Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5.
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 gamma(1)34.5 (a viral gene product that promotes the dephosphorylation of eIF-2alpha) 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). gamma(1)34.5 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-2alpha dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in gamma(1)34.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2alpha dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in gamma(1)34.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective gamma(1)34.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type gamma(1)34.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type gamma(1)34.5 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.
Nakamura
Hideo
H
Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Kasuya
Hideki
H
Mullen
John T
JT
Yoon
Sam S
SS
Pawlik
Timothy M
TM
Chandrasekhar
Soundararajalu
S
Donahue
James M
JM
Chiocca
E Antonio
EA
Chung
Richard Y
RY
Tanabe
Kenneth K
KK
D000818:Animals; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003588:Cytopathogenic Effect, Viral; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation; D019073:HT29 Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D015852:Eukaryotic Initiation Factor-2; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; C054366:herpes simplex virus type 1-protein ICP6; D012264:Ribonucleotide Reductases; D010749:Phosphoprotein Phosphatases