Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity

O’Shea, Clodagh C.; Johnson, Leisa; Bagus, Bridget; Choi, Serah; Nicholas, Cory R.; Shen, Annie; Boyle, Larry; Pandey, Kusum; Soria, Conrado; Kunich, John C.; Shen, Yuqiao; Habets, Gaston; Ginzinger, Dave; McCormick, Frank

doi:10.1016/j.ccr.2004.11.012

Cited by 336 publications

(316 citation statements)

References 63 publications

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“…The functions of E1B 55 kDa include p53 degradation, RNA export and host protein shutoff, and the loss of these functions is an important determinant of the tumor cell selectivity of the ZD55 virus. 27 Compared with nonreplicating adenoviral vectors, ZD55 selectively replicates in tumor cells and thereby augments the spread of therapeutic gene expression. We previously have reported that ZD55-delivering therapeutic genes (for example TRAIL and IL-24) suppresses tumor growth and induces tumor cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil

Chu

Sun

et al. 2008

Gene Ther

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Apollon, a membrane-associated inhibitor of apoptosis protein, protects cells against apoptosis and is upregulated in certain tumor cells. In this study, the effects of Apollon protein knockdown by RNA interference on the growth of human HeLa, HT-1080 and MCF-7 cells in vitro and in vivo were investigated. An oncolytic adenovirus (ZD55) containing the RNA polymerase III-dependent U6 promoter to express short hairpin RNA (shRNA) directed against Apollon (ZD55-siApollon) was constructed. Our data show that ZD55-siApollon successfully exerts a gene knockdown effect and causes the inhibition of tumor cell growth both in culture and in athymic mice in vivo. Cell cycle analysis, 4 0 ,6-diamidino-2-phenylindole staining and western blot analysis reveal that ZD55-siApollon-mediated suppression of Apollon induces apoptosis. Intratumoral injection of ZD55-siApollon significantly inhibits tumor growth in HT-1080 xenograft mice. Furthermore, ZD55-siApollon enhances the antitumor effect of 5-fluorouracil, a chemotherapeutic agent. In conclusion, these results suggest that the depletion of Apollon by oncolytic adenovirus-shRNA delivery system provides a promising method for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil

Chu

Sun

et al. 2008

Gene Ther

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“…32 This result was confirmed by other laboratory. 33 These two independent studies applied an E1B55K mutant R239A (ONYX-053), which produces a mutated E1B55K protein that specifically lacks the binding ability with p53. These studies demonstrated that loss of E1B55K function in inactivation of p53 or lack of E1B55K protein in dl1520 infection leads to accumulation of p53 in infected cells, as expected.…”

Section: Adenoviruses-induced Cell Cycle Changes In Hep3b and Saos2 Cmentioning

confidence: 99%

“…In addition, further studies showed that the viral RNA export functions of E1B55K is involved in viral replication and dl1520-sensitive tumor cells may provide with altered mechanisms of factors with E1B55K functions for RNA export. 33 Heat shock response rescues late viral RNA export and renders refractory tumor cells permissive to dl1520. 53 A specific question that we investigated in this study is how dl1520 can efficiently replicate in some cancer cells, but its replication is limited in other cancer cells.…”

Section: Adenoviruses-induced Cell Cycle Changes In Hep3b and Saos2 Cmentioning

confidence: 99%

“…[30][31][32] Recent reports show that infection with viruses deleted with E1B55K or expressing E1B55K that specifically lacks p53 binding function resulted in accumulation of p53 proteins. 32,33 The p53 protein accumulated in virus-infected cells is transcriptionally inactive. Expression of MDM and p21 (p53-responsive genes) was not affected by the increased p53.…”

Section: Introductionmentioning

confidence: 99%

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Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells

Zheng

et al. 2005

Cancer Gene Ther

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E1B55K-deleted dl1520 could selectively replicate in cancer cells and has been used in clinical trials as an antitumor agent. The mechanism of virus selective replication in cancer cells, including a possible role of p53, is unclear. Studies with established cancer cell lines have demonstrated that some cancer cells are resistant to dl1520 replication, regardless of the p53 status. Hep3B cells supported the E1b-deleted adenoviruses to replicate, whereas Saos2 cells were resistant to viral replication. We applied p53-null Hep3B and Saos2 cells as models to clarify the replication ability of E1B55K-deleted adenoviruses with different expression levels of E1a. We show that lower E1A expression in Saos2 may be the reason for the poor replication in some cancer cells due to the fact that E1a promoter was less activated in Saos2 than in Hep3B. We also demonstrate that the E1B55K protein can increase E1A expression in Saos2 cells for efficient virus replication. In addition, the upstream regions of the E1a promoter have transcriptional activity in Hep3B cells but not in Saos2 cells. The viral E1B55K protein may activate cancer cellular factor(s) that targets the upstream regions of the E1a gene to increase its expression. This is the first study demonstrating that E1B55K protein affects the E1A production levels that is related to cancer selective replication. Our studies have suggested that increase of E1A expression from E1b-deleted adenoviruses may enhance killing cancer cells that otherwise are resistant to viral replication.

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“…1,2 The replication of E1B-55 kDa-deleted adenovirus is severely impeded in normal cells compared with wild-type adenovirus, probably because the E1B-55 kDa protein functions in assisting late viral mRNA export from the nucleus. 3 Tumor cells can recover E1B-55 kDa function in late viral mRNA transportation to the cytoplasm. The concept of using an oncolytic virus in tumor treatment was exemplified by the development of H101, 4 a similar E1B-55 kDa-deleted type 5 adenovirus with additional deletions in the E3 region.…”

Section: Introductionmentioning

confidence: 99%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

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Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSPmediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 Â 10 7 to 3.0 Â 10 12 viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 Â 10 12 VP and transient grade IV thrombocytopenia at the dose of 3.0 Â 10 12 VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4 + and CD8 + T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

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Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity

Cited by 336 publications

References 63 publications

Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil

Oncolytic adenovirus-mediated shRNA against Apollon inhibits tumor cell growth and enhances antitumor effect of 5-fluorouracil

Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

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