Adenoviral vectors capable of replication improve the efficacy of HSVtk/GCV suicide gene therapy of cancer

Wildner, Oliver; Morris, John C.; Vahanian, Nicholas N.; Ford, Harry; Ramsey, W. Jay; Blaese, R. Michael

doi:10.1038/sj.gt.3300810

Cited by 148 publications

(106 citation statements)

References 35 publications

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“…Overexpression of the death protein, expression of TRAIL or deletion of the E1b-19kD gene, all have been shown to improve viral spread and efficacy of replicating adenoviruses in vitro and in vivo. 20,35,43,52,53 Various suicide genes [54][55][56][57][58] or TNF-a [59][60][61] have also been expressed with replication-competent vectors to improve cell killing, although with mixed results.…”

Section: Discussionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kD and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy.

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Section: Discussionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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“…The intrinsic oncolytic effects of E1B-55K-deleted adenoviruses could be significantly enhanced in several solid xenograft tumor models when prodrug (GCV alone or in combination with 5-fluorocytosine (5-FC)) was withheld until maximum vector replication and gene expression occurred. [68][69][70] However, GCV administration was not beneficial to the intrinsic oncolytic activity of an adenovirus (Ad.OW34) with a much more robust replication than the E1B-55K-deleted vector Ad.TK RC , expressing the entire adenovirus E1 region as well as HSV-tk under conditions that favor active viral replication and spread, 14 probably because the potential HSV-tk/GCV-mediated enhancement of the intrinsic viral oncolytic activity was balanced out by the virostatic effects of GCV.…”

Section: Discussionmentioning

confidence: 99%

“…These results also explain why the time point when GCV is given after intratumoral injection of the replication-competent vector expressing HSV-tk is crucial for its oncolytic effect. 70 In vitro and in vivo the effect of GCV on Ad.OW34 vector replication was significantly greater than that of CDV. The in vitro effect of ACV on Ad.OW34 vector replication was more than 100-fold lower compared to GCV.…”

Section: Discussionmentioning

confidence: 99%

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

et al. 2003

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Replication-competent adenoviral vectors hold the promise to be more efficient gene delivery vehicles than their replicationdeficient counterparts, but they are also associated with a higher risk for adverse effects, especially in light of the fact that there is no established effective therapy for serious, disseminated adenovirus infection. To assess whether the therapeutic options to inhibit adenoviral replication can be enhanced by expressing a suicide gene, we examined the antiadenoviral effects of 15 drugs against wild-type adenovirus type 5 (Ad5) and an Ad5-based replication-competent vector expressing herpes simplex virus-1 thymidine kinase (HSV-tk) (Ad.OW34) using a real-time polymerase chain reaction -based assay and flow cytometry. Ad5 and Ad.OW34 were highly susceptible to the fluorinated pyrimidine analogs 5-fluoro-2 0 -deoxyuridine (FUdR), 5-fluorouridine (FUR), and trifluorothymidine (TFT), with a mean 50% inhibitory concentration (IC 50 ) ranging from 0.12 to 0.32 mM. The mean IC 50 of ribavirin and cidofovir (CDV) for Ad5, the most frequently used drugs to treat adenovirus disease, was 6.87 and 3.19 mM, respectively. In contrast to Ad5, the Ad.OW34 vector was susceptible to (E)-5-(2-bromovinyl)-2 0 -deoxyuridine (BVdU, IC 50 0.09 mM), ganciclovir (GCV, IC 50 0.19 mM), and acyclovir (ACV, IC 50 32.04 mM). Additionally, we demonstrated in an animal model that Ad.OW34 vector replication can be inhibited significantly by GCV, CDV, and TFT by 35.2, 7.7, and 3.7-fold, respectively, compared to untreated animals. The observed antiadenoviral effects were primarily not through cell killing, since the in vitro 50% cytotoxic concentrations (CC 50 ) were more than 1000 times higher than the antiadenoviral IC 50 of the drugs examined, even in cells stably expressing HSV-tk. Since for HSV-tk-dependent inhibition of adenoviral vectors, stability of HSV-tk expression is crucial, we examined Ad.OW34 vector stability, by passaging the vector 10 times serially in the presence of 10 mM GCV. The HSV-tk/GCV system neither changed the susceptibility of Ad.OW34 to GCV significantly nor detectable vector rearrangements occurred, suggesting that the system might be suitable as a fail-safe mechanism to stop adenoviral vector replication.

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“…Another Ad, Ad.TK RC was generated with the CMV-IE promoter driving the HSV-TK, Ad5 E1a and E1b 19 kDa genes and deletion of E1b 55 kDa gene and E3 region. 38 In combination with gancyclovir, this Ad showed a significant increase in survival of animals in a human melanoma xenograft model in athymic nude mice. However, the use of the CMV promoter limited its effective translational use because of toxicity toward normal cells.…”

Section: Introductionmentioning

confidence: 96%

A cancer terminator virus eradicates both primary and distant human melanomas

Sarkar

et al. 2008

Cancer Gene Ther

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The prognosis and response to conventional therapies of malignant melanoma inversely correlate with disease progression. With increasing thickness, melanomas acquire metastatic potential and become inherently resistant to radiotherapy and chemotherapy. These harsh realities mandate the design of improved therapeutic modalities, especially those targeting metastases. To develop an approach to effectively treat this aggressive disease, we constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV produces large quantities of MDA-7/IL-24 protein as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal human immortal melanocytes and human melanoma cells demonstrates cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 CTV into xenografts derived from MeWo human metastatic melanoma cells in athymic nude mice completely eliminated not only primary treated tumors but also distant non-treated tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for treating patients with advanced melanomas with metastases.

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Adenoviral vectors capable of replication improve the efficacy of HSVtk/GCV suicide gene therapy of cancer

Cited by 148 publications

References 35 publications

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs

A cancer terminator virus eradicates both primary and distant human melanomas

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