Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus.
We have generated a thymidine kinase gene-deleted vaccinia virus (VV) (Copenhagen strain) that expressed the fusion suicide gene FCU1 derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. Intratumoral inoculation of this thymidine kinase gene-deleted VV encoding FCU1 (VV-FCU1) in the presence of systemically administered prodrug 5-fluorocytosine (5-FC) produced statistically significant reductions in the growth of subcutaneous human colon cancer in nude mice compared with thymidine kinase gene-deleted VV treatments or with control 5-fluorouracil alone. A limitation of prodrug therapies has often been the requirement for the direct injection of the virus into relatively large, accessible tumors. Here we demonstrate vector targeting of tumors growing subcutaneously following systemic administration of VV-FCU1. More importantly we also demonstrate that the systemic injection of VV-FCU1 in nude mice bearing orthotopic liver metastasis of a human colon cancer, with concomitant administration of 5-FC, leads to substantial tumor growth retardation. In conclusion, the insertion of the fusion FCU1 suicide gene potentiates the oncolytic efficiency of the thymidine kinase gene-deleted VV and represents a potentially efficient means for gene therapy of distant metastasis from colon and other cancers.
Foloppe
J
J
Transgene SA, 11 rue de Molsheim, Strasbourg Cedex, France.
Kintz
J
J
Futin
N
N
Findeli
A
A
Cordier
P
P
Schlesinger
Y
Y
Hoffmann
C
C
Tosch
C
C
Balloul
J-M
JM
Erbs
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000628:therapy*; D043525:Cytosine Deaminase / Q000235:genetics; D005437:Flucytosine / Q000627:therapeutic use; D018390:Gene Targeting; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007267:Injections; D008113:Liver Neoplasms / Q000556:secondary / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D010430:Pentosyltransferases / Q000235:genetics; D011355:Prodrugs / Q000627:therapeutic use; D014161:Transduction, Genetic / Q000379:methods*; D014183:Transplantation, Heterologous; D014616:Vaccinia virus / Q000235:genetics*; D014779:Virus Replication
D000970:Antineoplastic Agents; D011355:Prodrugs; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase