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Drug resistance

Multiple opponents

Nature Reviews Cancer volume 4, page 924 (2004)Cite this article

Imatinib, a tyrosine-kinase inhibitor effective against BCR-ABL1, KIT and platelet-derived growth factor receptor, is an orally administered drug. Given that BCRP is highly expressed within the gastrointestinal tract and is a member of the ABC family of drug transporters, it seems likely that BCRP is involved in limiting the uptake of imatinib into the blood, thereby limiting the biological availability of imatinib. So, Burger et al. asked if imatinib is a substrate of BCRP. Initially, the authors used two breast cancer cell sublines that overexpressed either wild-type (Arg482) or mutant (Thr482) BCRP, a mutation previously shown to affect substrate specificity. Carbon-14 labelled imatinib was used to measure drug uptake. Both wild-type overexpressing cells and mutant-BCRP expressing cells had significantly less drug accumulation than controls, indicating that both the mutant and wild-type BCRP proteins act as drug-efflux pumps for imatinib. Real-time PCR analyses and western-blot data confirmed that other ABC drug-efflux proteins — MDR1, MRP1 and MRP2 – were not overexpressed in these cells.

To further examine this interaction, the authors monitored the efflux of imatinib and three other known BCRP substrates: mitoxantrone, and methotrexate and doxorubicin, two substrates that are exclusive targets for wild-type or mutant BCRP, respectively. Imatinib is exported in a similar manner to mitoxantrone by both wild-type and mutant-BCRP expressing cells. In addition, efflux of imatinib was reduced in the presence of a BCRP-specific inhibitor, further demonstrating that imatinib is a bona fide substrate for BCRP.

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References

ORIGINAL RESEARCH PAPERS

  1. Burger, H. et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 104, 2940–2942 (2004)

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FURTHER READING

  1. Burger, H. & Nooter, K. Pharmacokinetic resistance to imatinib mesylate: role of the ABC drug pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the oral bioavailability of imatinib. Cell Cycle 3 Dec 2004 (http://landesbioscience.com/journals/cc/abstract.php?id=1331)

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Authors
  1. Nicola McCarthy
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McCarthy, N. Multiple opponents. Nat Rev Cancer 4, 924 (2004). https://doi.org/10.1038/nrc1514

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  • DOI: https://doi.org/10.1038/nrc1514

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