MDR1 reversal: criteria for clinical trials designed to overcome the multidrug resistance phenotype

Multidrug resistance (MDR) is a widely studied mechanism of cellular resistance to structurally unrelated cytotoxic agents. The MDR phenotype is related to the overexpression of the MDR1 gene product, P-glycoprotein (P-gp), a transmembrane drug efflux pump. The capacity to compete with the cytotoxic drug for the active outward transport process, thus inhibiting the activity of the P-gp pump, has been demonstrated for numerous non-cytotoxic compounds, termed MDR modulators. The possibility of modulating the activity of the P-gp pump has initiated numerous clinical trials, using a wide range of chemosensitizers. This article reviews these substances, discusses problems that may arise in connection with the concurrent administration of P-gp modulators and chemotherapeutic agents and provides guidelines for the design of future clinical trials. Furthermore, now data are presented concerning the potential of idarubicin to overcome the MDR phenotype.