Hendrikse N H, Franssen E J, van der Graaf W T, Vaalburg W, de Vries E G
PET Center, University Hospital, Groningen, The Netherlands.
Eur J Nucl Med. 1999 Mar;26(3):283-93. doi: 10.1007/s002590050390.
Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99mTc radiopharmaceuticals, such as 99mTc-tetrofosmin and several 99Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [11C]colchicine, [11C]verapamil and [11C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [11C]colchicine and [11C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP2 gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo.
多种机制参与了化疗药物的多药耐药性（MDR），如药物外排泵、P-糖蛋白（Pgp）和多药耐药相关蛋白（MRP）。在本综述中，描述了参与MDR的机制，并对结果进行了综述，特别关注Pgp和MRP的体内成像。各种检测方法可提供有关药物外排泵在mRNA和蛋白质水平存在情况的信息。然而，这些方法无法提供Pgp和MRP在体内动态功能的信息。对于Pgp和MRP介导的转运研究，可采用单光子发射断层扫描（SPET）和正电子发射断层扫描（PET）。锝-99m甲氧基异丁基异腈是Pgp和MRP的底物，已用于肿瘤成像的临床研究，并用于观察Pgp泵调节后Pgp介导转运的阻断情况。其他99mTc放射性药物，如99mTc-替曲膦和几种99mTc-Q络合物，也是Pgp的底物，但迄今为止，这些化合物仅有体外和动物研究结果。包括[11C]秋水仙碱、[11C]维拉帕米和[11C]柔红霉素在内的几种药物已被评估用于PET体内定量Pgp介导的转运。结果表明，放射性标记的秋水仙碱、维拉帕米和柔红霉素是用于成像肿瘤中Pgp功能的可行底物。[11C]秋水仙碱和[11C]维拉帕米在胸部区域的摄取相对较高，降低了这两种示踪剂用于监测该区域肿瘤中Pgp介导的药物转运的价值。此外，必须牢记，只有在不存在和存在Pgp阻断的情况下比较放射性标记底物的Pgp介导转运，才能获得关于Pgp介导药代动力学的定量信息。白三烯是MRP的特异性底物。因此，N-[11C]乙酰白三烯E4提供了一个非侵入性研究MRP功能的机会。在MRP2突变的GY/TR大鼠中获得的结果已证明可观察到MRP介导的转运。这种示踪剂可用于研究体内MRP转运功能异常，例如在MRP2基因缺陷的杜宾-约翰逊患者中。所获得的结果表明，使用SPET和PET研究体内MDR转运体的功能是可行的。
