KINETICS OF THE MULTIDRUG TRANSPORTER (P-GLYCOPROTEIN) AND ITS REVERSAL

Most cancer deaths result from the cancer's either being intrinsically resistant to chemotherapeutic drugs or becoming resistant after being initially sensitive. Often, in cells grown in cell culture, drug resi stance correlates with the presence of one or more of the so-called P- glycoproteins or multidrug resistance proteins, products of the mdr fa mily of genes. This review is largely concerned with the transport kin etics of the P-glycoproteins. We first present a brief overview of the P-glycoproteins, their properties, and their clinical significance. L ater sections of the review expand on this material with special empha sis on the substrates of P-glycoprotein and how they cross the cell me mbrane, on the transport kinetics of the P-glycoprotein, on reversers of its action, and on its activity as an ATPase. In a final section, w e consider the mechanism of action of P-glycoprotein as an actively tr ansporting membrane pump. The characteristic of P-glycoprotein conside red the most difficult to explain is its very broad specificity (or la ck of specificity), but there are precedents for this property in well -known proteins such as serum albumin, which binds a range of molecula r types, including substrates and reversers of P-glycoprotein, seeming ly as broad as does P-glycoprotein. Pointing out this analogy does not provide a molecular explanation for the substrate-binding properties of P-glycoprotein but does make those properties more assimilable.