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.