Abstract 2947: Apatinib and cytotoxic agents showed synergistic inhibitory effects in gastric cancer cells and fluorescent xenograft model
Authors: Feng Jiuhuan , Qin Shukui 
Published: August 2018

Background: Fluoropyrimidine and platinum-based combinations are the main treatment option for incurable advanced gastric cancer. While anti-angiogenic agents have been reported to bring survival benefit for gastric cancer patients after standard therapy. Apatinib is a small-molecular angiogenesis inhibitor that highly binds and selectively targets VEGFR-2. It has been approved by CFDA for treating pre-treated metastatic gastric cancer. The present study aimed to explore the anti-tumor effects of apatinib combined with traditional cytotoxic agents such as paclitaxel (TAX), oxaliplatin (L-OHP), 5- fluorouracil (5-FU) in vitro and in vivo.

Methods: Three human gastric adenocarcinoma cell lines (MKN-28, SGC-7901, BGC-823) were cultured for in vitro experiment. Apatinib with different dose (4 μg/mL, 8 μg/mL, and 16 μg/mL) combined with TAX, L-OHP or 5-FU were added to cells. MTT assay was performed to detect cell proliferation. The coefficient of drug interaction (CDI) value was calculated to analyze the synergistic inhibitory effects of drug combination. Tumor cell invasion and migration ability were detected by Transwell assay, and flow cytometry was performed to detect cell apoptosis. The in vivo anti-tumor effects of apatinib combined with cytotoxic agents were investigated in the green fluorescent protein-labeled gastric cancer-bearing mice.

Results: Compared with TAX, L-OHP or 5-FU alone, the combination of apatinib with these agents significantly inhibited cell proliferation in all three cell lines (P &lt; 0.05). Based on the CDI values, the most obvious synergistic effect was obtained in the combination of apatinib with TAX. Additionally, apatinib at 4 μg/mL was selected for further analysis since apatinib at this dose showed more obvious and comprehensive synergistic effect in different combinations. Apatinib combined with TAX, L-OHP or 5-FU also significantly decreased the invasion and migration ability of tumor cells, and induced an obvious increase of cell apoptosis (P &lt; 0.05). For in vivo assay, apatinib alone or cytotoxic agents alone could significantly inhibited tumor growth compared to control, while the combination of apatinib with above cytotoxic agents had more inhibitory effects (P &lt; 0.05). Moreover, based on the changes in green fluorescence signal in mice, the tumor volume in mice treated with apatinib combined with cytotoxic agents, especially with TAX and 5-Fu, was markedly decreased than that in mice treated with cytotoxic agents alone. Furthermore, the combination of apatinib with TAX, L-OHP or 5-FU also significantly decreased the microvessel density when compared to these agents alone (P &lt; 0.05).

Conclusion: Apatinib and cytotoxic agents have synergistic inhibitory effects in gastric cancer. The combination of apatinib with these agents may bring efficacy benefit for advanced gastric cancer patients in clinical practice.

Citation Format: Jiuhuan Feng, Shukui Qin. Apatinib and cytotoxic agents showed synergistic inhibitory effects in gastric cancer cells and fluorescent xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2947.