Selectively replicating adenoviruses targeting deregulated E2F activity are potent, systemic antitumor agents.
We have engineered a human adenovirus, ONYX-411, that selectively replicates in human tumor cells, but not normal cells, depending upon the status of their retinoblastoma tumor suppressor protein (pRB) pathway. Early and late viral gene expression as well as DNA replication were significantly reduced in a functional pRB-pathway-dependent manner, resulting in a restricted replication profile similar to that of nonreplicating adenoviruses in normal cells both in vitro and in vivo. In contrast, the viral life cycle and tumor cell killing activity of ONYX-411 was comparable to that of wild-type adenovirus following infection of human tumor cells in vitro as well as after systemic administration in tumor-bearing animals.
Johnson
Leisa
L
Onyx Pharmaceuticals, Richmond, California 94806, USA. ljohnson@exelixis.com
Shen
Annie
A
Boyle
Larry
L
Kunich
John
J
Pandey
Kusum
K
Lemmon
Marilyn
M
Hermiston
Terry
T
Giedlin
Marty
M
McCormick
Frank
F
Fattaey
Ali
A
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics* / Q000472:pathogenicity; D000818:Animals; D000970:Antineoplastic Agents; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D004261:DNA Replication; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins; D003673:Defective Viruses; D050684:E2F Transcription Factors; D005347:Fibroblasts / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000473:pathology; D014779:Virus Replication / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D014157:Transcription Factors