Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

Abstract

Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1-10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 mM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1-10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg -1 ) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP.

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

“…Although multimodal approaches such as intraperitoneal chemotherapy and hyperthermic intraperitoneal chemoperfusion (HIPEC) have been explored32, there is no standard treatment to effectively prevent peritoneal dissemination. We recently reported that intraperitoneal administration of OBP-301 in combination with cisplatin efficiently suppresses the peritoneal dissemination of ovarian cancer cells in vivo 33. Intraperitoneal administration of OBP-401 is also useful for in vivo identification of peritoneally disseminated human cancer cells in fluorescence-guided surgery34.…”

Efficient virotherapy for osteosarcoma by telomerase-specific oncolytic adenovirus

“…Telomelysin (OBP-301), a telomerase-specific replicationselective adenovirus, has been shown to induce notable tumor-targeted oncolysis in a broad range of human cancers Watanabe et al 2006;Hashimoto et al 2008;Hioki et al 2008;Takakura et al 2010), and a phase I trial in patients with advanced solid tumors is currently in progress . In this study, we showed for the first time that this novel potential anti-tumor adenovirus, Telomelysin, induces apoptotic cell death-mediated oncolysis in human osteosarcoma both in vitro and in vivo.…”

“…We have therefore developed an oncolytic adenovirus (Telomelysin, in which the hTERT promoter controls the expression of E1A and E1B genes that are linked with an internal ribosome entry site (IRES; Kawashima et al 2004). Our previous studies demonstrated that Telomelysin exhibits tumor-restricted replication and excellent cytotoxicity against many different types of cancers, but not of normal cells or tissues Watanabe et al 2006;Hashimoto et al 2008;Hioki et al 2008;Takakura et al 2010). To the best of our knowledge, Telomelysin is the first hTERT-specific oncolytic adenovirus to be tested in a phase I clinical trial for various types of solid tumors.…”

Chemovirotherapy of Pancreatic Adenocarcinoma by Combining Oncolytic Vaccinia Virus GLV-1h68 with nab -Paclitaxel Plus Gemcitabine

“…High-dose combination therapy was actually unable to further increase the levels of tumor cell death already being induced by low-dose chemovirotherapy 59, 60. Furthermore, virus-mediated chemosensitization was shown to be powerful enough to render chemotherapy-resistant tumor cells sensitive for low-dose chemotherapy 61, 62…”