Doxorubicin Synergizes with 34.5ENVE to Enhance Antitumor Efficacy against Metastatic Ovarian Cancer

Abstract

Purpose Novel therapeutic regimens are needed to improve dismal outcomes associated with late-stage ovarian cancer. Oncolytic viruses are currently being tested in patients with ovarian cancer. Here we tested the therapeutic efficacy of combining doxorubicin with 34.5ENVE, an oncolytic herpes simplex virus transcriptionally driven by a modified stem cell-specific nestin promoter, and encoding for anti-angiogenic Vasculostatin-120 (VStat120) for use against progressive ovarian cancer. Experimental Design Anti-tumor efficacy of 34.5ENVE was assessed in ovarian cancer cell lines, mouse ascites-derived tumor cells, and primary patient ascites-derived tumor cells by standard MTT assay. The ability of conditioned medium derived from 34.5ENVE-infected ovarian cancer cells to inhibit endothelial cell migration was measured by a transwell chamber assay. Scope of cytotoxic interactions between 34.5ENVE and doxorubicin were evaluated using Chou-Talalay synergy analysis. Viral replication, HSV receptor expression, and apoptosis were evaluated. Efficacy of oncolytic viral therapy in combination with doxorubicin was evaluated in vivo in the murine xenograft model of human ovarian cancer. Results Treatment with 34.5ENVE reduced cell viability of ovarian cancer cell lines, and mouse ascites-derived and patient ascites-derived ovarian tumor cells. Conditioned media from tumor cells infected with 34.5ENVE reduced endothelial cell migration. When combined with doxorubicin, 34.5ENVE killed synergistically with a significant increase in caspase-3/7 activation, and an increase in sub-G1 population of cells. The combination of doxorubicin and 34.5ENVE significantly prolonged survival in nude mice bearing intraperitoneal ovarian cancer tumors. Conclusions This study indicates significant antitumor efficacy of 34.5ENVE alone, and in combination with doxorubicin against disseminated peritoneal ovarian cancer.

Bortezomib Treatment Sensitizes Oncolytic HSV-1–Treated Tumors to NK Cell Immunotherapy

“…All cells were negative for mycoplasma . The construction and generation of 34.5ENVE has been previously described and virus was prepared and titered as previously described (6, 7). Virus was propagated in Vero cells as described (8).…”

“…Twenty-four hours later, 0.01 MOI of oHSV was added to the cells. 24 hrs after oHSV infection, 100 ul of Caspase 3/7 substrate was added to the cells for one hour and luminescence was measured by a Fluostar Optima plate reader (BMG Labtech) in triplicate as directed by the manufacturer (7). …”

“…72 hours after virus infection, cells and media were collected and frozen/thawed three times to release the viruses. The number of infectious particles present in the resulting supernatant was determined by performing a standard plaque forming unit assay on Vero cells (6, 7). All assays were performed in triplicate.…”

The chemotherapeutic potential of doxorubicin-loaded PEG-b-PLGA nanopolymersomes in mouse breast cancer model

“…Treatment possibilities for breast cancer mainly include radiation therapy, hormone therapy, surgical resection and chemotherapy [3].…”

Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells

“…32,33 Previous studies have shown combined application of oncolytic HSV-1 along with topoisomerase II inhibitors. 34 This study showed that combined application of a topoisomerase I inhibitor along with oncolytic HSV-1 improves oncolysis in vitro and prolonged the survival of tumor-bearing mice in vivo. Given the repertoire of DNA topoisomerase I functions, all the effects of topoisomerase I inhibition by SN-38 and irinotecan are not entirely ascribed to limited SRSF2 phosphorylation.…”