TY - JOUR
T1 - MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents
AU - Woodahl, Erica L.
AU - Crouthamel, Matthew H.
AU - Bui, Tot
AU - Shen, Danny D.
AU - Ho, Rodney J.Y.
N1 - Funding Information:
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.
PY - 2009/6
Y1 - 2009/6
N2 - 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.
AB - 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.
KW - ABCB1
KW - Cancer chemotherapy
KW - MDR1
KW - P-Glycoprotein
KW - Pharmacogenomics
KW - Transepithelial permeability
UR - http://www.scopus.com/inward/record.url?scp=67349191460&partnerID=8YFLogxK
U2 - 10.1007/s00280-008-0906-4
DO - 10.1007/s00280-008-0906-4
M3 - Article
C2 - 19123050
AN - SCOPUS:67349191460
SN - 0344-5704
VL - 64
SP - 183
EP - 188
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
ER -
