Background: Scirrhous gastric cancer (SGC), which is characterized by poorly differentiated tumor cells that diffusely infiltrate the gastric wall, accounts for 10% of all gastric cancers, and often causes peritoneal metastasis. The prognosis of SGC patients is very poor, because no effective treatment to overcome peritoneal metastasis of SGC has been developed yet. In recent years, intraperitoneal (i.p.) administration of paclitaxel (PTX) has been focused against various cancers with peritoneal metastasis and has been also attempted to SGC, but regrettably its effect is not satisfactory. Therefore, a novel therapeutic strategy is required for the treatment of SGC with peritoneal metastasis.
Methods: We previously developed a telomerase-specific replication-competent adenovirus, OBP-401 (TelomeScan), which can replicate only within the tumor cells selectively and express green fluorescent protein (GFP). OBP-401 infection also induces tumor-specific cell death in monotherapy and combination therapy with chemotherapy. In this study, we assessed the in vitro and in vivo antitumor effects of combination therapy with OBP-401 and chemotherapeutic agent, paclitaxel (PTX), in human SGC cell lines (GCIY and KATO III) and SGC xenograft peritoneal metastasis model, respectively. The molecular mechanism underlying synergistic effect of the combination therapy was evaluated in aspects of cell death and replication efficiency of OBP-401.
Results: SGC cells were visualized as GFP-positive cells selectively by the infection of OBP-401, whereas normal fibroblast cells were not. OBP-401 synergistically suppressed the viability of human SGC cells in combination with PTX. OBP-401 monotherapy dose-dependently induced apoptosis and autophagy, although PTX monotherapy induced only apoptosis. The combination therapy induced autophagy at a lower concentration of OBP-401. In the time-lapse imaging of treatment, the combination therapy enhanced the replication efficiency of OBP-401 in tumor cells. Moreover, the combination therapy with i.p. administration of OBP-401 and PTX also significantly inhibited the tumor growth of peritoneal metastasis, as compared to monotherapy.
Conclusion: These results suggest that OBP-401 has a promising potential to detect peritoneal micrometastasis of SGC intraoperatively and the combination therapy with i.p. induction of OBP-401 and PTX would be a novel theranostic strategy for the treatment of SGC with peritoneal metastasis.
Citation Format: Wataru Ishikawa, Satoru Kikuchi, Hiroshi Tazawa, Toshiaki Ohara, Shinji Kuroda, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara. Novel theranostic strategy against peritoneal metastasis of scirrhous gastric cancer: Combination with fluorescence oncolytic adenovirus and chemotherapy [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 4807.