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

Cancer chemotherapy and pharmacology 2009 Jun

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

Citation

Erica L Woodahl, Matthew H Crouthamel, Tot Bui, Danny D Shen, Rodney J Y Ho. MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer chemotherapy and pharmacology. 2009 Jun;64(1):183-8