Membrane Transporters as Determinants of the Pharmacology of Platinum Anticancer Drugs
Johnson J. Liu,
Mark J. McKeage.
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.
Keywords: ABC transporter, membrane transporter, platinum-based anticancer drug, platinum resistance, platinum toxicity,
solute carrier transporter
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