Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 1, pp 183–188 | Cite as

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

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 (MDR1 wt ) or G1199A (MDR1 1199A ), anticancer drug sensitivity and transepithelial permeability were evaluated.

Results

The recombinant cells MDR1 wt and MDR1 1199A displayed comparable doxorubicin resistance. However, MDR1 1199A 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 MDR1 wt - and MDR1 1199A -expressing cells, while P-gp-mediated transport was greater for vinblastine and vincristine in MDR1 1199A 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

MDR1 ABCB1 P-Glycoprotein Pharmacogenomics Cancer chemotherapy Transepithelial 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

Notes

Acknowledgments

Supported in part by NIH grants GM62883, AI52663, NS39178, ES07033, and HL56548. ELW is a recipient of the NIH Pharmaceutical Sciences Training Grant (GM07750), and the William E. Bradley Fellowship in Pharmaceutics. Sequencing work was supported by the University School of Pharmacy DNA Sequencing and Gene Analysis Center. RJYH is also supported by the Milo Gibaldi Endowment.

References

  1. 1.
    Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59–98PubMedCrossRefGoogle Scholar
  2. 2.
    Woodahl EL, Ho RJ (2004) The role of MDR1 genetic polymorphisms in interindividual variability in P-glycoprotein expression and function. Curr Drug Metab 5:11–19PubMedCrossRefGoogle Scholar
  3. 3.
    Woodahl EL, Yang Z, Bui T et al (2004) Multidrug resistance gene G1199A polymorphism alters efflux transport activity of P-glycoprotein. J Pharmacol Exp Ther 310:1199–1207PubMedCrossRefGoogle Scholar
  4. 4.
    Cascorbi I, Gerloff T, Johne A et al (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69:169–174PubMedCrossRefGoogle Scholar
  5. 5.
    Woodahl EL, Yang Z, Bui T et al (2005) MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells. Aids 19:1617–1625PubMedCrossRefGoogle Scholar
  6. 6.
    Crouthamel MH, Wu D, Yang Z et al (2006) A novel MDR1 G1199T variant alters drug resistance and efflux transport activity of P-glycoprotein in recombinant Hek cells. J Pharm Sci 95:2767–2777PubMedCrossRefGoogle Scholar
  7. 7.
    Green H, Soderkvist P, Rosenberg P et al (2008) ABCB1 G1199A polymorphism and ovarian cancer response to paclitaxel. J Pharm Sci 97:2045–2048PubMedCrossRefGoogle Scholar
  8. 8.
    Polli JW, Wring SA, Humphreys JE et al (2001) Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther 299:620–628PubMedGoogle Scholar
  9. 9.
    Fine HA, Mayer RJ (1993) Primary central nervous system lymphoma. Ann Intern Med 119:1093–1104PubMedGoogle Scholar
  10. 10.
    Deangelis LM (1995) Current management of primary central nervous system lymphoma. Oncology (Williston Park) 9:63–71 discussion 71, 75–66, 78Google Scholar
  11. 11.
    Haroun RI, Brem H (2000) Local drug delivery. Curr Opin Oncol 12:187–193PubMedCrossRefGoogle Scholar
  12. 12.
    Balmaceda C (1998) Advances in brain tumor chemosensitivity. Curr Opin Oncol 10:194–200PubMedCrossRefGoogle Scholar
  13. 13.
    Ohnishi T, Tamai I, Sakanaka K et al (1995) In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood–brain barrier. Biochem Pharmacol 49:1541–1544PubMedCrossRefGoogle Scholar
  14. 14.
    Soffietti R, Ruda R, Bradac GB et al (1998) PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery 43:1066–1073PubMedCrossRefGoogle Scholar
  15. 15.
    Kellie SJ, Koopmans P, Earl J et al (2004) Increasing the dosage of vincristine: a clinical and pharmacokinetic study of continuous-infusion vincristine in children with central nervous system tumors. Cancer 100:2637–2643PubMedCrossRefGoogle Scholar
  16. 16.
    Rutkowski S, Bode U, Deinlein F et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986PubMedCrossRefGoogle Scholar
  17. 17.
    Massimino M, Gandola L, Luksch R et al (2005) Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for childhood high-grade glioma. Neuro Oncol 7:41–48PubMedCrossRefGoogle Scholar
  18. 18.
    Suarez CR, Raj AB, Bertolone SJ et al (2004) Carboplatinum and vincristine chemotherapy for central nervous system gliofibroma: case report and review of the literature. J Pediatr Hematol Oncol 26:756–760PubMedCrossRefGoogle Scholar
  19. 19.
    Menna P, Salvatorelli E, Minotti G (2007) Doxorubicin degradation in cardiomyocytes. J Pharmacol Exp Ther 322:408–419PubMedCrossRefGoogle Scholar
  20. 20.
    Gonzalez RJ, Tarloff JB (2004) Expression and activities of several drug-metabolizing enzymes in LLC-PK1 cells. Toxicol In Vitro 18:887–894PubMedCrossRefGoogle Scholar

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

Personalised recommendations