2005 Fiscal Year Final Research Report Summary
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
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Cerebral neurosurgery
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Research Institution | Akita University |
Principal Investigator |
SASAJIMA Toshio Akita Univ., Sch.of Med., Associate Prof., 医学部, 助教授 (40235289)
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Project Period (FY) |
2004 – 2005
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Keywords | malignant brain tumors / ^<99m>Tc-MIBI / drug resistance / MDR1 inhibitors / vincristine / tumor proliferation / amino acid metabolism |
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
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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
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