MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents
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- Woodahl, E.L., Crouthamel, M.H., Bui, T. et al. Cancer Chemother Pharmacol (2009) 64: 183. doi:10.1007/s00280-008-0906-4
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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.
Using stable recombinant epithelial cells expressing wild-type (MDR1wt) or G1199A (MDR11199A), anticancer drug sensitivity and transepithelial permeability were evaluated.
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).
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.
KeywordsMDR1ABCB1P-GlycoproteinPharmacogenomicsCancer chemotherapyTransepithelial permeability
- MDR1 or ABCB1
Multidrug resistance gene
Single nucleotide polymorphism
MDR1 G1199A polymorphism
Effective drug concentration necessary for 50% cell death
Transepithelial electrical resistance values
Apical-to-basolateral apparent permeability
Basolateral-to-apical apparent permeability