Mechanisms of resistance to cisplatin

The use of cisplatin in cancer chemotherapy is Limited by acquired or intri nsic resistance of cells to the drug. Cisplatin enters the cells and its ch loride ligands are replaced by water, forming aquated species that react wi th nucleophilic sites in cellular macromolecules. The presence of the cispl atin adducts in DNA is thought to trigger cell cycle arrest and apoptosis. Knowledge of the mechanism of action of cisplatin has improved our understa nding of resistance. Decerased intracellular concentration due to decreased drug uptake, increased reflux or increased inactivation by sulfhydryl mole cules such as glutathione can cause resistance to cisplatin. Incresed excis ion of the adducts from DNA by repair pathways or increased lesion bypass c an also result in resistance. Finally, altered expression of regulatory pro teins involved in signal transduction pathways that control the apoptotic p athway can also affect sensitivity to the drug. An improved understanding o f the mechanisms of resistance operative in vivo has identified targets for intervention and may increase the utility of cisplatin for the treatment o f cancer. (C) 2001 Elsevier Science B.V. All rights reserved.