Replicative retroviral vectors for cancer gene therapy.
Poor efficiency of gene transfer into cancer cells constitutes the major bottleneck of current cancer gene therapy. We reasoned that because tumors are masses of rapidly dividing cells, they would be most efficiently transduced with vector systems allowing transgene propagation. We thus designed two replicative retrovirus-derived vector systems: one inherently replicative vector, and one defective vector propagated by a helper retrovirus. In vitro, both systems achieved very efficient transgene propagation. In immunocompetent mice, replicative vectors transduced >85% tumor cells, whereas defective vectors transduced <1% under similar conditions. It is noteworthy that viral propagation could be efficiently blocked by azido-thymidine, in vitro and in vivo. In a model of established brain tumors treated with suicide genes, replicative retroviral vectors (RRVs) were approximately 1000 times more efficient than defective adenoviral vectors. These results demonstrate the advantage and potential of RRVs and strongly support their development for cancer gene therapy.
Solly
Sounkary K
SK
Biologie et Thérapeutique des Pathologies Immunitaires, CNRS/UPMC UMR 7087, Hôpital Pitié-Salpêtrière, Paris, France.
Trajcevski
Stephane
S
Frisén
Charlotte
C
Holzer
Georg W
GW
Nelson
Elisabeth
E
Clerc
Béatrice
B
Abordo-Adesida
Evelyn
E
Castro
Maria
M
Lowenstein
Pedro
P
Klatzmann
David
D
D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008979:Moloney murine leukemia virus / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins