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Pumping Out Drugs

The Potential Impact of ABC Transporters on Resistance to Base, Nucleoside, and Nucleotide Analogs*
  • Piet Borst
  • Peter Wielinga
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Several adenosine triphosphate-binding cassette transporters can transport nucleoside analogs out of cells against steep concentration gradients, resulting in resistance to these drugs. At least three members of the family of human multidrug resistance-associated proteins (MRPs) (MRP4, 5, and 8) are able to transport not only the cyclic nucleotides cyclic adenosine 5′-monophosphate and cyclic guanosine 5′-monophosphate but also some nucleoside-monophosphate analogs. This can result in resistance to their base, nucleoside, or nucleotide precursors, at least in cell lines with high levels of the transporter. MRP4- and MRP5-transfected cells showed resistance (although at a low level) to the thiopurines 6-mercaptopurine and 6-thioguanine and to the antiviral agent adefovir. MRP8-transfected cells also show resistance to adefovir, dideoxycytidine, and the fluoropyrimidines 5-fluorouracil and 5-fluorodeoxyuridine, possibly because MRP8 can efflux the monophosphate derivative of these analogs. However, the affinity of these transporters for the nucleotide analogs studied thus far is relatively low (millimolar rather than micromolar), and this limits their potential impact on resistance. This review summarizes briefly how adenosine triphosphate-binding cassette transporters in general, and MRPs in particular, could affect the disposition and cellular accumulation of anticancer agents.

Key Words

ABC transporters BCRP efflux pumps MRP4 MRP5 multidrug resistance proteins nucleoside monophosphates PMEA thiopurines 

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Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Piet Borst
    • 1
  • Peter Wielinga
    • 2
  1. 1.Division of Molecular BiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.National Institute for Public Health and Environment (RIVM)BilthovenThe Netherlands

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