The oncolytic effect of recombinant vesicular stomatitis virus is enhanced by expression of the fusion cytosine deaminase/uracil phosphoribosyltransferase suicide gene.

Abstract

Vesicular stomatitis virus (VSV) has recently been demonstrated to exhibit significant oncolytic capabilities against a wide variety of tumor models in vitro and in vivo. To potentially enhance the oncolytic effect, we generated a novel recombinant VSV (rVSV) that expressed the fusion suicide gene Escherichia coli cytosine deaminase (CD)/uracil phosphoribosyltransferase (UPRT). rVSV encoding the CD/UPRT fusion gene (VSV-C:U) exhibited normal growth properties and generated high levels of biologically active CD/UPRT that could catalyze the modification of 5-fluorocytosine into chemotherapeutic 5-fluorouracil (5-FU), which exhibited considerable bystander effect. Intratumoral inoculation of VSV-C:U in the presence of the systemically administered prodrug 5-fluorocytosine produced statistically significant reductions in the malignant growth of syngeneic lymphoma (A20) or mammary carcinoma (TSA) in BALB/c mice compared with rVSV treatments or with control 5-FU alone. Aside from detecting prolonged therapeutic levels of 5-FU in VSV-C:U-treated animals harboring TSA tumors and enhancing bystander killing of tumor cells, we demonstrated marked activation of IFN-gamma-secreting cytotoxic T cells by enzyme-linked immunospot analysis that may have also facilitated tumor killing. In conclusion, the insertion of the fusion CD/UPRT suicide gene potentiates the oncolytic efficiency of VSV by generating a strong bystander effect and by contributing to the activation of the immune system against the tumor without detrimentally altering the kinetics of virus-mediated oncolysis and may be useful in the treatment of malignant disease.

• Authors: Mercedes Porosnicu, Abdul Mian, Glen N Barber
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 23 Pg. 8366-76 (Dec 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14678998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prodrugs
• Recombinant Fusion Proteins
• Flucytosine
• Pentosyltransferases
• uracil phosphoribosyltransferase
• Cytosine Deaminase
• Fluorouracil

Topics

• Animals
• Cell Line, Tumor
• Cytosine Deaminase (genetics, metabolism)
• Escherichia coli (enzymology, genetics)
• Flucytosine (pharmacokinetics)
• Fluorouracil (pharmacokinetics)
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Humans
• Mice
• Mice, Inbred BALB C
• Neoplasms, Experimental (enzymology, genetics, therapy)
• Pentosyltransferases (genetics, metabolism)
• Prodrugs (pharmacokinetics)
• Recombinant Fusion Proteins (genetics, metabolism)
• Vesicular stomatitis Indiana virus (enzymology, genetics, physiology)
• Virus Replication (physiology)