^(99)Tc^m-MIBI显像评价肿瘤多药耐药及其逆转效果

Using ^(99)Tc^m-MIBI to evaluate tumor multidrug resistance and monitor the reversing of chemosensitizer

目的 探讨99Tcm 甲氧基异丁基异腈 (MIBI)在肿瘤细胞的摄取与肿瘤多药耐药蛋白P 糖蛋白 (P gp)表达水平的关系 ,评价化疗增敏剂对肿瘤多药耐药性的逆转效果。方法 采用人乳腺癌耐药细胞株MCF 7 Adr建立荷瘤鼠动物模型 (n =10 ) ,以维拉帕米 (VRP)为逆转剂 ,随机分为逆转剂组和对照组 ,进行逆转前后 15、6 0、90、12 0min99Tcm MIBI显像 ,对照组裸鼠在逆转前显像后处死 ,逆转剂组在逆转后显像后处死 ,检测逆转前后肿瘤P gp的表达水平和多药耐药基因mdr1的mRNA水平 ,以及各重要脏器的每克组织百分注射剂量率 (%ID g)。结果 除 12 0min外 ,余各时间点肿瘤与对侧正常相应部位放射性计数比值 (T N)差异有显著性 ,逆转后肿瘤T N由 1上升为 >1 2。逆转后耐药基因mdr1mRNA表达水平明显下降 (t=4 873,P =0 0 0 8)。逆转前、后肿瘤P gp表达水平分别为 0 10 38±0 0 0 78和 0 0 0 96± 0 0 0 5 9,差异有显著性 (t=3 5 79,P =0 0 2 3)。逆转后肿瘤、肝脏、肾脏对99Tcm MIBI的摄取明显增加 ,%ID g变化百分比分别为 10 6 83%、4 0 35 %、16 6 0 7% ,心脏对99Tcm MIBI的摄取略有下降 ,为 - 12 82 %。结论 99Tcm MIBI显像可较好评价和显示肿瘤由P gp所致多药耐药性 ,以及化疗增敏剂的逆转效果。

Objective To study the correlation between uptake of 99 Tc m-methoxyisobutylisonitrile (MIBI) and multidrug-resistant P-glycoprotein (gp),and to evaluate the effect of chemosensitizer. Methods Tumor bearing mice model was established by implanting human cancer cell line MCF-7/Adr,the model mice were randomized into two groups: chemosensitizer verapamil group and control group. Before and after giving verapamil, 99 Tc m-MIBI imaging was performed at 15,60,90,120 min,respectively. Mice of the control group were sacrificed after the pre-verapamil imaging,and mice of the verapamil group were sacrificed after the post-verapamil imaging to get %ID/g of tumor and major organs. The level of P-gp was measured with immunocytochemical assay and mRNA of mdr1 gene determined with RT-PCR was obtained simultaneously. Results After giving verapamil the T/N ratio of tumor increased significantly except on 120 min imaging. 99 Tc m-MIBI uptake difference between the verapamil group and control group was obvious ( P =0.045,0.015,0.042,respectively). The expression of mdr1 mRNA decreased significantly after verapamil reversing( t =4.873,P =0.008). The level of P-gp declined from 0.1038±0.0078 to 0.0096±0.0059 ( t =3.579,P =0.023). The 99 Tc m-MIBI uptake of tumor,liver and kidney rose obviously after reversing,%ID/g increments were 106.83%, 40.35%,166.07%,respectively whereas it was slightly declined,-12.82%,in heart. Conclusion 99 Tc m-MIBI imaging may evaluate multidrug resistance (MDR) mediated by P-gp and be used to monitor the reversing effect of chemosensitizer in P-gp positive tumors.