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

• Project/Area Number: 16591426
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Akita University
• Principal Investigator: SASAJIMA Toshio Akita Univ., Sch.of Med., Associate Prof., 医学部, 助教授 (40235289)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: 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

Research Abstract

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 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.