Concurrent and sequential administration of sunitinib malate and docetaxel in human non-small cell lung cancer cells and xenografts

Abstract

Optimal scheduling of chemotherapy with molecular-targeted agents is important to maximize clinical benefit. We compared the effects of concurrent and sequential administration of docetaxel and multi-target inhibitor sunitinib malate on tumor cells and xenografts and studied several mechanisms involved in drug interaction to provide experimental data in support of their clinical use in non-small cell lung cancer (NSCLC). Human umbilical vein endothelial cells (HUVECs), NCI-H460 human non-small lung carcinomas cells, and NCI-H460 xenograft were treated with docetaxel and Sunitinib malate, using concurrent and sequential treatment schedules. Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium (MTS) assay. Cell cycle analysis was conducted using flow cytometry. Extracellular signal-regulated kinases (ERK1/2) phosphorylation was evaluated by immunoblot analysis. Effects on xenografts were assessed by tumor growth delay. There were no significant difference in the cell proliferation and cell cycle distribution of NCI-H460 cells between concurrent treatment and the first sequential treatment. Both docetaxel and sunitinib malate had no effect on each other in inhibiting ERK1/2 phosphorylation in sequential treatments, while docetaxel eliminated inhibitory activity of sunitinib malate on ERK1/2 phosphorylation in concurrent treatment. For NCI-H460 xenografts, the first sequential treatment showed superior effect to concurrent treatment on inhibiting tumor growth. Combined treatment with sunitinib malate and docetaxel had a greater therapeutic effect than monotherapy, and the first sequential scheduling was more effective than concurrent scheduling, which partly due to the effect of docetaxel on receptor tyrosine kinase (RTK) signaling pathway.