Antitumor efficacy of cytosine deaminase-armed vaccinia virus plus 5-fluorocytosine in colorectal cancers

Yuedi Ding,Lili Deng,Bin Zhou,Biao Huang,Jun Fan

doi:10.1186/s12935-020-01340-6

Abstract

BackgroundVaccinia viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Cytosine deaminase (CD), which is derived from bacteria or yeast, can convert a relatively nontoxic prodrug 5-fluorocytosine (5-FC) into the active anticancer drug 5-Fluorouracil (5-FU). Vaccinia virus armed with the prodrug-activator CD gene would result in augmented antitumor effects that combined the effect of vaccinia virus and 5-FU together, and particularly limited the anticancer drug to tumor regions.MethodsThe attenuated vaccinia Tian Tan strain Guang 9 (VG9), with active yeast CD expression and thymidine kinase (TK) deficiency, was successfully constructed. Then, in vitro and in vivo antitumor efficacy of vaccinia VG9-CD plus 5-FC administration was evaluated in colorectal cancer cells.ResultsVaccinia viruses displayed different oncolytic potency in vitro cells, no relationship with whether they were cancer cells or normal cells. In colorectal tumor models, mice treated with vaccinia VG9-TK− showed better tumor remission ability and prolonged survival. Moreover, vaccinia VG9-CD in combination with gavage administration of 5-FC displayed the best antitumor efficacy, especially for the prolongation of survival.ConclusionsVaccinia VG9-CD in combination with 5-FC plays combined effect of vaccinia virus and chemotherapy, and becomes a promising virotherapy for cancer.

Highlights

Vaccinia viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property
Characterization of vaccinia vaccinia Tian Tan strain Guang 9 (VG9)‐Cytosine deaminase (CD) The recombinant vaccinia VG9-CD was generated from attenuated Tian Tan vaccinia strain Guang9 and replaced Thymidine kinase (TK) gene of the VG9 by yeast CD gene with the shuttle plasmid pCB-CD
The plasmid profile of pCB-CD was shown in Fig. 1a. 10 strains of purified recombinants were obtained by 6 rounds of plaqued selection

Summary

Introduction

Vaccinia viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Vaccinia virus armed with the prodrug-activator CD gene would result in augmented antitumor effects that combined the effect of vaccinia virus and 5-FU together, and limited the anticancer drug to tumor regions. A number of therapeutic methods have been applied to colorectal cancer, surgical excision is an effective method to remove cancer lesions, cytotoxic drug are used as a first line of defense [5,6,7]. Ding et al Cancer Cell Int (2020) 20:243 therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property [17, 18]. Genetic insertion of therapeutic transgenes into the TK region, could express exogenous therapeutic proteins within the confines of the tumor, which lead to enhanced antitumor efficacy [20]

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Conclusion