Abstract
e14069 Background: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has attracted many attentions due to its encouraging anticancer activity in clinic third-line treatment across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer (NSCLC) and colorectal cancer. Its usage in second-line with chemotherapeutic drugs is still under exploration. This study is focus on the antitumor effect of apatinib combined with docetaxel (DTX) on NSCLC and its pharmacokinetic material basis. Methods: Apatinib (150 mg/kg, every day, p.o.) with or without DTX (8 mg/kg, q3d for four times, i.p.) was administered in A549 xenograft nude mice. The antitumor effect, histopathology of important organs and serum transaminases for liver function were detected. The metabolomic changes in serum were profiled by GC/MS and analyzed for the treatment outcome. The effect of apatinib on DTX concentrations in plasma, tumor and other tissues were determined by LC-MS/MS. The expressions of multidrug resistant transporters were detected. Effects of apatinib on the uptake, efflux and subcellular distribution of DTX in A549 cell and A549/DTX (DTX resistant) cell were investigated. Results: Apatinib enhanced the antitumor effect of DTX with alleviated DTX-induced inflammatory cells infiltration in liver and decreased serum transaminases (ALT and AST). Metabolomic results showed that serum endogenic molecules of apatinib and DTX co-treatment mice were closer to that of normal nude mice when compared to the DTX group. Apatinib significantly increased DTX concentration in tumor (up to 1.82 times) without enhancement in serum, heart, liver, lung and kidney. Additionally, apatinib decreased the DTX-induced upregulation of P-glycoprotein in tumor. In vitro, apatinib increased the cell/subcellular accumulation (especially in cytosol) and decreased the efflux of DTX in A549/DTX cells, while apatinib exerted no significant effect on cellular pharmacokinetics of DTX in A549 cells. Conclusions: Apatinib has a potential application prospect in second-line therapy combined with DTX for NSCLC patients, especially for multidrug resistant patients.
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