Effect of murine liver cell proliferation on herpes viral behavior: implications for oncolytic viral therapy.
Replication-competent herpes simplex oncolytic viruses are promising anticancer agents that partly target increased DNA synthesis in tumor cells. Investigators have proposed that these DNA viruses may be combined with liver resection to enhance killing of liver malignancies. Whether or not the cellular alterations associated with hepatic regeneration affect the efficacy and toxicity of these promising anticancer agents is unknown. This study examined the behavior of two oncolytic viruses, NV1020 and G207, during liver regeneration. When delivered during the peak of liver regeneration, replication and appearance of both G207 and NV1020 in hepatic tissue are enhanced as demonstrated by histochemical staining for the marker gene lac Z, immunohistochemical staining, and quantitative polymerase chain reaction. This increased appearance of virus in liver tissue correlates with increases in cellular ribonucleotide reductase activity and DNA synthesis and is also associated with increased viral binding. However, increased viral presence is transient, and viral detection declines to baseline within 7 days. When these viruses were delivered to animals even as early as 7 days after hepatectomy, there proved to be no measurable viral replication in any organ and no increased morbidity or mortality. In conclusion, the early stages of hepatic regeneration after resection provide an environment suitable for viral replication. Administration of replication-competent herpes simplex virus during the peak of hepatocyte regeneration (24-48 hours) permits viral productivity in tissue that otherwise does not support viral growth. The increase in hepatotoxicity after hepatectomy is short-lived and can be predicted by peak hepatocyte DNA synthesis.
Delman
Keith A
KA
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Zager
Jonathan S
JS
Bhargava
Amit
A
Petrowsky
Henrik
H
Malhotra
Sandeep
S
Ebright
Michael I
MI
Bennett
Joseph J
JJ
Gusani
Niraj J
NJ
Kooby
David A
DA
Roberts
Gretchen D
GD
Fong
Yuman
Y
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D022781:Hepatocytes / Q000166:cytology*; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D014780:Viruses / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D001616:beta-Galactosidase / Q000096:biosynthesis
D001616:beta-Galactosidase