Modified vaccinia virus Ankara as a vector for suicide gene therapy.
Modified vaccinia virus Ankara (MVA) has been used successfully to express various antigens for the development of vaccines. Here we show that MVA can also be used as an efficient vector for the transfer of suicide genes to cancer cells. We have generated a new and highly potent suicide gene, FCU1, which encodes a fusion protein derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We now describe the therapeutic benefit of using MVA to deliver and express the FCU1 gene in cancer cells. MVA-mediated transfer of the FCU1 gene to various human tumor cells results in the production of a bifunctional intracellular enzyme, such that exposure to the prodrug 5-FC suppresses the growth of the tumor cells both in vitro and in vivo. Moreover, we report a more potent tumor growth delay at lower doses of 5-FC using MVA-FCU1 in comparison to adenovirus encoding FCU1. Prolonged therapeutic levels of cytotoxic 5-FU were detected in tumors in mice treated with both MVA-FCU1 and 5-FC while no detectable 5-FU was found in the circulation. This original combination between MVA and FCU1 represents a potentially safe and attractive therapeutic option to test in man.
Erbs
P
P
Transgene S.A., 11 rue de Molsheim, Strasbourg Cedex, France. erbs@transgene.fr
Findeli
A
A
Kintz
J
J
Cordier
P
P
Hoffmann
C
C
Geist
M
M
Balloul
J-M
JM
D000256:Adenoviridae; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D045744:Cell Line, Tumor; D002642:Chick Embryo; D043525:Cytosine Deaminase / Q000096:biosynthesis / Q000235:genetics*; D005437:Flucytosine / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D010430:Pentosyltransferases / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014161:Transduction, Genetic; D014616:Vaccinia virus / Q000201:enzymology / Q000235:genetics*
D000963:Antimetabolites; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase