摘要
背景与目的肿瘤细胞过量表达P鄄糖蛋白穴P-glycoprotein.P-gp雪导致多药耐药穴multidrug resistance,MDR雪是目前肿瘤化疗的一大障碍,使用多药耐药逆转剂与抗癌药物联合化疗是克服临床多药耐药的重要方法。本研究对一种新的多芳基取代咪唑化合物FG020327的体外逆转活性及其逆转机制进行了探讨。方法以MTT法检测FG020327对多药耐药肿瘤细胞MCF-7/ADR及KBv200的耐药逆转活性;以荧光分光光度计法检测FG020327对MCF-7/ADR细胞内抗癌药物阿霉素累积的影响;以罗丹明蓄积实验检测该化合物对P-gp功能的影响。结果FG020327在体外具有较强的逆转活性,在5μmol/L浓度下使多药耐药细胞KBv200对长春新碱的敏感性增加44.9倍,逆转活性是公认的强逆转剂维拉帕米的3倍熏但它对敏感株对抗癌药物的敏感性基本无影响。2.5、5和10μmol/L的FG020327使MCF-7/ADR细胞中阿霉素的累积分别增加2.3、2.7和3.7倍,但是在敏感株MCF鄄7细胞却观察不到阿霉素累积的增加。FG020327浓度依赖性增加KBv200细胞内的罗丹明蓄积,但对敏感株KB细胞内的罗丹明蓄积无影响。结论FG020327具有较强的体外逆转MDR的活性,它可能通过抑制P鄄gp功能及增加MDR细胞内抗癌药物的累积逆转MDR。
BACKGROUND & OBJECTIVE: Over-expression of P-glyco-protein (P-gp) in tumor cells results in multidrug resistance (MDR), and failure of chemotherapy. Combined therapy of MDR-related cytotoxins plus MDR modulators is a promising strategy to overcome clinical MDR. This study was to explore MDR reversal activity of a novel compound FG020327, and its mechanism. METHODS: MTT assay was used to evaluate MDR reversal activity of FG020327 in 2 P-gp expressing tumor cell lines, KBv200 and MCF-7/ADR. Adriamycin (ADM) accumulation in MCF-7/ADR cells was detected by fluorescence spectrophotometry. The effect of FG020327 on P-gp function was showed by rhodamine 123 (Rh123) accumulation and efflux in KBv200 cells. RESULTS: FG020327 significantly enhanced sensitivity of MDR cells to anti- tumor drugs. Five μmol/L of FG020327 enhanced sensitivity of KBv200 cells to vincristine (VCR) by 44.9 folds, the reversal activity of which was 3 times that of verapamil (VRP). However, FG020327 had little effect on drug-sensitive MCF-7 cells and KB cells. FG020327 of 2.5, 5, and 10 μmol/L also enhanced ADM accumulation in MCF-7/ADR cells by 2.3, 2.7, and 3.7 folds, respectively, but didn't affect ADM accumulation in MCF-7 cells. FG020327 enhanced Rh123 accumulation in KBv200 cells,but not in KB cells. CONCLUSIONS: FG020327 is an efficient modulator. The reversal of drug-resistance by FG020327 is probably related to enhanced anti-tumor drug accumulation, and inhibition of P-gp function in MDR tumor cells.
出处
《癌症》
SCIE
CAS
CSCD
北大核心
2005年第2期189-193,共5页
Chinese Journal of Cancer
基金
广东省自然科学基金(No.021813)~~
