Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate

Murray D. Norris; David De Graaf; Michelle Haber; Maria Kavallaris; Janice Madafiglio; Jayne Gilbert; Edward Kwan; Bernard W. Stewart; Eugene B. Mechetner; Andrei V. Gudkov; Igor B. Roninson

doi:10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8

Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate

Murray D. Norris
, David De Graaf
, Michelle Haber
, Maria Kavallaris
, Janice Madafiglio
, Jayne Gilbert
, Edward Kwan
, Bernard W. Stewart
, Eugene B. Mechetner
, Andrei V. Gudkov
, Igor B. Roninson

Roswell Park - Cell Stress and Biophysical Oncology

Sydney Children's Hospital
University of Illinois at Chicago
Oncotech Inc.

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

89 Scopus citations

Abstract

Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDRI P-glycoprotein (Pgp), a pleiotropic efflux pump acting on different hydrophobic compounds that enter cells by passive diffusion. A series of human leukemic CCRF-CEM sublines, isolated by multi-step selection for very high resistance to MTX, exhibit multiple mechanisms of MTX resistance, including decreased carrier-mediated uptake of MTX and DHFR gene amplification. These sublines show cross-resistance to drugs of the multi-drug resistance (MDR) family, which is correlated with relative resistance to MTX. The MTX-selected sublines show increased expression and function of the MDR1 gene, based on the measurement of MDR1 mRNA, Pgp and rhodamine 123 accumulation. Sequence analysis of the MDR1 cDNA from MTX-selected CCRF-CEM cells revealed no mutations in the protein coding region. MTX resistance in these cell lines is partially reversible by a Pgp-specific monoclonal antibody (MAb) UIC2 and a monovalent Fab fragment of UIC2. Our results indicate that Pgp can contribute to multifactorial resistance to MTX.

Original language	English
Pages (from-to)	613-619
Number of pages	7
Journal	International Journal of Cancer
Volume	65
Issue number	5
DOIs	https://doi.org/10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8
State	Published - Mar 1 1996

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10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8

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Norris, M. D., De Graaf, D., Haber, M., Kavallaris, M., Madafiglio, J., Gilbert, J., Kwan, E., Stewart, B. W., Mechetner, E. B., Gudkov, A. V., & Roninson, I. B. (1996). Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. International Journal of Cancer, 65(5), 613-619. https://doi.org/10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8

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title = "Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate",

abstract = "Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDRI P-glycoprotein (Pgp), a pleiotropic efflux pump acting on different hydrophobic compounds that enter cells by passive diffusion. A series of human leukemic CCRF-CEM sublines, isolated by multi-step selection for very high resistance to MTX, exhibit multiple mechanisms of MTX resistance, including decreased carrier-mediated uptake of MTX and DHFR gene amplification. These sublines show cross-resistance to drugs of the multi-drug resistance (MDR) family, which is correlated with relative resistance to MTX. The MTX-selected sublines show increased expression and function of the MDR1 gene, based on the measurement of MDR1 mRNA, Pgp and rhodamine 123 accumulation. Sequence analysis of the MDR1 cDNA from MTX-selected CCRF-CEM cells revealed no mutations in the protein coding region. MTX resistance in these cell lines is partially reversible by a Pgp-specific monoclonal antibody (MAb) UIC2 and a monovalent Fab fragment of UIC2. Our results indicate that Pgp can contribute to multifactorial resistance to MTX.",

author = "Norris, \{Murray D.\} and \{De Graaf\}, David and Michelle Haber and Maria Kavallaris and Janice Madafiglio and Jayne Gilbert and Edward Kwan and Stewart, \{Bernard W.\} and Mechetner, \{Eugene B.\} and Gudkov, \{Andrei V.\} and Roninson, \{Igor B.\}",

year = "1996",

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doi = "10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8",

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Norris, MD, De Graaf, D, Haber, M, Kavallaris, M, Madafiglio, J, Gilbert, J, Kwan, E, Stewart, BW, Mechetner, EB, Gudkov, AV & Roninson, IB 1996, 'Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate', International Journal of Cancer, vol. 65, no. 5, pp. 613-619. https://doi.org/10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8

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T1 - Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate

AU - Norris, Murray D.

AU - De Graaf, David

AU - Haber, Michelle

AU - Kavallaris, Maria

AU - Madafiglio, Janice

AU - Gilbert, Jayne

AU - Kwan, Edward

AU - Stewart, Bernard W.

AU - Mechetner, Eugene B.

AU - Gudkov, Andrei V.

AU - Roninson, Igor B.

PY - 1996/3/1

Y1 - 1996/3/1

N2 - Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDRI P-glycoprotein (Pgp), a pleiotropic efflux pump acting on different hydrophobic compounds that enter cells by passive diffusion. A series of human leukemic CCRF-CEM sublines, isolated by multi-step selection for very high resistance to MTX, exhibit multiple mechanisms of MTX resistance, including decreased carrier-mediated uptake of MTX and DHFR gene amplification. These sublines show cross-resistance to drugs of the multi-drug resistance (MDR) family, which is correlated with relative resistance to MTX. The MTX-selected sublines show increased expression and function of the MDR1 gene, based on the measurement of MDR1 mRNA, Pgp and rhodamine 123 accumulation. Sequence analysis of the MDR1 cDNA from MTX-selected CCRF-CEM cells revealed no mutations in the protein coding region. MTX resistance in these cell lines is partially reversible by a Pgp-specific monoclonal antibody (MAb) UIC2 and a monovalent Fab fragment of UIC2. Our results indicate that Pgp can contribute to multifactorial resistance to MTX.

AB - Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDRI P-glycoprotein (Pgp), a pleiotropic efflux pump acting on different hydrophobic compounds that enter cells by passive diffusion. A series of human leukemic CCRF-CEM sublines, isolated by multi-step selection for very high resistance to MTX, exhibit multiple mechanisms of MTX resistance, including decreased carrier-mediated uptake of MTX and DHFR gene amplification. These sublines show cross-resistance to drugs of the multi-drug resistance (MDR) family, which is correlated with relative resistance to MTX. The MTX-selected sublines show increased expression and function of the MDR1 gene, based on the measurement of MDR1 mRNA, Pgp and rhodamine 123 accumulation. Sequence analysis of the MDR1 cDNA from MTX-selected CCRF-CEM cells revealed no mutations in the protein coding region. MTX resistance in these cell lines is partially reversible by a Pgp-specific monoclonal antibody (MAb) UIC2 and a monovalent Fab fragment of UIC2. Our results indicate that Pgp can contribute to multifactorial resistance to MTX.

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U2 - 10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8

DO - 10.1002/(SICI)1097-0215(19960301)65:5<613::AID-IJC10>3.0.CO;2-8

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SP - 613

EP - 619

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 5

ER -

Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate

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