Oncolytic adenovirus that overproduces ADP and replicates selectively in tumors due to hTERT promoter-regulated E4 gene expression.
We have constructed a novel oncolytic adenovirus (Ad) vector, named VRX-011, in which the replication of the vector is targeted to cancer cells by the replacement of the wild-type Ad E4 promoter with the human telomerase reverse transcriptase (hTERT) promoter. Genes in the Ad E4 transcription unit are essential for Ad replication; therefore, VRX-011 will grow efficiently only in cells in which the hTERT promoter is active, that is, in a wide range of cancer and immortalized cells but not in most somatic cells. Consistent with these expectations, VRX-011 replicated efficiently in all cancer cell lines examined, while its growth was restricted in various primary and normal cells. VRX-011 overexpresses ADP (also known as E3-11.6K), an Ad protein required for efficient cell lysis and release of virions from cells at late stages of infection. This overexpression enhances cell-to-cell spread and could significantly increase antitumor efficacy. In a xenograft model in nude mice, both intratumoral and intravenous administration of VRX-011 effectively suppressed the growth of subcutaneous Hep3B human liver tumors. Also, intravenous delivery of VRX-011 greatly reduced the number and size of A549 human lung cancer cell nodules in a disseminated lung tumor model in nude mice. Importantly, tail vein administration of different doses of VRX-011 in C57BL/6 mice showed minimal liver toxicity. Considering its broad range of lytic replication in cancer cells, its attenuated phenotype in primary cells, its efficacy in suppressing xenografts, and its low toxicity in mouse liver, VRX-011 is a promising candidate for further evaluation as an anticancer therapeutic.
Kuppuswamy
M
M
Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St Louis, MO 63104, USA.
Spencer
J F
JF
Doronin
K
K
Tollefson
A E
AE
Wold
W S M
WS
Toth
K
K
D000244:Adenosine Diphosphate / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D017504:Adenovirus E4 Proteins / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009369:Neoplasms / Q000628:therapy* / Q000821:virology; D009374:Neoplasms, Experimental; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes; D014779:Virus Replication
D017504:Adenovirus E4 Proteins; D004268:DNA-Binding Proteins; D000244:Adenosine Diphosphate; D019098:Telomerase