Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 1, pp 183–188

MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents

  • Erica L. Woodahl
  • Matthew H. Crouthamel
  • Tot Bui
  • Danny D. Shen
  • Rodney J. Y. Ho
Short Communication

DOI: 10.1007/s00280-008-0906-4

Cite this article as:
Woodahl, E.L., Crouthamel, M.H., Bui, T. et al. Cancer Chemother Pharmacol (2009) 64: 183. doi:10.1007/s00280-008-0906-4

Abstract

Purpose

P-glycoprotein (P-gp), encoded by MDR1 (or ABCB1), is important in anticancer drug delivery and resistance. We evaluated alterations in P-gp-mediated transport of anticancer agents due to the MDR1 G1199A polymorphism.

Methods

Using stable recombinant epithelial cells expressing wild-type (MDR1wt) or G1199A (MDR11199A), anticancer drug sensitivity and transepithelial permeability were evaluated.

Results

The recombinant cells MDR1wt and MDR11199A displayed comparable doxorubicin resistance. However, MDR11199A cells displayed greater resistance to vinblastine, vincristine, paclitaxel, and VP-16 (11-, 2.9-, 1.9-, and 2.9-fold, respectively). Alterations in transepithelial permeability paralleled these changes. Efflux of doxorubicin was similar between MDR1wt- and MDR11199A-expressing cells, while P-gp-mediated transport was greater for vinblastine and vincristine in MDR11199A cells (2.9- and 2.0-fold, respectively).

Conclusions

The occurrence and magnitude of the MDR1 G1199A effect is drug specific. Overall, the MDR1 G1199A polymorphism may impact anticancer efficacy through modulation of drug distribution and delivery to target tumor cells.

Keywords

MDR1ABCB1P-GlycoproteinPharmacogenomicsCancer chemotherapyTransepithelial permeability

Abbreviations

MDR1 or ABCB1

Multidrug resistance gene

P-gp

P-glycoprotein

ABC

ATP-binding cassette

BBB

Blood–brain-barrier

SNP

Single nucleotide polymorphism

MDR1wt

Wild-type MDR1

MDR11199A

MDR1 G1199A polymorphism

EC50

Effective drug concentration necessary for 50% cell death

TEER

Transepithelial electrical resistance values

Papp

Apparent permeability

PappA→B

Apical-to-basolateral apparent permeability

PappB→A

Basolateral-to-apical apparent permeability

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Erica L. Woodahl
    • 1
    • 2
  • Matthew H. Crouthamel
    • 1
  • Tot Bui
    • 1
  • Danny D. Shen
    • 1
  • Rodney J. Y. Ho
    • 1
  1. 1.Department of PharmaceuticsUniversity of WashingtonSeattleUSA
  2. 2.Department of Biomedical and Pharmaceutical SciencesUniversity of MontanaMissoulaUSA