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Efficacy of Oncolytic Herpesvirus NV1020 Can Be Enhanced by Combination with Chemotherapeutics in Colon Carcinoma Cells
- Source :
- Human Gene Therapy. 17:1241-1253
- Publication Year :
- 2006
- Publisher :
- Mary Ann Liebert Inc, 2006.
-
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.
- Subjects :
- Combination therapy
Colorectal cancer
Antineoplastic Agents
Herpesvirus 1, Human
Virus Replication
Mice
In vivo
Cell Line, Tumor
Genetics
medicine
Animals
Humans
Cytotoxic T cell
Viability assay
Clonogenic assay
Molecular Biology
Mice, Inbred BALB C
business.industry
Genetic Therapy
medicine.disease
Combined Modality Therapy
Oncolytic virus
Oxaliplatin
Colonic Neoplasms
Immunology
Cancer research
Molecular Medicine
Fluorouracil
business
medicine.drug
Subjects
Details
- ISSN :
- 15577422 and 10430342
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Human Gene Therapy
- Accession number :
- edsair.doi.dedup.....4d885179a7bf100a647d2fede0d271a0