Inhibitors of multidrug resistance

P-glycoprotein expression on tumor cells is a frequent cause of pleiotropic drug resistance in cell lines and tumor specimens. Besides the multidrug resistance gene (MDR1), other mechanisms of increased drug extrusion have been described, such as the MDR-related protein and the lung resistance protein. In addition, other gene-regulated processes may lead to cell survival after exposure to cytostatic agents. It has been shown that p-glycoprotein can be circumvented in vitro by noncytotoxic agents such as verapamil and cyclosporin A, which interact pharmacologically with p-glycoprotein-mediated efflux. More recently, molecular approaches to downregulate p-glycoprotein expression or function have been studied. These approaches and the clinical results obtained so far will be discussed.