Paterson Institute for Cancer Research, University of Manchester, Manchester Cancer Research Centre and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Cancer Res. 2010 Jul 15;70(14):5931-41. doi: 10.1158/0008-5472.CAN-10-0694. Epub 2010 Jun 15.
Elevated 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.
Src 家族激酶（SFK）活性升高与肿瘤侵袭和转移有关。SFK 抑制剂 saracatinib（AZD0530）目前正在包括结直肠癌（CRC）患者在内的 II 期临床试验中进行研究，SFK 活性与预后不良之间的联系尤为明显。saracatinib 可能会与其他药物联合使用，特别是与氟尿嘧啶（5-FU）和奥沙利铂联合使用，应用于 CRC 治疗。本研究旨在确定 saracatinib 对 CRC 细胞中奥沙利铂和 5-FU 疗效的影响。saracatinib 不调节 5-FU 的疗效，但通过非 SFK 依赖性机制减少奥沙利铂的摄取，以特定方案拮抗奥沙利铂。saracatinib 类似于已知有机阳离子转运体（OCT）抑制剂的药效团，并且在过表达 OCT2 的细胞中最大程度地降低了奥沙利铂的疗效。这些数据表明，saracatinib 通过抑制 OCT2 来减弱 CRC 中的奥沙利铂摄取，这可能是考虑该 SFK 抑制剂临床开发的一个因素。
Cancer Cell Int. 2021-12-7
Int J Mol Sci. 2021-6-28
Rev Physiol Biochem Pharmacol. 2021
Biochem Pharmacol. 2010-4-2
Mol Oncol. 2009-2-7
Zotero 插件