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

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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

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

Int J Cancer. 1996 Mar 1;65(5):613-9.

PubMed ID

8598312 [ View in PubMed

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Abstract

Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDR1 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Methotrexate	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details