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

doi:10.1007/s00280-008-0906-4

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

University of Washington

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English
Pages (from-to)	183-188
Number of pages	6
Journal	Cancer Chemotherapy and Pharmacology
Volume	64
Issue number	1
DOIs	https://doi.org/10.1007/s00280-008-0906-4
State	Published - Jun 2009

Funding

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.

Funder number
HL56548, ES07033, NS39178, AI52663, GM07750
R01GM062883

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ABCB1
Cancer chemotherapy
MDR1
P-Glycoprotein
Pharmacogenomics
Transepithelial permeability

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10.1007/s00280-008-0906-4

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@article{922c77adfe5a4b2c9df1434aedee267a,

title = "MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents",

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 = "ABCB1, Cancer chemotherapy, MDR1, P-Glycoprotein, Pharmacogenomics, Transepithelial permeability",

author = "Woodahl, \{Erica L.\} and Crouthamel, \{Matthew H.\} and Tot Bui and Shen, \{Danny D.\} and Ho, \{Rodney J.Y.\}",

note = "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.",

year = "2009",

month = jun,

doi = "10.1007/s00280-008-0906-4",

language = "English",

volume = "64",

pages = "183--188",

journal = "Cancer Chemotherapy and Pharmacology",

issn = "0344-5704",

publisher = "Springer Science and Business Media Deutschland GmbH",

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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 - https://www.scopus.com/pages/publications/67349191460

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 -

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

Abstract

Funding

UN SDGs

Keywords

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