| Interaction of imatinib with human organic ion carriers. | |
| | |
MedLine Citation:
|
PMID: 18483382 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
PURPOSE: The activity of imatinib in leukemia has recently been linked with expression of the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized the contribution of solute carriers to imatinib transport in an effort to further understand mechanisms involved in the intracellular uptake and retention (IUR) of the drug. EXPERIMENTAL DESIGN: IUR of [3H]imatinib was studied in Xenopus laevis oocytes and HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene expression was determined in nine leukemia cell lines using the Affymetrix U133 array. RESULTS: Imatinib was not found to be a substrate for OCT1 in oocytes (P = 0.21), whereas in HEK293 cells IUR was increased by only 1.20-fold relative to control cells (P = 0.002). Furthermore, in 74 cancer patients, the oral clearance of imatinib was not significantly altered in individuals carrying reduced-function variants in SLC22A1 (P = 0.99). Microarray analysis indicated that SLC22A1 was interrelated with gene expression of various transporters, including ABCB1, ABCC4, ABCG2 (negative), and OATP1A2 (positive). Imatinib was confirmed to be a substrate for the three efflux transporters (P < 0.05) as well as for OATP1A2 (P = 0.0001). CONCLUSIONS: This study suggests that SLC22A1 expression is a composite surrogate for expression of various transporters relevant to imatinib IUR. This observation provides a mechanistic explanation for previous studies that have linked SLC22A1 with the antitumor activity of imatinib. Because of its high expression in the intestine, ciliary body, gliomas, and leukemia cells, OATP1A2 may play a key role in imatinib pharmacokinetics-pharmacodynamics. |
| | |
Authors:
|
Shuiying Hu; Ryan M Franke; Kelly K Filipski; Chaoxin Hu; Shelley J Orwick; Ernst A de Bruijn; Herman Burger; Sharyn D Baker; Alex Sparreboom |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 14 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2008 May |
Date Detail:
|
Created Date: 2008-05-16 Completed Date: 2008-08-18 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
|
Languages: eng Pagination: 3141-8 Citation Subset: IM |
Affiliation:
|
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphia, TN 38105, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Antineoplastic Agents / metabolism* Cell Line, Tumor Drug Resistance, Neoplasm / genetics* Gastrointestinal Stromal Tumors / drug therapy, genetics* Gene Expression Humans Organic Cation Transporter 1 / genetics*, metabolism Piperazines / metabolism* Polymerase Chain Reaction Pyrimidines / metabolism* Xenopus laevis |
| Chemical | |
Reg. No./Substance:
|
0/Antineoplastic Agents; 0/Organic Cation Transporter 1; 0/Piperazines; 0/Pyrimidines; 152459-95-5/imatinib |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Histone deacetylase inhibition and blockade of the glycolytic pathway synergistically induce gliobla...
Next Document: A BTB/POZ gene, NAC-1, a tumor recurrence-associated gene, as a potential target for Taxol resistanc...