Abstract
In the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction cancer, it has been reported that the combination of trastuzumab with capecitabine plus cisplatin, or with 5-fluorouracil (5-FU) plus cisplatin, significantly increased overall survival compared with chemotherapy alone (ToGA trial). In addition, adjuvant therapy with capecitabine plus oxaliplatin (XELOX) improved the survival of patients who received curative D2 gastrectomy (CLASSIC trial). However, the efficacy of the combination of trastuzumab with XELOX for patients with HER2-positive gastric cancer remains unknown. The aim of this study, was to investigate the efficacy of the combination of trastuzumab with XELOX in a HER2-positive human gastric cancer xenograft model. Combination treatment with these three agents (trastuzumab 20 mg/kg, capecitabine 359 mg/kg and oxaliplatin 10 mg/kg), was found to exhibit a significantly stronger antitumor activity in NCI-N87 xenografts compared with either trastuzumab or XELOX alone. In this model, treatment with trastuzumab alone or trastuzumab plus oxaliplatin enhanced the expression of thymidine phosphorylase (TP), a key enzyme in the generation of 5-FU from capecitabine in tumor tissues. In in vitro experiments, trastuzumab induced TP mRNA expression in NCI-N87 cells. In addition, NCI-N87 cells co-cultured with the natural killer (NK) cell line CD16(158V)/NK-92 exhibited increased expression of TP mRNA. When NCI-N87 cells were cultured with CD16(158V)/NK-92 cells in the presence of trastuzumab, the mRNA expression of cytokines reported to have the ability to induce TP was upregulated in tumor cells. Furthermore, a medium conditioned by CD16(158V)/NK-92 cells also upregulated the expression of TP mRNA in NCI-N87 cells. These results suggest that trastuzumab promotes TP expression, either by acting directly on NCI-N87 cells, or indirectly via a mechanism that includes trastuzumab-mediated interactions between NK and NCI-N87 cells. Therefore, the combination of trastuzumab with XELOX may be a potent therapy for HER2-positive gastric cancer.