Membrane Transport of Platinum Compounds

Abstract

Small molecules cross membranes by either passive diffusion or are transported actively by transmembrane proteins. If given enough time, however, essentially any molecule will diffuse across a lipid bilayer down its concentration gradient. The rate at which this happens depends on size of the molecule and its hydrophobicity (solubility in oil). Based on these observations most platinum compounds which are small uncharged molecules, are expected to cross membranes relatively easily by passive diffusion. This is, however, only partly true. On the one hand platinum compounds, and specificly cisplatin (cDDP), cross membranes by passive diffusion since the accumulation is not saturable nor is it inhibited by structural analogs. On the other hand, cisplatin transport can be modulated both by a variety of pharmacologic agents that do not cause general permeabilization of the membrane, and by the activation of intracellular signal transduction pathways. Whatever is responsible for the transport modulation, probably more than one mechanism is involved in the transport of platinum compounds across cell membranes. The importance of each of these transport mechanisms is still unclear, however transport of platinum compounds is often down modulated during the emergence of platinum drug resistance. Therefore most of the studies dealing with transport of platinum compounds are performed in platinum drug-resistant variants. In this chapter we will describe the current understanding of membrane transport of platinum compounds in both sensitive and resistant cells and the importance of specific transport molecules in the sequestration of platinum compounds and platinum complexes.