Journal of Clinical Oncology, Vol 16, 3674-3690, Copyright © 1998 by American Society of Clinical Oncology
Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance
DM Bradshaw and RJ Arceci
Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
For cytotoxic agents to have an effect on tumor cells, drugs must first be
transported into the cell, potentially be metabolized to an active form,
and interact appropriately with target molecules. A final common pathway of
cytotoxic agents is usually the initiation of programmed cell death, or
apoptosis. Tumor cells overcome the effects of cytotoxic agents at one or
more of these levels. The classic multidrug-resistance (MDR) phenotype, as
mediated by the drug efflux pump, P-glycoprotein, is one of the most
extensively studied mechanisms of drug resistance. Additional drug
transporters, such as the multidrug resistance- associated proteins (MRPs),
have also been identified and can convey drug-resistance phenotypes.
Important questions remain as to how and whether such transport systems can
be specifically measured and effectively targeted to improve therapeutic
outcomes. Furthermore, alterations in drug targets, drug metabolism, repair
of DNA damage caused by drugs, and the inability to initiate programmed
cell death can all contribute to drug resistance and must be ultimately
considered in the explanation of tumor-cell resistance to therapy.
Continued exploration of the pharmacologic methods to circumvent drug
resistance, as well as strategies that involve targeted therapy and
immunomodulation, should increase the specificity and efficacy of
treatments for patients with cancer.
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