Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of γ134.5 (a viral gene product that promotes the dephosphorylation of eIF-2α) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). γ134.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2α dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in γ134.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2α dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in γ134.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective γ134.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type γ134.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type γ134.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab’s to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo.
Hideo Nakamura, Hideki Kasuya, John T. Mullen, Sam S. Yoon, Timothy M. Pawlik, Soundararajalu Chandrasekhar, James M. Donahue, E. Antonio Chiocca, Richard Y. Chung, Kenneth K. Tanabe