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.