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dc.contributor.authorMorrow, Christopher J
dc.contributor.authorGhattas, Mohammad
dc.contributor.authorSmith, Christopher
dc.contributor.authorBönisch, Heinz
dc.contributor.authorBryce, Richard A
dc.contributor.authorHickinson, D Mark
dc.contributor.authorGreen, Tim P
dc.contributor.authorDive, Caroline
dc.date.accessioned2010-08-10T16:23:04Z
dc.date.available2010-08-10T16:23:04Z
dc.date.issued2010-07-15
dc.identifier.citationSrc family kinase inhibitor Saracatinib (AZD0530) impairs oxaliplatin uptake in colorectal cancer cells and blocks organic cation transporters. 2010, 70 (14):5931-41 Cancer Resen
dc.identifier.issn1538-7445
dc.identifier.pmid20551056
dc.identifier.doi10.1158/0008-5472.CAN-10-0694
dc.identifier.urihttp://hdl.handle.net/10541/109426
dc.description.abstractElevated Src family kinase (SFK) activity is associated with tumor invasion and metastasis. The SFK inhibitor saracatinib (AZD0530) is currently in phase II trials in patients including those with colorectal cancer (CRC), where links between SFK activity and poor prognosis are particularly striking. Saracatinib is likely to be used clinically in combination regimens, specifically with 5-fluorouracil (5-FU) and oxaliplatin, in CRC. The aim of this study was to determine the effect of saracatinib on oxaliplatin and 5-FU efficacy in CRC cells. Saracatinib did not modulate 5-FU efficacy but antagonized oxaliplatin in a schedule-specific manner through reduced oxaliplatin uptake via an SFK-independent mechanism. Saracatinib resembles the pharmacophore of known organic cation transporter (OCT) inhibitors and reduced oxaliplatin efficacy maximally in cells overexpressing OCT2. These data suggest that oxaliplatin uptake in CRC is attenuated by saracatinib via inhibition of OCT2, a potential consideration for the clinical development of this SFK inhibitor.
dc.language.isoenen
dc.subjectColorectal Canceren
dc.subjectc-Srcen
dc.subject.meshOrganic Cation Transport Proteins
dc.subject.meshColorectal Neoplasms
dc.subject.meshBenzodioxoles
dc.subject.meshsrc-Family Kinases
dc.subject.meshQuinazolines
dc.titleSrc family kinase inhibitor Saracatinib (AZD0530) impairs oxaliplatin uptake in colorectal cancer cells and blocks organic cation transporters.en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, University of Manchester, Manchester Cancer Research Centre and Manchester Academic Health Sciences Centre, Manchester, United Kingdom. cmorrow@picr.man.ac.uken
dc.identifier.journalCancer Researchen
dc.identifier.pmcidPMC2906706
html.description.abstractElevated Src family kinase (SFK) activity is associated with tumor invasion and metastasis. The SFK inhibitor saracatinib (AZD0530) is currently in phase II trials in patients including those with colorectal cancer (CRC), where links between SFK activity and poor prognosis are particularly striking. Saracatinib is likely to be used clinically in combination regimens, specifically with 5-fluorouracil (5-FU) and oxaliplatin, in CRC. The aim of this study was to determine the effect of saracatinib on oxaliplatin and 5-FU efficacy in CRC cells. Saracatinib did not modulate 5-FU efficacy but antagonized oxaliplatin in a schedule-specific manner through reduced oxaliplatin uptake via an SFK-independent mechanism. Saracatinib resembles the pharmacophore of known organic cation transporter (OCT) inhibitors and reduced oxaliplatin efficacy maximally in cells overexpressing OCT2. These data suggest that oxaliplatin uptake in CRC is attenuated by saracatinib via inhibition of OCT2, a potential consideration for the clinical development of this SFK inhibitor.


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