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

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.

Oncolytic virotherapy with human telomerase reverse transcriptase promoter regulation enhances cytotoxic effects against gastric cancer

“…It was previously reported that hTERT expression is observed in most cancer cells, and almost no hTERT expression is observed in non-cancerous cells (44)(45)(46)(47). Moreover, a telomerase-specific oncolytic adenovirus, OBP-301, was found to considerably reduce tumor weight and increase survival in a nude mouse model of gastric cancer (48)(49)(50).…”

Intraperitoneal oncolytic virotherapy for patients with malignant ascites: Characterization of clinical efficacy and antitumor immune response

“… 21 Intraperitoneal administration of the oncolytic adenovirus OBP-401 demonstrated significant efficacy in treating peritoneal metastasis in a gastric cancer model. 22 A Phase I trial for the oncolytic vaccinia virus GL-ONC1 in patients with peritoneal carcinomatosis showed tolerability and efficient replication in cancer cells. 23 …”

Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer

“…administration of OBP-301 synergistically suppressed the peritoneal metastasis of GC in combination with paclitaxel (PTX). 18 In phase I clinical studies, OBP-301 was well tolerated by patients with various cancers. 19 , 20 We have further developed OBP-702 as a modification of OBP-301 that expresses the wild-type p53 gene, so OBP-702 can suppress the viability of various types of tumor cells more efficiently compared with OBP-301 via exogenous p53 overexpression in tumor cells.…”