Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer

Wataru Ishikawa,Satoru Kikuchi,Toshihiro Ogawa,Motoyasu Tabuchi,Hiroshi Tazawa,Shinji Kuroda,Kazuhiro Noma,Masahiko Nishizaki,Shunsuke Kagawa,Yasuo Urata,Toshiyoshi Fujiwara

doi:10.1016/j.omto.2020.06.021

Abstract

Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer, and the prognosis is extremely poor due to the resistance of systemic chemotherapy. Here, we demonstrate that intraperitoneal (i.p.) administration of a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency (OBP-401) synergistically suppressed the peritoneal metastasis of gastric cancer in combination with paclitaxel (PTX). OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX enhanced the antitumor effect of OBP-401 due to enhanced viral replication in cancer cells. The combination therapy increased induction of mitotic catastrophe, resulting in accelerated autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by i.p. administration of OBP-401 in an orthotopic human gastric cancer peritoneal dissemination model. PTX enhanced the deep penetration of OBP-401 into the disseminated nodules. Moreover, a non-invasive in vivo imaging system demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited growth of peritoneal metastatic tumors and the amount of malignant ascites. i.p. virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer.

Highlights

Peritoneal metastasis is the most common form of distant metastasis and recurrence in gastric cancer, and the prognosis remains extremely poor, even with current advanced modalities.[1,2,3] At present, no curative treatment options exist for peritoneal metastasis
To investigate the synergistic antitumor effect of OBP401 and PTX in human gastric cancer cells, we evaluated the effect of combination therapy visually using a live and dead assay
Calculation of the combination index indicated a synergistic antitumor effect of combination therapy in both types of human gastric cancer cells (Figure 1C). These results suggest that the combination of OBP-401 and PTX has a synergistic antitumor effect on human gastric cancer cells

Summary

Introduction

Peritoneal metastasis is the most common form of distant metastasis and recurrence in gastric cancer, and the prognosis remains extremely poor, even with current advanced modalities.[1,2,3] At present, no curative treatment options exist for peritoneal metastasis. Several phase III trials have demonstrated that i.p. chemotherapy has a survival benefit compared with systemic chemotherapy in patients with advanced ovarian cancer.[8,9,10] In gastric cancer with peritoneal metastasis, some phase II trials have demonstrated the effectiveness of i.p. paclitaxel (PTX), which can be retained in the peritoneal cavity for a long time due to its molecular characteristics including its large size and water insolubility, in addition to systemic chemotherapy.[11,12,13] Recently, a phase III trial has suggested the possibility of improved survival of i.p. PTX with systemic chemotherapy.[14] the outcome of gastric cancer patients with peritoneal metastasis is unsatisfactory, and new or improved strategies are needed

Methods

Results

Conclusion