Visualization of multidrug resistance in vivo

Abstract

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.

Technetium-99m Sestamibi Single Photon Emission Computed Tomography Findings Correlated With P-glycoprotein Expression, Encoded by the Multidrug Resistance Gene-1 Messenger Ribonucleic Acid, in Intracranial Meningiomas

“…30) Pgp and other types of drug resistance-related gene, such as multidrug resistance-associated protein (MRP) and O 6 -methylguanine-DNA methyltransferase, are highly expressed in meningiomas. 7,10,14,34,36) Our study revealed that Pgp was expressed in 14 of 21 (66.7%) meningiomas, MDR-1 mRNA in eight of 11 (72.7%) meningiomas, and that the RI of 99m Tc-MIBI SPECT was correlated significantly with both Pgp and MDR-1 mRNA expression. These results indicate that Pgp, an MDR-1 gene product, contributes to the washout mechanism of 99m Tc-MIBI.…”

Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine

“…In effect, Pgp indirectly modulates intracellular Rluc enzyme kinetics by regulating the transmembrane translocation and availability of substrate. This fundamentally differs from readouts obtained with fluorescent probes such as rhodamine 123 and Hoechst 33342 (34,35), BCECF-AM and SPQ (36), or activated fluorescent compounds such as calcein-AM (37) or radiotracer substrates (23,38,39) that interact with Pgp. These probes and their output signals are retained for significant times after exposure of the cells to the probes, or alternatively, the Pgp-mediated readout depends on washout kinetics over time.…”

Comparison of99mTc-sestamibi and doxorubicin to monitor inhibition of P-glycoprotein function

“…Sestamibi imaging is a more recent approach to characterization of Pgp status in tumours and its use is expanding. This method provides a rapid, non-invasive, and repeatable assessment of cellular and tumour Pgp function and in monitoring of Pgp function modulation and response to chemotherapeutic treatment (Del Vecchio et al, 1999;Hendrikse et al, 1999).…”

“…Tc-sestamibi and doxorubicin to monitor inhibition of P-glycoprotein function Sestamibi and functional analogues, combined with various modulators of Pgp function, have been studied in vitro, in animal models, and extended to the clinic (Del Vecchio et al, 1999;Hendrikse et al, 1999). Because of the combined potential of sestamibi imaging and doxorubicin flow cytometry to assess Pgp function, we undertook a comparison of the two methods in the same in vitro system in order to determine the relationship between their results and to assess the diagnostic and predictive value of sestamibi imaging.…”