Membrane transporters govern the movement of drugs and their metabolites across
biological membranes, thereby determining their pharmacokinetics, efficacy and
adverse drug reactions.
Platinum-based anticancer drugs are a mainstay of
chemotherapy for many human
malignancies. However, their clinical utility is limited by
tumor resistance and normal tissue toxicities, which are determined at least in part by the level of tissue accumulation of
platinum. Recently, several members of the
ATP-binding cassette (ABC), solute carrier (SLC) and
ATPase membrane protein superfamilies have been found to contribute to the net accumulation of
platinum drugs in malignant and normal tissues. Herein, a review has been carried out to critically evaluate current preclinical and clinical evidence implicating
membrane transporters as determinants of the pharmacology of
cisplatin,
oxaliplatin,
carboplatin and related investigational compounds. The evidence includes studies of recombinant cell systems with genetically modified expression of individual
membrane transporters,
platinum-resistant or -sensitive human
cancer cells and in vivo xenografted
tumors, animal models of
platinum-induced nephro-, oto- or neurotoxicity, and clinical studies of associations between the
membrane transporter tumor expression and patient outcomes from
platinum-based
chemotherapy. Understanding the role of
membrane transporters as determinants of the pharmacology of
platinum drugs will be a basis for targeting these
drug transporters in individualized and optimized
platinum-based
cancer therapy, and new
drug development.