Considerations for intravascular administration of oncolytic herpes virus for the treatment of multiple liver metastases.
OBJECTIVE
Oncolytic viral therapy is a newly developed modality for treating tumors. Many clinical trials using oncolytic virus have been performed worldwide, but most of them have used local injection in the tumor. Determination of the effect and safety of intravascular virus injection instead of local injection is necessary for clinical use against multiple liver metastases and systemic metastases.


METHODS
To evaluate the efficacy and safety of intravascular virus therapy, mice bearing multiple liver metastases were treated by intraportal or intravenous administration of the herpes simplex virus type 1 (HSV-1) mutant, hrR3. Mice treated with hrR3 were killed and organs were harvested for lacZ staining and PCR analysis. Inactivation of oncolytic virus in bloodstream was assessed by neutralization assay in vitro. Infectious activity of hrR3 with vascular endothelial cells was evaluated by replication and cytotoxicity assay.


RESULTS
The survival rate of animals treated by hrR3 was significantly improved compared with the untreated group. lacZ staining and PCR analysis demonstrated detectable virus in the tumor but not in normal tissue or other organs except for the adrenal glands. We also showed that vascular endothelial cells allowed virus replication, while normal hepatocytes did not, and human anti-HSV antibody revealed attenuation of the infectious activity of hrR3.


CONCLUSIONS
Intravascular delivery of hrR3 is effective in treating multiple liver metastases, however, several points must be kept in mind at the time of human clinical trials using intravascular virus administration in order to avoid critical side effects.
Nomura
Naohiro
N
Department of Surgery II, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. sjypy948@yahoo.co.jp
Kasuya
Hideki
H
Watanabe
Izuru
I
Shikano
Toshio
T
Shirota
Takashi
T
Misawa
Makoto
M
Sugimoto
Hiroyuki
H
Kanazumi
Naohito
N
Nomoto
Shuji
S
Takeda
Shin
S
Nakao
Akimasa
A
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000201:enzymology / Q000821:virology; D005822:Genetic Vectors; D022781:Hepatocytes / Q000201:enzymology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007275:Injections, Intravenous; D007763:Lac Operon; D008113:Liver Neoplasms / Q000201:enzymology / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000096:biosynthesis; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D007074:Immunoglobulin G; D012264:Ribonucleotide Reductases