Efficacy of Oncolytic Herpesvirus NV1020 Can Be Enhanced by Combination with Chemotherapeutics in Colon Carcinoma Cells

Abstract

NV1020, an oncolytic herpes simplex virus type 1, can destroy colon cancer cells by selectively replicating within these cells, while sparing normal cells. NV1020 is currently under investigation in a clinical phase I/II trial as an agent for the treatment of colon cancer liver metastases, in combination with conventional chemotherapeutic agents such as 5-fluorouracil (5-FU), SN38 (the active metabolite of irinotecan), and oxaliplatin. To study the synergy of NV1020 and chemotherapy, cytotoxicity and viral replication were evaluated in vitro by treating various human and murine colon carcinoma cell lines, using a colorimetric viability assay, a clonogenic assay, and a plaque-forming assay. In vivo experiments, using a subcutaneous syngeneic CT-26 tumor model in BALB/c mice, were performed to determine the efficacy of combination therapy. In vitro studies showed that the efficacy of NV1020 on human colon carcinoma cell lines HT-29, WiDr, and HCT-116 was additively or synergistically enhanced in combination with 5-FU, SN38, or oxaliplatin. The sequence of application was not important and effects were still apparent after a 21-day incubation period. Three intra-tumoral treatments with NV1020 (1 x 10(7) plaque-forming units), followed by three subcutaneous treatments with 5-FU (50 mg/kg), resulted in substantially higher inhibition of tumor growth and prolongation of survival compared with monotherapies (NV1020/5-FU vs. NV1020, p = 0.027). On WiDr cells, reduced replication of NV1020, in combination with 5-FU, indicated that additive and synergistic effects of combination therapy must be independent from viral replication. These results suggest that NV1020, in combination with chemotherapy, is a promising therapy for treating patients with metastatic colorectal cancer of the liver. We hypothesize that infection of cells with NV1020 sensitizes the infected cells for the cytotoxic effect of the chemotherapeutics.

Oncolytic Herpes simplex virus expressing yeast cytosine deaminase: relationship between viral replication, transgene expression, prodrug bioactivation

“…Specifically, 5-FU has been shown to increase viral replication in vitro and extend animal survival in vivo (33). In addition the additive and synergistic effect of combining HSV-1 oncolysis with 5-FU (rather than bioactivation of 5-FC) has been reported as well (34). Several studies have suggested that enhancement of viral replication by chemotherapeutics leading to increased cell death could be a possible explanation for the detected synergistic effects (35–37).…”

Bugs and Drugs: Oncolytic Virotherapy in Combination with Chemotherapy

“…These synergistic effects allowed for a dose reduction for both virus and drug without compromising cytotoxicity [100]. Other oncolytic HSV-1 strains have also shown enhanced cytotoxicity in combination with 5-FU [88, 119]. The HSV-1 oncolytic strain G207 has been shown to synergize with 5-FU resulting in a prolonged survival of mice with peritoneal dissemination of gallbladder cancer.…”

Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling

“…While this does not always prove to be the case [39, 40], we hypothesized that the combination of RT and RT3D would result in an increase in viral replication, ultimately resulting in cell death. Our data clearly validated this hypothesis, with both one–step growth curves and plaque assays displaying a significant increase in viral replication with the addition of RT (Figure 3A, Supplementary Figure S2).…”