Abstract
Oncolytic virotherapy is a promising therapeutic approach for the treatment of cancer. TG6002 is a recombinant oncolytic vaccinia virus deleted in the thymidine kinase and ribonucleotide reductase genes and armed with the suicide gene FCU1, which encodes a bifunctional chimeric protein that efficiently catalyzes the direct conversion of the nontoxic 5-fluorocytosine into the toxic metabolite 5-fluorouracil. In translational research, canine tumors and especially mammary cancers are relevant surrogates for human cancers and can be used as preclinical models. Here, we report that TG6002 is able to replicate in canine tumor cell lines and is oncolytic in such cells cultured in 2D or 3D as well as canine mammary tumor explants. Furthermore, intratumoral injections of TG6002 lead to inhibition of the proliferation of canine tumor cells grafted into mice. 5-fluorocytosine treatment of mice significantly improves the anti-tumoral activity of TG6002 infection, a finding that can be correlated with its conversion into 5-fluorouracil within infected fresh canine tumor biopsies. In conclusion, our study suggests that TG6002 associated with 5-fluorocytosine is a promising therapy for human and canine cancers.
Highlights
Cancer is one of the leading causes of death for both humans and pet animals
Susceptibility of Human and Canine Tumor Cell Lines To evaluate the relative ability of double-deleted vaccinia virus (VACV) to enter and produce infectious progeny in canine tumor cells, we performed a replication assay in a canine mammary carcinoma cell line (REM134) and a canine tumor cell line (A72) in parallel with two well-known human cancer cell lines, HeLa and MDA-MB-231.21,22 As shown in Figure 1A, the A72 cell line produced the highest virus yield with an amplification factor of 2 Â 107 after infection at a multiplicity of infection (MOI) of 10À5; 20 times more than the amplification factor in HeLa, 500 times more than in MDA-MB-231, and 1,000 times more than in REM134
The REM134 cell line was the least productive for VACV replication but with an amplification factor similar to that obtained in MDA-MB-231
Summary
Cancer is one of the leading causes of death for both humans and pet animals. Current treatment strategies involve surgery, radiation, chemotherapy, and immunotherapy. A genetically engineered herpes simplex virus (Imlygic) has been approved by the European Medicines Agency and the U.S Food and Drug Administration for the local treatment of unresectable melanoma.[1] Oncolytic viruses are naturally occurring or engineered viruses that selectively infect and replicate in cancer cells, inducing oncolysis and antitumoral immune responses while sparing healthy tissue. Targeting of these viruses to cancer cells is based on natural tropism and the deletion of viral genes required for replication in non-dividing cells.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
