Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer

• Published in: Pharmaceutical research Vol. 36; no. 1; pp. 1 - 10
• Main Authors: Kobayashi, Masato, Tsujiuchi, Takafumi, Okui, Yuya, Mizutani, Asuka, Nishi, Kodai, Nakanishi, Takeo, Nishii, Ryuichi, Fukuchi, Kazuki, Tamai, Ikumi, Kawai, Keiichi
• Format: Journal Article
• Language: English
• Published: New York Springer US 2019; Springer Nature B.V
• Subjects: Adenocarcinoma; Affinity; Bile; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Breast cancer; Cancer; Drug resistance; Exports; Inhibitors; Material requirements planning; MDR1 protein; Medical Law; Melanoma; Metabolism; Multidrug resistance; Multidrug resistant organisms; P-Glycoprotein; Pharmacology/Toxicology; Pharmacy; Prostate; Research Paper; Tumor cell lines; Verapamil; Vesicles; Tc-MIBI; Tc-tetrofosmin; multidrug resistance; adenosine triphosphate-binding cassette transporters; multidrug resistance-associated protein
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-018-2548-5

Background Little is known about the affinity and stability of 99m Tc-labeled 2-methoxyisobutylisonitrile ( 99m Tc-MIBI) and tetrofosmin ( 99m Tc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99m Tc-labeled compounds for these transporters and their stability. Methods 99m Tc-MIBI and 99m Tc-TF were incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1–4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99m Tc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability was evaluated. Results In vesicles, 99m Tc-labeled compounds had affinity for MDR1 and MRP1. 99m Tc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99m Tc-labeled compounds. 99m Tc-MIBI uptake with inhibitors was higher than 99m Tc-TF uptake with inhibitors. 99m Tc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99m Tc-MIBI was metabolized, whereas 99m Tc-TF had high stability. Conclusion 99m Tc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99m Tc-TF, which is exported via MDR1 and MRP1–3 (MRP1 > MDR1; MRP1, 2 > MRP3). Because 99m Tc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99m Tc-TF has high stability and accurately reflects the function of MDR1 and MRP1–3.