Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer
Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer
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DOI：
10.1007/s11095-018-2548-5
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发表时间：
2019-01-01
影响因子：
3.7
通讯作者：
Kawai, Keiichi
中科院分区：
文献类型：
--
作者：
Kobayashi, Masato;Tsujiuchi, Takafumi;Kawai, Keiichi
背景关于 Tc-99m 标记的 2-甲氧基异丁基异腈 (Tc-99m-MIBI) 和替曲膦 (Tc-99m-TF) 在癌症中多种耐药转运蛋白成像中的亲和力和稳定性知之甚少。我们检查了 Tc-99m 标记的化合物对这些转运蛋白的亲和力及其稳定性。方法(99m)Tc-MIBI 和 Tc-99m-TF 在表达 P-糖蛋白 (MDR1)、多药耐药相关蛋白 (MRP)1-4 或乳腺癌耐药蛋白的囊泡中孵育，有或没有维拉帕米（MDR1 抑制剂）或 MK-571（MRP 抑制剂）。使用 SK-N-SH 神经母细胞瘤、SK-MEL-28 黑色素瘤和 PC-3 前列腺癌细胞系建立 Tc-99m 标记化合物的时间活性曲线，并测量这些细胞中多重耐药性转运蛋白的表达。稳定性评价。结果在囊泡中，Tc-99m标记的化合物对MDR1和MRP1具有亲和力。 Tc-99m-TF 对 MRP2 和 MRP3 具有额外的亲和力。在表达 MDR1 和 MRP1 的 SK-N-SH 细胞中，MK-571 对两种 Tc-99m 标记化合物的摄取量最高。使用抑制剂的 Tc-99m-MIBI 摄取高于使用抑制剂的 Tc-99m-TF 摄取。 Tc-99m-TF 在表达 MRP1 和 MRP2 的 SK-MEL-28 细胞中比表达 MRP1 和 MRP3 的 PC-3 细胞中摄取更多。 Tc-99m-MIBI被代谢，而Tc-99m-TF具有较高的稳定性。结论（99m）Tc-MIBI通过MDR1和MRP1（MRP1>MDR1）输出，与通过MDR1和MRP1-3输出（MRP1，2>MRP3）的Tc-99m-TF相比，水平更高且更快。由于 Tc-99m-MIBI 会被代谢，因此通过较早的晚期成像扫描时间，可以实现用于监测 MDR 的临床成像，并缩短检查时间。 Tc-99m-TF稳定性高，准确反映MDR1和MRP1-3的功能。
BackgroundLittle is known about the affinity and stability of Tc-99m-labeled 2-methoxyisobutylisonitrile (Tc-99m-MIBI) and tetrofosmin (Tc-99m-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of Tc-99m-labeled compounds for these transporters and their stability.Methods(99m)Tc-MIBI and Tc-99m-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 Tc-99m-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.ResultsIn vesicles, Tc-99m-labeled compounds had affinity for MDR1 and MRP1. Tc-99m-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 Tc-99m-labeled compounds. Tc-99m-MIBI uptake with inhibitors was higher than Tc-99m-TF uptake with inhibitors. Tc-99m-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. Tc-99m-MIBI was metabolized, whereas Tc-99m-TF had high stability.Conclusion(99m)Tc-MIBI is exported via MDR1 and MRP1 (MRP1>MDR1) at greater levels and more quickly compared to Tc-99m-TF, which is exported via MDR1 and MRP1-3 (MRP1>MDR1; MRP1, 2>MRP3). Because Tc-99m-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. Tc-99m-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.