Noninvasive detection of multidrug resistance in patients with hematological malignancies: are we there yet?

The success of chemotherapy in the treatment of malignancies may be limited by cellular mechanisms leading to drug resistance. In hematological malignancies, mechanisms leading to the development of multidrug resistance (MDR) include overexpression of the membrane-based export pump P-glycoprotein (Pgp) and the MDR-associated protein (MRP). Recently, the overexpression of the lung-resistance protein (LRP) has also been associated with reduced intracellular drug accumulation. A major problem in assessing the significance of the expression of these resistance proteins in clinical MDR has been the variability of detection techniques either at the mRNA or protein level. Currently, the detection of resistance proteins relies heavily on antibody and cDNA probes, and these methods may not be informative about the in vivo function of Pgp, MRP, or LRP. Nuclear medicine imaging techniques such as single-photon emission tomography (SPECT) and positron emission tomography (PET) have been evaluated for noninvasive determination of the presence and the function of Pgp- and MRP-mediated transport systems. Technetium 99m ((99m)Tc)-sestamibi, an agent in clinical use for myocardial perfusion and tumor imaging, is recognized as a substrate for Pgp and MRP, and has been used to visualize Pgp expression. (99m)Tc-tetrofosmin is also a substrate for the Pgp efflux pump mechanism and is used to evaluate Pgp function in in vitro and in vivo studies. Recently, radiopharmaceuticals including carbon 11-labeled colchicine, verapamil, and daunorubicin have been used in cell line and animal studies for the evaluation of Pgp-mediated transport functions using PET technology. Preliminary results suggest that the potential to detect MDR in tumors prior to or after exposure to chemotherapeutic agents exists in imaging using either (99m)Tc-labeled compounds and SPECT or positron emitting compounds and PET.