Potentiation of oncolytic adenoviral vector efficacy with gutless vectors encoding GMCSF or TRAIL
Autor: | Paul L. Hallenbeck, J. Andrew Bristol, Kiran Sakhuja, Dawn B. Kayda, Michael Kaleko, Yvette Hudson, John L. Jakubczak, Sheila Connelly, David L. Ennist, Kevin D. Burroughs |
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Rok vydání: | 2004 |
Předmět: |
Cancer Research
Transgene Genetic Vectors Antineoplastic Agents Biology Adenoviridae Viral vector TNF-Related Apoptosis-Inducing Ligand Mice In vivo Cell Line Tumor Animals Humans Vector (molecular biology) Molecular Biology Gene Mice Inbred BALB C Membrane Glycoproteins Tumor Necrosis Factor-alpha Granulocyte-Macrophage Colony-Stimulating Factor Neoplasms Experimental Virology In vitro Oncolytic virus Cell culture Cancer research Molecular Medicine Female Apoptosis Regulatory Proteins Helper Viruses |
Zdroj: | Cancer Gene Therapy. 11:92-102 |
ISSN: | 1476-5500 0929-1903 |
Popis: | Oncolytic adenoviral vectors selectively replicate in and lyse human tumor cells, providing a promising means for targeted tumor destruction. However, oncolytic vectors have limited capacity for incorporation of additional genetic material that could encode therapeutic transgenes and/or transcriptional regulatory control elements to augment the efficacy and/or safety of the vector. Therefore, we hypothesized that coadministration of an oncolytic vector with a replication-defective, gutless adenoviral vector encoding a therapeutic transgene would result in replication of both vectors within a tumor and potentiate antitumor efficacy relative to the use of either vector alone. We constructed gutless vectors encoding the murine granulocyte-macrophage colony-stimulating factor (AGVmGMF) or human tumor necrosis factor alpha-related apoptosis-inducing ligand (AGVhTRAIL) gene and tested the ability of these vectors to augment the efficacy of an oncolytic vector (Ar6pAE2fE3F) in a potentiating vector strategy. In Hep3B cells in vitro, cotreatment with Ar6pAE2fE3F increased transgene expression from AGVhTRAIL and permitted replication of AGVhTRAIL, suggesting that an oncolytic vector can propagate gutless vector spread in vivo. In pre-established Hep3B xenograft tumors, neither gutless vector alone inhibited tumor growth; however, coadministration of AGVmGMF or AGVhTRAIL with Ar6pAE2fE3F significantly reduced tumor growth relative to Ar6pAE2fE3F alone. Additionally, use of AGVhTRAIL with Ar6pAE2fE3F increased the number of complete or partial tumor regressions observed at study end. These data provide evidence that coadministration of an oncolytic vector with a gutless vector holds promise for potentiating tumor ablation efficacy. |
Databáze: | OpenAIRE |
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