Recent Advances in Multidrug Resistance Modulators

Multidrug resistance (MDR) is a type of resistance to structurally unrelated chemotherapeutic drugs, and is one of the main obstacles in the chemotherapy of cancer, malaria and other diseases. In the case of cancer, its inhibition by combination of chemosensitizers with antitumor compounds continues to be a very active field of research, since the availability of safe and potent reversal agents would be very beneficial for clinical use. The discovery of new structures with MDR modulating properties is taking place at a fast pace, together with the clinical evaluation of the most promising of the previously known compounds. Most modulators act by binding to membrane transport proteins (specially P-gp and MRP) and inhibiting their drug-effluxing activity, but some of them act by indirect mechanisms, including inhibition of the expression of the mdr1 gene. General structure- activity studies of this therapeutic group are hampered by the very heterogeneous chemical structure of the compounds, although some conclusions regarding the location of binding domains of P-gp and the structural requirements for MDR reversal have been drawn recently.