relation between the polymorphism of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP), encoded by ABCB1 and ABCG2 genes, respectively, and the pharmacokinetic variability and clinical response during the treatment with sorafenib of hepatocellular carcinoma.
At the Paul Brousse Hospital in Villejuif, France, 47 consecutive patients with advanced HCC treated with a single agent sorafenib, were enrolled. Sorafenib exposure was measured by its plasma concentration 3 h after oral administration of 400 mg (bid) by liquid chromatography. All enrolled patients were genotyped for ABCB1 (rs2032582; rs1045642) and ABCG2 (rs2231137; rs2231142; rs2622604) by blood genomic DNA extraction and Mass ARRAY genotyping. The clinical response was evaluated after 3months of treatment according to the RECIST criteria.
Significant associations between sorafenib exposure and the studied polymorphisms were observed for ABCB1 3435C>T, ABCG2 34G>A, ABCG2 1143C>T and ABCG2 421C>A, but not for ABCB1 2677G>TA SNP. In heterozygous patients for ABCB1 3435 C>T, ABCG2 34 G>A and ABCG2 1143 C>T polymorphisms were significantly associated with the lowest sorafenib plasma levels. Those patients presented a tendency to have the best clinical evolution.
Heterozygous forms of the studied polymorphisms could be associated with a better therapeutic response.
我们研究了分别由ABCB1和ABCG2基因编码的P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）的多态性与肝细胞癌患者使用索拉非尼治疗期间的药代动力学变异性及临床反应之间的关系。
在法国维勒瑞夫的保罗·布罗斯医院，连续纳入了47例接受单药索拉非尼治疗的晚期肝癌患者。通过液相色谱法测定口服400mg（每日两次）后3小时的血浆浓度来衡量索拉非尼的暴露量。通过血液基因组DNA提取和Mass ARRAY基因分型对所有纳入患者进行ABCB1（rs2032582；rs1045642）和ABCG2（rs2231137；rs2231142；rs2622604）基因分型。根据RECIST标准在治疗3个月后评估临床反应。
观察到索拉非尼暴露与ABCB1 3435C>T、ABCG2 34G>A、ABCG2 1143C>T和ABCG2 421C>A的研究多态性之间存在显著关联，但与ABCB1 2677G>TA SNP无关。在ABCB1 3435 C>T、ABCG2 34 G>A和ABCG2 1143 C>T多态性的杂合患者中，索拉非尼血浆水平显著最低。这些患者呈现出最佳临床进展的趋势。
所研究多态性的杂合形式可能与更好的治疗反应相关。
