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

本研究旨在探讨~（60）<99m>Tc-MIBI是否适用于阐明恶性肿瘤的多药耐药性和预测MDR 1抑制剂对抗肿瘤药物的增效作用。体外实验：用低剂量长春新碱（VCR）诱导恶性肿瘤细胞（RG 2和C6胶质瘤，步行者256癌：W256）产生多药耐药。MTT法显示，与未用药细胞株（RG 2、C6、W256）相比，耐药细胞株（RG 2 R、C6 R、W256 R）的存活分数明显增加。在所有VCR耐药亚系中，RT-PCR显示MDR 1 mRNA的表达高于药物初始细胞系。高<99m>表达MDR 1 mRNA的VCR耐药细胞株的~（60）Tc-MIBI的Vds明显低于低表达MDR 1 mRNA的未用药细胞株。在<99m>未用药细胞系和VCR耐药细胞亚系中，~（13）Tc-MIBI的Vd与MDR 1 mRNA表达呈负相关。第二种基因治疗后 ...更多信息 MDR 1抑制剂PSC 833、MS 2 0 9对VCR细胞毒作用增强。体内<99m>实验：将C6和C6 R细胞分别接种于Sprague-Dawley大鼠左右两侧基底节区，观察其对MDR 1抑制剂的敏感性。在<99m>肿瘤植入后10天使用^ Tc-MIBI进行放射自显影。在<99m>用或不用MDR 1抑制剂（PSC 833，MS 209）处理的大鼠中测量13 Tc-MIBI摄取。Tc-MIBI<99m>在两种肿瘤中的蓄积强度均高于非肿瘤区域。C6<99m>细胞对~（13）Tc-MIBI的摄取明显高于C6 R细胞。MDR <99m>1抑制剂治疗后，两种肿瘤的13 Tc-MIBI摄取均显著增加。还通过放射自显影法，使用α-<14>C-甲基-L-蛋氨酸（Met）和MIB-5指数评价了VCR联合或不联合MDR 1抑制剂的治疗作用。MDR 1抑制剂治疗后用VCR治疗的两种肿瘤的Met摄取和MIB-5指数均显著低于单独用VCR治疗的肿瘤。<99m>Tc-MIBI SPECT可用于检测恶性脑肿瘤患者MDR 1介导的耐药性和监测MDR 1抑制剂的治疗效果。少