Imaging probes for non-invasive tumoral detection and functional monitoring of cancer multidrug resistance.

Filipa Mendes

doi:10.20517/cdr.2019.86

Abstract

Aim: Several cationic radiotracers originally developed as myocardial perfusion agents have shown potential for both early detection of cancer and non-invasive monitoring of multiple drug resistance (MDR) by single photon emission computed tomography. We have introduced two cationic complexes, 99mTc-DMEOP [di-methoxy-tris-pyrazolyl-99mTc-(CO)3] and 99mTc-TMEOP [tri-methoxy-tris-pyrazolyl-99mTc-(CO)3], which showed excellent preclinical results as cardiac imaging probes, namely a persistent heart uptake with rapid blood and liver clearance. This study aimed at the evaluation of their usefulness for tumoral detection and functional assessment of MDR.Methods: The uptake and efflux kinetics of 99mTc-DMEOP and 99mTc-TMEOP were evaluated in human prostate, lung, and breast cancer cell lines, including drug-resistant cell lines that are known to overexpress the MDR P-glycoprotein (Pgp). The effects of MDR modulators were also studied. In vivo studies were performed in xenografted tumor models, and the MDR phenotype of the tumors was confirmed by Western blot.Results: The uptake kinetics of both complexes in human cancer cell lines is comparable with the one found for 99mTc-Sestamibi, increasing over time. The uptake of 99mTc-TMEOP is greatly reduced in cells overexpressing Pgp and increased in the presence of a Pgp modulator. In nude mice, the tumor uptake of 99mTc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp tumors.Conclusion: The uptake kinetics of both complexes in human cancer cell lines is comparable with the one found for 99mTc-Sestamibi, increasing over time. The uptake of 99mTc-TMEOP is greatly reduced in cells overexpressing Pgp, and increased in the presence of a Pgp modulator. In nude mice, the tumor uptake of 99mTc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp tumors.

Highlights

Cancer is a leading cause of death worldwide
The tumor uptake of 99mTc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp tumors
The most widely studied cellular mechanisms of tumor resistance are those associated with drug efflux mechanisms involving members of the adenosine triphosphate (ATP)binding cassette (ABC) membrane transporter family, most importantly P-glycoprotein (Pgp), and multidrug-resistant protein 1 (MRP1) and homologs (MRP2-6) and breast cancer resistance protein (BCRP)

Summary

Introduction

Cancer is a leading cause of death worldwide. The World Health Organization reported that cancer accounted for 9.6 million deaths (around 17% of all deaths worldwide) in 2018[1].A major obstacle to successful cancer chemotherapy is drug resistance[2,3]. The most widely studied cellular mechanisms of tumor resistance are those associated with drug efflux mechanisms involving members of the adenosine triphosphate (ATP)binding cassette (ABC) membrane transporter family, most importantly P-glycoprotein (Pgp), and multidrug-resistant protein 1 (MRP1) and homologs (MRP2-6) and breast cancer resistance protein (BCRP). These transporters are found in normal cells, where their role has been identified as one of protection against, and clearance of, excessive extracellular and intracellular concentrations of xenobiotics and toxins. An overarching feature of ABC transporter-expressing tumor cells is their reduced ability to accumulate certain cytotoxic agents intracellularly, resulting in ineffective cellular levels that fail to bring about cell death[3,4]

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