Regional versus systemic delivery of recombinant vaccinia virus as suicide gene therapy for murine liver metastases.
OBJECTIVE
Specific and efficient tumor-targeted gene delivery is the major goal for successful cancer gene therapy.


BACKGROUND
A recombinant thymidine kinase-deleted vaccinia virus (vv) encoding the firefly luciferase (luc) reporter gene or the prodrug converter gene cytosine deaminase (CD) was constructed. The authors compared the extent, duration, and pattern of transgene (luc) expression in vivo after portal venous, intraperitoneal, or intravenous virus administration and survival after treatment with the vv containing CD followed by the prodrug 5-fluorocytosine (5-FC) in a murine model of disseminated liver metastases from colon cancer.


METHODS
Recombinant vv containing the luc transgene within the thymidine kinase locus was administered to mice with isolated liver metastases from an MC38 adenocarcinoma. Transgene expression was determined in tumor and organs at various time points. Tumor-bearing mice were treated with recombinant vv containing CD and 5-FC or with appropriate controls and followed for survival.


RESULTS
Tumor-specific gene delivery was achieved irrespective of administration route, with gene expression in tumors increased by up to 100,000-fold compared with normal tissues. There was significantly increased transgene expression in tumor after portal venous or intraperitoneal virus administration (p = 0.001 vs. systemic). Treatment using a CD-expressing vv and systemic 5-FC resulted in a significant survival benefit in all treatment groups compared with controls (p < 0.007); there was no additional benefit for portal venous or intraperitoneal virus administration.


CONCLUSIONS
Suicide gene therapy using vv with the CD/5-FC system leads to tumor-specific gene expression and improved survival and can result in cure of established liver metastases.
Gnant
M F
MF
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Puhlmann
M
M
Bartlett
D L
DL
Alexander
H R
HR
D000230:Adenocarcinoma / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D000818:Animals; D043525:Cytosine Deaminase; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D008113:Liver Neoplasms / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009700:Nucleoside Deaminases / Q000235:genetics; D015996:Survival Rate; D014162:Transfection; D014616:Vaccinia virus / Q000235:genetics*
D008156:Luciferases; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase