Modulation of DNA strand break induction and repair bytyrosine kinase inhibitors targeted against EGFR and HER2

摘要: Purpose: The human epidermal growth factor receptors EGFR (erbB1) and HER2 (erbB2/neu) are involved in mediating resistance to chemotherapy ionising radiation (IR). In vitro studies demonstrate that small molecule tyrosine kinase inhibitors (TKIs) which target these can increase the effectiveness of DNA damaging agents. However, these combinations have failed produce clinical results anticipated one potential explanation is inhibition HER2 cell signalling pathways by TKIs short lived, with cells able switch alternative mechanisms through HER3. The purpose this study was examine whether duration exposure modulates the induction repair damage produced or IR describes attempts elucidate role chemotherapy. Experimental design: Two HER targeting TKIs, lapatinib gefitinib were investigated. The effect combination cisplatin doxorubicin on cell proliferation schedule examined drug assays. The influence lesions induced cisplatin, IR, doxorubicin, etoposide m-AMSA investigated using the alkaline neutral Comet assays measurement γH2AX RAD51 foci. DNA expression arrays used identify potential which HER2 produces transfected HER2. Results: Lapatinib synergistically inhibit proliferation with cisplatin a dependent manner. Duration has no effect lesions but significantly reduces the production double strand breaks part through down-regulation expression topoisomerase IIα (Topo IIα), increasing resistance drugs. Conclusions: These indicate scheduling targeted against EGFR important continuous drugs induces to doxorubicin, m-AMSA, reduced their target, Topo IIα. The importance should be considered when combining chemotherapy in practice.