Multidrug resistance (MDR), which is mediated by multiple
drug efflux
ATP-binding cassette (
ABC) transporters, is a critical issue in the treatment of acute
leukemia, with permeability
glycoprotein (P-gp),
multidrug resistance-associated protein 1, and
breast cancer resistance
protein (i.e., ABCG2) consistently being shown to be key effectors of MDR in cell line studies. Studies have demonstrated that intrinsic MDR can arise as a result of specific gene expression profiles and that
drug-induced overexpression of P-gp and other MDR
proteins can result in acquired resistance, with multiple
ABC transporters having been shown to be overexpressed in cell lines selected for resistance to multiple drugs used to treat acute
leukemia. Furthermore, numerous anticancer drugs, including agents commonly used for the treatment of acute
leukemia (e.g.,
doxorubicin,
vincristine,
mitoxantrone, and
methotrexate), have been shown to be P-gp substrates or to be susceptible to efflux mediated by other MDR
proteins, and multiple clinical studies have demonstrated associations between P-gp or other MDR
protein expression and responses to
therapy or survival rates in acute
leukemia. Here we review the importance of MDR in
cancer, with a focus on acute
leukemia, and we highlight the need for rapid accurate assessment of MDR status for optimal treatment selection. We also address the latest research on overcoming MDR, from inhibition of P-gp and other MDR
proteins through various approaches (including direct antagonism and gene silencing) to the design of novel agents or novel delivery systems for existing therapeutic agents, to evade cellular efflux.