Journal ArticleDOI
MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs.
John D. Schuetz,Michele Connelly,Daxi Sun,Sheela G. Paibir,Patricia M. Flynn,R V Srinivas,Alok Kumar,Arnold Fridland +7 more
TLDR
In the study of alternative or additional mechanisms of resistance operating during antiviral therapy, overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA and azidothymidine monophosphate from cells and, thus, with resistance to these drugs.Abstract:
Dideoxynucleosides, which are potent inhibitors of HIV reverse transcriptase and other viral DNA polymerases, are a common component of highly active anti-retroviral therapy (HAART) (ref. 1). Six reverse transcriptase inhibitors have been approved for human use: azidothymidine; 2'3'-dideoxycytidine; 2'3'-dideoxyinosine; 2',3'-didehydro-3'deoxythymidine; 2',3'-dideoxy-3'-thiacytidine; and 4-[2-amino-6-(cyclopropylamino) -9H-purin-9-yl]-2-cyclopentene-1-methanol. Although drug-resistant HIV strains resulting from genetic mutation have emerged in patients treated with HAART (ref. 1), some patients show signs of drug resistance in the absence of drug-resistant viruses2,3. In our study of alternative or additional mechanisms of resistance operating during antiviral therapy, overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA (9-(2-phosphonylmethoxyethyl)adenine) and azidothymidine monophosphate from cells and, thus, with resistance to these drugs. Overexpression of MRP4 mRNA and MRP4 protein severely impaired the antiviral efficacy of PMEA, azidothymidine and other nucleoside analogs. Increased resistance to PMEA and amplification of the MRP4 gene correlated with enhanced drug efflux; transfer of chromosome 13 containing the amplified MRP4 gene conferred resistance to PMEA. MRP4 is the first transporter, to our knowledge, directly linked to the efflux of nucleoside monophosphate analogs from mammalian cells.read more
Citations
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Multidrug resistance in cancer: role of ATP–dependent transporters
TL;DR: The ability to predict and circumvent drug resistance is likely to improve chemotherapy, and it has become apparent that resistance exists against every effective drug, even the authors' newest agents.
Journal ArticleDOI
Targeting multidrug resistance in cancer
Gergely Szakács,Jill K. Paterson,Joseph A. Ludwig,Catherine Booth-Genthe,Michael M. Gottesman +4 more
TL;DR: Various approaches to combating multidrug-resistant cancer are described, including the development of drugs that engage, evade or exploit efflux by ABC transporters.
Journal ArticleDOI
The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype
Sheng Zhou,John D. Schuetz,Kevin D. Bunting,Anne-Marie Colapietro,Janardhan Sampath,John J. Morris,Irina Lagutina,Gerard Grosveld,Mitsujiro Osawa,Hiromitsu Nakauchi,Brian P. Sorrentino +10 more
TL;DR: Results show that expression of the Bcrp1/ABCG2 gene is an important determinant of the SP phenotype, and that it might serve as a marker for stem cells from various sources.
Journal ArticleDOI
The human ATP-binding cassette (ABC) transporter superfamily
TL;DR: The ATP-binding cassette (ABC) transporters are essential for many processes in the cell and mutations in these genes cause or contribute to several human genetic disorders including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response.
Journal ArticleDOI
The Human ATP-Binding Cassette (ABC) Transporter Superfamily
TL;DR: The current knowledge of the human ABC genes, their role in inherited disease, and understanding of the topology of these genes within the membrane are reviewed.
References
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Journal ArticleDOI
Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase.
P A Furman,J A Fyfe,M H St Clair,Kent J. Weinhold,Rideout Janet L,G A Freeman,S N Lehrman,Dani P. Bolognesi,Samuel Broder,Hiroaki Mitsuya +9 more
TL;DR: The results reported here suggest that azidothymidine is nonselectively phosphorylated but that the triphosphate derivative efficiently and selectively binds to the HIV reverse transcriptase.
Journal Article
Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines.
Marcel Kool,M. De Haas,George L. Scheffer,R.J. Scheper,M. J. T. Van Eijk,J. A. Juijn,Frank Baas,Piet Borst +7 more
TL;DR: In this paper, the authors identified three new homologues of MRP1, the gene encoding the multidrug resistanceassociated protein, and cMOAT (or MRP2 ), the canalicular multispecific organic anion transporter gene.
Journal ArticleDOI
Antiretroviral drug resistance testing in adults with HIV infection: Implications for clinical management
M. S. Hirsch,Brian Conway,Richard T. D'Aquila,Victoria A. Johnson,Françoise Brun-Vézinet,Bonaventura Clotet,Lisa M. Demeter,Scott M. Hammer,Donna M. Jacobsen,Daniel R. Kuritzkes,Clive Loveday,John W. Mellors,Stefano Vella,Douglas D. Richman +13 more
TL;DR: Genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may prove useful for individual patient management and need validation, standardization, and a clearer definition of their clinical roles.
Journal Article
Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells.
TL;DR: The apparent coordinated coexpression of the CYP3A gene family and P-glycoprotein in the LS180 cells suggests that for common orally administered drugs, P- glycoprotein may play an important role in net drug absorption and drug/drug interactions of shared CYP 3A4/P-gly Coprotein substrates.