99mTc‐MIBI imaging for prediction of therapeutic effects of second‐generation MDR1 inhibitors in malignant brain tumors

• Published in: International journal of cancer 2007-12, Vol.121 (12), p.2637-2645
• Main Authors: Sasajima, Toshio, Shimada, Naoya, Naitoh, Yuichiro, Takahashi, Masataka, Hu, Yi, Satoh, Tomo, Mizoi, Kazuo
• Format: Article
• Language: English
• Subjects: 99mTc‐MIBI; Antineoplastic agents; Biological and medical sciences; Chemotherapy; malignant brain tumors; Medical sciences; MS‐209; multidrug resistance; Pharmacology. Drug treatments; PSC833; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.23011

The aim of this study was to explore whether 99mTc‐methoxyisobutylisonitrile (99mTc‐MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second‐generation MDR1 inhibitors (PSC833, MS‐209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR‐resistant sublines compared to those of drug‐naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR‐resistant cells than drug‐naive cells in each line. Volume distribution (Vd) of 99mTc‐MIBI was negatively correlated with MDR1 mRNA expression among drug‐naive and VCR‐resistant cells. MDR1 inhibitors decreased surviving fractions and increased Vd of 99mTc‐MIBI significantly in VCR‐resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that 99mTc‐MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of 99mTc‐MIBI revealed higher uptake in drug‐naive cells at basal ganglia compared with VCR‐resistant cells at the opposite basal ganglia of rats. Oral administration of the second‐generation MDR1 inhibitors significantly increased 99mTc‐MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using 14C‐methyl‐L‐methionine (14C‐Met) and MIB‐5 index. 14C‐Met uptake and MIB‐5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of 99mTc‐MIBI accumulation is considered informative for detecting MDR1‐mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors. © 2007 Wiley‐Liss, Inc.