Linked Life Data

20345483

Source:http://linkedlifedata.com/resource/pubmed/id/20345483

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2010-8-16
pubmed:abstractText
Sunitinib malate (Sutent, SU11248) is a small-molecule multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Some TKIs can overcome multidrug resistance conferred by ATP-binding cassette transporter, P-glycoprotein (P-gp)/ABCB1, multidrug resistance-associated protein 1 (MRP1)/ABCC1, and breast cancer resistance protein (BCRP)/ABCG2. Here, we analyzed the effects of sunitinib on P-gp and on wild-type and germ-line mutant BCRPs. Sunitinib remarkably reversed BCRP-mediated and partially reversed P-gp-mediated drug resistance in the respective transfectants. The in vitro vesicle transport assay indicated that sunitinib competitively inhibited BCRP-mediated estrone 3-sulfate transport and P-gp-mediated vincristine transport. These inhibitory effects of sunitinib were further analyzed in Q141K-, R482G-, R482S-, and F431L-variant BCRPs. Intriguingly, the F431L-variant BCRP, which is expressed by a germ-line mutant allele 1291T>C, was almost insensitive to both sunitinib- and fumitremorgin C (FTC)-mediated inhibition in a cell proliferation assay. Sunitinib and FTC did not inhibit (125)I-iodoarylazidoprazosin-binding to F431L-BCRP. Thus, residue Phe-431 of BCRP is important for the pharmacological interaction with sunitinib and FTC. Collectively, this is the first report showing a differential effect of a germ-line variation of the BCRP/ABCG2 gene on the pharmacological interaction between small-molecule TKIs and BCRP. These findings would be useful for improving our understanding of the pharmaceutical effects of sunitinib in personalized chemotherapy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/ABCG2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/ATP-Binding Cassette Transporters, http://linkedlifedata.com/resource/pubmed/chemical/Azides, http://linkedlifedata.com/resource/pubmed/chemical/Estrone, http://linkedlifedata.com/resource/pubmed/chemical/Indoles, http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins, http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein, http://linkedlifedata.com/resource/pubmed/chemical/Prazosin, http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles, http://linkedlifedata.com/resource/pubmed/chemical/Vincristine, http://linkedlifedata.com/resource/pubmed/chemical/azidoprazosin, http://linkedlifedata.com/resource/pubmed/chemical/estrone sulfate, http://linkedlifedata.com/resource/pubmed/chemical/sunitinib
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1349-7006
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
101
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1493-500
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Pharmacological interaction with sunitinib is abolished by a germ-line mutation (1291T>C) of BCRP/ABCG2 gene.
pubmed:affiliation
Division of Chemotherapy, Keio University, Tokyo, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't