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http://purl.uniprot.org/citations/18559609http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/18559609http://www.w3.org/2000/01/rdf-schema#comment"

Purpose

The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed.

Experimental design

The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors.

Results

Unlike imatinib, there was no significant difference in the dasatinib IUR at 37 degrees C and 4 degrees C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50(dasatinib) values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P < 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P < 0.05) and reduced IC50(dasatinib) (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC(50)(dasatinib).

Conclusion

Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.org/dc/terms/identifier"doi:10.1158/1078-0432.ccr-07-5095"xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Kumar S."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"White D.L."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Hughes T.P."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"To L.B."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Hewett D."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Dang P."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Melo J."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Eadie L."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Frede A."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Hiwase D.K."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Saunders V."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/author"Zrim S."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/date"2008"xsd:gYear
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/name"Clin Cancer Res"xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/pages"3881-3888"xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/title"Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications."xsd:string
http://purl.uniprot.org/citations/18559609http://purl.uniprot.org/core/volume"14"xsd:string
http://purl.uniprot.org/citations/18559609http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/18559609
http://purl.uniprot.org/citations/18559609http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/18559609
http://purl.uniprot.org/uniprot/#_F4ZUY5-mappedCitation-18559609http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/18559609
http://purl.uniprot.org/uniprot/#_A1L471-mappedCitation-18559609http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/18559609
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