Replication efficiency of oncolytic @entity6621 in cell cultures prognosticates the virulence and antitumor efficacy in XXXX .

@entity1 @entity137 @entity0 @entity15821 @entity5 @entity19 @entity27874 @entity6621
BACKGROUND: We have shown that insertion of the three @entity6621 (VACV) promoter-driven foreign gene expression cassettes encoding Renilla luciferase-Aequorea GFP fusion protein, b-galactosidase, and b-glucuronidase into the F14.5L, J2R, and @entity27874 loci of the VACV LIVP genome, respectively, results in a highly attenuated mutant strain @entity15821 -1h68. This strain shows @entity5 -specific replication and is capable of eradicating @entity5 with little or no virulence in @entity19 . This study aimed to distinguish the contribution of added VACV promoter-driven transcriptional units as inserts from the effects of insertional inactivation of three viral genes, and to determine the correlation between replication efficiency of oncolytic @entity6621 in cell cultures and the virulence and antitumor efficacy in @entity19 METHODS: A series of recombinant VACV strains was generated by replacing one, two, or all three of the expression cassettes in @entity15821 -1h68 with short non-coding DNA sequences. The replication efficiency and @entity5 cell killing capacity of these newly generated VACV strains were compared with those of the parent virus @entity15821 -1h68 in cell cultures. The virus replication efficiency in @entity5 and antitumor efficacy as well as the virulence were evaluated in nu/nu ( @entity19 bearing @entity1 @entity0 xenografts. RESULTS: we found that virus replication efficiency increased with removal of each of the expression cassettes. The increase in virus replication efficiency was proportionate to the strength of removed VACV promoters linked to foreign genes. The replication efficiency of the new VACV strains paralleled their @entity137 in cell cultures. The increased replication efficiency in @entity5 xenografts resulted in enhanced antitumor efficacy in @entity19 . Similarly, the enhanced virus replication efficiency was indicative of increased virulence in @entity19 . CONCLUSIONS: These data demonstrated that insertion of VACV promoter-driven transcriptional units into the viral genome for the purpose of insertional mutagenesis did modulate the efficiency of virus replication together with antitumor efficacy as well as virulence. Replication efficiency of oncolytic VACV in cell cultures can predict the virulence and therapeutic efficacy in @entity19 . These findings may be essential for rational design of safe and potent VACV strains for vaccination and virotherapy of @entity5 in @entity1 and animals.
