Synergistic effects of imatinib (STI 571) in combination with chemotherapeutic drugs in head and neck cancer
Synergistic effects of imatinib (STI 571) in combination with chemotherapeutic drugs in head and neck cancer
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DOI：
10.1097/01.cad.0000168392.04676.bb
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发表时间：
2005-08-01
影响因子：
2.3
通讯作者：
Ward, TH
中科院分区：
文献类型：
--
作者：
Bruce, IA;Slevin, NJ;Ward, TH
酪氨酸激酶抑制剂伊马替尼（STI 571; glivec）是bcr-abl、c-kit和血小板衍生生长因子受体的强效抑制剂。在腺样囊性癌（ACC）原代培养物和代表头颈部鳞状细胞癌（HNSCC）的已建立细胞系中，对伊马替尼单独使用和与已建立的化疗药物联合使用进行了评价。超过90%的ACC肿瘤是c-kit阳性的，这些原代培养被证明在评估化疗敏感性方面具有短期有用性。使用统计三维分析模型在广泛的药物组合中确定相互作用。ACC短期培养物和HNSCC细胞系都被证明在伊马替尼和顺铂联合使用时具有从相加到协同的反应。使用彗星X测定进一步研究伊马替尼对顺铂诱导的DNA交联的相互作用。相反，当伊马替尼和吉西他滨联合使用时，观察到显著的拮抗作用。由于吉西他滨被脱氧胞苷激酶（dCK）激活，因此研究了伊马替尼对该酶的影响。观察到dCK的剂量依赖性抑制，强调该激酶可能是伊马替尼的额外二级分子靶点。这项工作证明了顺铂和伊马替尼之间的协同作用，这可能被证明是在ACC和HNSCC的未来管理临床相关。
The tyrosine kinase inhibitor imatinib (STI 571; glivec) is potent inhibitor of bcr-abl, c-kit and platelet-derived growth factor receptors. Imatinib was evaluated both alone and in combination with established chemotherapeutic agents in adenoid cystic carcinoma (ACC) primary cultures and established cell lines representing squamous cell carcinoma of the head and neck (HNSCC). Over 90% of ACC tumors are c-kit-positive, and these primary cultures proved to be of short-term usefulness in assessing chemosensitivity. Interaction was determined over a wide range of drug combinations using a statistical threedimensional analysis model. Both ACC short-term cultures and HNSCC cell lines were demonstrated to have a response ranging from additive to synergistic when imatinib and cisplatin were combined. The interaction of imatinib on cisplatin-induced DNA cross-linking was further investigated using the comet-X assay. In contrast, significant antagonism was observed when imatinib and gemcitabine were combined. Since gemcitabine is activated by deoxycytidine kinase (dCK), the effect of imatinib on this enzyme was investigated. A dose-dependent inhibition of dCK was observed, highlighting this kinase as a possible additional secondary molecular target for imatinib. This work demonstrates a synergistic interaction between cisplatin and imatinib, which may prove to be clinically relevant in the future management of both ACC and HNSCC.