Keywords: Drug Resistance, Multiple, Neoplasm, P-Glycoprotein, Technetium T 99msestamibi, Tumor Retention, Adenosine Triphosphate, Antineoplastic Agent, Cation, Cyclosporin A, Dna Topoisomerase (atp Hydrolysing), Fluorodeoxyglucose F 18, Furifosmin Tc 99m, Glutathione Transferase, Membrane Protein, Methoxy Isobutyl Isonitrile Technetium Tc 99m, Multidrug Resistance Protein, Technetium 99m, Tetrofosmin Tc 99m, Valspodar, Verapamil, Area Under The Curve, Autoradiography, Clinical Trial, Conference Paper, Drug Clearance, Drug Transport, Drug Uptake, Human, Imaging, Immunoblotting, Malignant Neoplastic Disease, Monitoring, Nonhuman, Phenotype, Positron Emission Tomography, Protein Expression, Feasibility Studies, Forecasting, Gene Expression Regulation, Lung Neoplasms, Radiopharmaceuticals, Substrate Specificity, Technetium Tc 99m Sestamibi, Treatment Failure,
Affiliations: Medicina Nucleare, Dipto. di Sci. Biomorfol./Funzionali, Via S. Pansini 5, 80131 Naples, Italy
References: Not available.
Clinical imaging of multidrug resistance in cancer
The most well-characterized mechanism of multidrug resistance (MDR) involves P-glycoprotein (Pgp), a transmembrane protein acting as an ATP- dependent drug efflux pump. The recognition of 99mTc-Sestamibi and other lipophilic cations as transport substrates for Pgp provided the necessary tool for the clinical assessment of Pgp function in patients with cancer. Many clinical studies from different institutions and trials including a variety of malignancies indicate that both tumor uptake and clearance of 99mTc-Sestamibi are correlated with Pgp expression and may be used for the phenotypic assessment of multidrug resistance. Although both parameters may predict tumor response to chemotherapy, the extraction of efflux rate constants appeared to provide a more direct index of Pgp function as compared to tracer uptake ratio allowing to trace a continuous spectrum of drug transport activity. Preliminary studies reported the use of MDR imaging agents to monitor the modulating ability of revertant compounds. Although the results support the feasibility of this approach, the alteration of tracer pharmacokinetics induced by the modulators certainly constitutes a challenge in the development of a simple functional test suitable in clinical practice. The extension of the acquired imaging methodology to tumors with redundant intrinsic resistant mechanisms such as lung cancer requires further investigations on the relative contribution and clinical relevance of each mechanism. Due to the multifactorial nature of the phenomenon, the development of new tracers with substrate specificity for other known drug transporters would hopefully help to dissect the complex array of cellular mechanisms contributing to treatment failure.
Clinical imaging of multidrug resistance in cancer