The Multidrug Resistance Mechanisms and their Interactions with the Radiopharmaceutical Probes Used for an In Vivo Detection

Nathalie      Perek; Delphine      Denoyer

Abstract

The resistance of human malignancy to multiple chemotherapeutic agents ts remains a major obstacle in cancer therapy. This resistance phenomenon is called ”multiple“ because when cells are resistant they fail to respond to any of a wide range of anticancer agents. This leads to a complete ineffectiveness of any treatment and has dramatic consequences for the patients. This chemoresistance can be intrinsic -when tumour cells do not respond initially to the treatment- or acquired -when resistance appear during the therapy. Our understanding of the mechanisms responsible of the drug resistance has increased over the past few years. The tumour resistance is able to develop several strategies to inactivate the chemotherapeutic agents such as activation of the detoxification process, and overexpression of efflux pump proteins. The phenotype resistance of the cell is mainly characterised by an increased expression of membrane transport proteins such as the P-glycoprotein and the Multidrug Resist ance Protein - MRP1 - that act as real efflux pump to anticancer agent and contribute to physiological alterations i.e. intracellular pH and plasma membrane potentials. The detoxification procedure is also implicated with the Glutathione S transferase enzymes and the major anti oxidant of the cells the glutathione (GSH). More recently a newly reported transporter called ”Breast Resistance Cancer Protein“ has appeared. The role of all these transporters and the link with the detoxification systems in the clinical outcome of cancer chemotherapy is the subject of intense research. Particularly, one way of interest concerned in vivo investigations with radiolabelled compounds used in nuclear medicine. The understanding of how the radiolabelled compounds could interact with the phenotype resistance of the cells had a key role for further exploration of molecular imaging of the MDR phenotype.

Keywords: Radiopharmaceutical Probes, glutathione (GSH), Glutathione S-Transferase (GST), P-Glycoprotein, cyclosporin

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