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Updated: Jun 3, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy
S Leveille1, S Samuel, M-L Goulet
1Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Abstract:
Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MΔ51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MΔ51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.
Insights
This study shows that combining oncolytic viruses (OVs) with the prodrug 5-fluorocytosine (5FC) enhances cancer cell killing. Optimizing this combination therapy is crucial for improving treatment efficacy and animal survival in cancer models.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Oncolytic viruses (OVs) are emerging as potent cancer therapeutics.
- Combining OVs with chemotherapy and suicide gene strategies can enhance efficacy.
- Recombinant vesicular stomatitis virus (VSV)-MΔ51 expressing cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) is a promising candidate.
Purpose of the Study:
- To investigate the synergistic activity of VSV-MΔ51/CD::UPRT and the prodrug 5-fluorocytosine (5FC) for cancer treatment.
- To evaluate the combination's efficacy in various cancer cell lines and a preclinical animal model.
- To optimize the treatment regimen for improved outcomes.
Main Methods:
- Utilized recombinant VSV-MΔ51 virus expressing the CD::UPRT suicide gene.
- Tested combination therapy in vitro across a panel of VSV-sensitive and -resistant cancer cells (PC3, MCF7, TSA, Karpas, B16-F10).
- Assessed synergistic effects with 5FC and 5-fluorouracil, monitored viral replication, and optimized 5FC bioavailability in vivo.
Main Results:
- The VSV-MΔ51/CD::UPRT and 5FC combination demonstrated enhanced killing of non-infected bystander cells in vitro.
- Synergistic cancer cell killing was observed with VSV-MΔ51 and 5-fluorouracil.
- Optimized treatment regimens improved survival in animals with TSA mammary adenocarcinoma.
Conclusions:
- The combination of VSV-CD::UPRT and 5FC exhibits significant potency for oncolysis.
- Optimizing each component of multicomponent cancer therapies is essential for designing effective treatments.
- This strategy holds promise for enhancing OV-based cancer therapy.
