Experimental studies on potentiation of antitumor agent by the second generation MDR1 inhibitors in malignant brain tumors : Monitoring multidrug resistance using ^<99m>Tc-MIBI

第二代MDR1抑制剂在恶性脑肿瘤中增强抗肿瘤药物的实验研究：使用^<99m>Tc-MIBI监测多药耐药性

• 批准号: 16591426
• 负责人: SASAJIMA Toshio
• 金额: $ 2.24万
• 依托单位: Akita University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591426/
• 关键词: malignant brain tumors; ^<99m>Tc-MIBI; drug resistance; MDR1 inhibitors; vincristine; tumor proliferation; amino acid metabolism; 移植脳腫瘍; ^3H-ビンクリスチン; 三重標識組織放射能測定法; MTT assay

The aim of this study is to explore whether ^<99m>Tc-MIBI is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by MDR1 inhibitors in malignant tumors.In vitro experiments : Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma : W256) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated significant increase of surviving fractions in all VCR-resistant sublines (RG2R, C6R, W256R) compared with those of drug-naive cell lines (RG2, C6, W256). In all VCR-resistant sublines, RT-PCR revealed higher expression of MDR1 mRNA compared with drug-naive cell lines. Vds of ^<99m>Tc-MIBI in VCR-resistant sublines expressing higher level of MDR1 mRNA was significantly lower than those of drug-naive cell lines expressing lower levels of MDR1 mRNA. Vd of ^<99m>Tc-MIBI is negatively correlated with MDR1 mRNA expression among drug-naive cell lines and VCR-resistant sublines. After treatment with second ge … More neration MDR 1 inhibitors (PSC833, MS209), MTT assay revealed enhancing effects on VCR cytotoxity. Vd of ^<99m>Tc-MIBI significantly increased after treatment with MDR 1 inhibitors in all VCR-resistant sublines.In vivo experiments : C6 and C6R cells were inoculated in the right and left basal ganglia of Sprague-Dawley rats, respectively. Autoradiography using ^<99m>Tc-MIBI was performed 10 days after tumor implantation. The ^<99m>Tc-MIBI uptake was measured in rats treated with or without the MDR 1 inhibitors (PSC833, MS209). ^<99m>Tc-MIBI accumulated more intensely in both tumors than the nontumor regions. The ^<99m>Tc-MIBI uptake of C6 was significantly higher than that of C6R. The ^<99m>Tc-MIBI uptake of both tumors significantly increased after the MDR 1 inhibitor treatment. The therapeutic effects of VCR with or without the MDR 1 inhibitors were also evaluated by autoradiography using ^<14>C-methyl-L-methionine (Met) and MIB-5 index. Met uptake and MIB-5 index of both tumors treated with VCR following the MDR 1 inhibitor treatment significantly decreased than those of tumors treated with VCR alone.^<99m>Tc-MIBI SPECT could be suitable imaging for detecting MDR1-mediated drug resistance and for monitoring therapeutic effects of MDR1 inhibitors in patients with malignant brain tumors. Less

这项研究的目的是探索 ^<99m> TC-MIBI是否适合阐明MDR1抑制剂在恶性实验中通过MDR1抑制剂对抗肿瘤剂的增强性的预测。在体外实验中。诱导多药电阻。 MTT分析表明，与药物不含量的细胞系相比，所有耐VCR的sublines（RG2R，C6R，W256R）的存活部分显着增加（RG2R，W256R）（RG2，C6，W256）。在所有耐VCR的子序中，RT-PCR均显示MDR1 mRNA的表达更高，与药物含量为单位细胞系相比。在抗VCR的subline中，表达较高水平MDR1 mRNA的VDS vds vds含量明显低于表达较低水平MDR1 mRNA水平的药物细胞系的VD。 ^<99m> TC-MIBI的VD与药物对细胞系和抗VCR耐药的subline之间的MDR1 mRNA表达负相关。用第二个……更多的MDR 1抑制剂（PSC833，MS209）处理后，MTT分析显示对VCR细胞毒素的影响增强。在所有耐VCR的subline中，用MDR 1抑制剂处理后的VD ^<99m> TC-MIBI显着增加。在体内实验中：C6和C6R细胞分别在Sprague-Dawley大鼠的左右基底神经节中接种了C6和C6R细胞。肿瘤植入后10天，使用 ^<99m> TC-MIBI进行放射自显影。 ^<99m> TC-MIBI摄取量是在接受或没有MDR 1抑制剂治疗的大鼠中测量的（PSC833，MS209）。 ^<99m> TC-MIBI在两个肿瘤中都比非肿瘤区域更诚实。 ^<99m> C6的TC-MIBI摄取明显高于C6R。 MDR 1抑制剂治疗后，两种肿瘤的 ^<99m> TC-MIBI摄取显着增加。使用 ^<14> c-甲基-l-甲硫代（MET）和MIB-5指数的VCR具有或不带有MDR 1抑制剂的VCR的理论效应还通过放射自显影进行了评估。 MDR 1抑制剂治疗后，两种肿瘤的MET摄取和MIB-5指数明显降低，而单独使用VCR治疗的肿瘤的摄入量显着降低。^<99m> TC-MIBI SPECT可能是检测MDR1介导的耐药性和监测MDR1抑制剂抑制剂脑抑制剂的耐药性效果的MDR1降低耐药性的成像。较少的