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首页> 外文OA文献 >Study on potentiation of antitumor agent by MDR1 inhibitors in malignant tumor cells: Monitoring multidrug resistance using 99mTc-MIBI and comparison with expression of MDR1 mRNA
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Study on potentiation of antitumor agent by MDR1 inhibitors in malignant tumor cells: Monitoring multidrug resistance using 99mTc-MIBI and comparison with expression of MDR1 mRNA

机译：MDR1抑制剂在恶性肿瘤细胞中增强抗肿瘤药的研究：使用99mTc-MIBI监测多药耐药性并与MDR1 mRNA表达进行比较

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The aim of this study was to explore whether 99mTc-methoxyisobutylisonitrile(MIBn is suitable for elucidation of multidrug resistance and prediction ofpotentiation of antitumor agents by MDRI inhibitors in malignant tumor cells.Tumor cells (RG2 and C6 gliomas, Walker 256 mammary carcinoma) were continuouslyincubated with low dose vincristine to induce and maintain multidrug resistance.MTT assays demonstrated significant increases of surviving fractions in all vincristne(VCR) -resistant sublines as compared with those of drug-naive cell lines. Double-labelaccumulation studies (99mTc-MIBI, 14C-TdR) were performed in all drug-naive celllines and VCR-resistant sublines. In all VCR-resistant sublines, RT-PCR revealed higherexpression of MDRI mRNA as compared with drug-naive cell lines. 99mTc-MIBIaccumulation in VCR-resistant sublines expressing higher levels of MDRI mRNA wassignificantly lower than in drug-naive cell lines expressing lower levels of MDRI mRNA.However, there were no significant differences in cell proliferation as measured by 14CTdRaccumulation rate. 99mTc-MIBI accumulation is negatively correlated with MDRImRNA levels among drug-naive cell lines and VCR-resistant sublines. These findingsindicated that the development of drug resistance was associated with enhanced 99mTcMIBIextrusion. After pretreatment with MDRI inhibitors (verapamil, cyclosporin A,FK506), surviving fractions of all VCR-resistant sublines significantly decreased ascompared with those of non-treated VCR-resistant sublines. MTT assays revealedenhanced effects on VCR cytotoxity following pretreatment with MDRI inhibitors.ggmTc-MIBI accumulation significantly increased after one-hour pretreatment withMDRI inhibitors in all VCR-resistant sublines. In contrast, there were no significantdifferences in MDRI mRNA levels between non-treated and MDRI inhibitor-treatedVCR-resistant sublines. MDRI inhibitors had no significant effects on cell proliferationas measured by 14C-TdR accumulation rate. These findings indicated that MIBI-dependentmechanisms allowing VCR extrusion were functionally inhibited by MDRI inhibitors.ggmTc-MIBI may be a suitable imaging agent for detecting MDRI-mediated drugresistance and for monitoring therapeutic effects of MDRI inhibitors in malignanttumors. ggmTc-MIBI SPECT is expected to provide more definitive criteria for monitoringmultidrug resistance and for predicting potentiation of antitumor agents by MDRI inhibitors in patients with malignant brain tumors.
机译：这项研究的目的是探讨99mTc-甲氧基异丁基异腈（MIBn）是否适用于阐明恶性肿瘤细胞中的多药耐药性以及MDRI抑制剂预测抗肿瘤药的潜力。 MTT分析显示，与未使用药物的细胞系相比，所有长春新碱（VCR）耐药亚系的存活分数均显着增加，与未使用药物的细胞系相比，双标记蓄积研究（99mTc-MIBI，14C- TdR）在所有未使用过药物的细胞系和对VCR耐药的亚系中进行；在所有对VCR耐药的亚系中，RT-PCR显示与未使用过药物的细胞系相比，MDRI mRNA的表达更高。 MDRI mRNA的水平显着低于表达MDRI mRNA较低水平的未经药物处理的细胞系。通过14CTdR积累率测量的细胞增殖差异。在未使用药物的细胞系和VCR耐药亚系中，99mTc-MIBI积累与MDRImRNA水平呈负相关。这些发现表明耐药性的发展与增强的99mTcMIBI挤出有关。用MDRI抑制剂（维拉帕米，环孢菌素A，FK506）预处理后，与未治疗的VCR耐药亚株相比，所有VCR耐药亚株的存活分数均显着降低。 MTT分析显示，用MDRI抑制剂预处理后，对VCR细胞毒性的作用增强。在所有VCR耐药亚系中，用MDRI抑制剂预处理1小时后，ggmTc-MIBI积累显着增加。相反，在未处理的和MDRI抑制剂处理的VCR抗性亚系之间，MDRI mRNA水平没有显着差异。如通过14C-TdR积累速率测量，MDRI抑制剂对细胞增殖没有显着影响。这些发现表明MDRI抑制剂在功能上抑制了允许VCR挤出的MIBI依赖性机制。ggmTc-MIBI可能是检测MDRI介导的耐药性和监测MDRI抑制剂在恶性肿瘤中的治疗作用的合适显像剂。 ggmTc-MIBI SPECT有望为监测多药耐药性和预测MDRI抑制剂对脑部恶性肿瘤患者的抗肿瘤药提供更明确的标准。

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