Cancer Management and Research (May 2019)
Apatinib enhances chemosensitivity of gastric cancer to paclitaxel and 5-fluorouracil
Abstract
Zhiyuan Xu,1,* Can Hu,2,* Shangqi Chen,2 Chunli Zhang,3 Jianfa Yu,4 Xiaofeng Wang,2 Hang Lv,5 Xiangdong Cheng11Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 2First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System Tumor, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this work Background and aim: Paclitaxel (PTX) plus 5-fluorouracil (5-Fu) has become the standard chemotherapy for advanced gastric cancer (GC). Apatinib, a small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, improves outcomes in GC patients as a third-line treatment. However, its impact on the chemosensitivity of GC remains to be determined. Hence, we aimed to assess the efficacy and safety of apatinib combined with chemotherapy in vivo and in vitro.Methods: The MGC803 cell viability was determined by Cell Counting Kit-8 assay, and the interactions between apatinib and conventional cytotoxic agents revealed by combination index values were calculated using Calcusyn 2.0 software. We also used a zebrafish embryo xenograft model to validate the synergistic interactions. Furthermore, 4 patients with late-stage GC were enrolled to explore the efficacy and safety of PTX/Tegafur Gimeracil Oteracil Potassium (S1) (PS) chemotherapy plus apatinib in conversion surgery.Results: Apatinib showed synergistic interactions with both PTX and 5-Fu in vivo. The zebrafish embryo xenograft model also demonstrated that apatinib significantly enhanced the antitumor activity of PTX and 5-Fu. Apatinib plus PS chemotherapy was well tolerated before surgery. Objective response to preoperative SPA treatment was achieved in all 4 patients. No postoperative bleeding events or wound-healing complications were observed. No postperative morbidity occurred and no morbidity was encountered. Pathological examination showed that all patients had grade Ib pathological response.Conclusion: The experimental data suggested that apatinib improves the efficacy of PTX and 5-Fu both in vitro and in vivo. Clinical evidence showed that a combination of PS chemotherapy with apatinib may be an efficient and acceptable safety treatment for late-stage GC, especially in conversion surgery.Keywords: gastric cancer, apatinib, conversion surgery, targeted therapy
