p53/E1b58kDa Complex Regulates Adenovirus Replication

Ridgway, Patricia; Hall, Alexandra; Myers, Colleen J.; Braithwaite, Antony W.

doi:10.1006/viro.1997.8782

Cited by 31 publications

(44 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). The results obtained when U-251 MG cells were infected with both viruses (Ad5¢24 and Ad5CMV-p53) agree with previous reports that p53 can cooperate with other viral and cell proteins to enhance adenovirally mediated cell death (12).…”

Section: Resultssupporting

confidence: 90%

p53 enhances the Δ-24 conditionally replicative adenovirus anti-glioma effect

Mitlianga

Sioka²,

Vartholomatos³

et al. 2006

Oncol Rep

View full text Add to dashboard Cite

Abstract. Previous studies have demonstrated that the conditionally replicative adenovirus Ad5¢24 is a powerful cytolytic agent against glioma selectively affecting cells with a defective p16/Rb/E2F pathway. The p53 protein is also known to be an apoptotic factor for glioma cells. In this study, we examined the simultaneous delivery of the combination of exogenous p53 and Ad5¢24 adenovirus in glioma cells. Infecting cells with low doses of adenovirus p53 and Ad5¢24 resulted in an additive effect on cell death. The cell death induced by both agents was independent of the p53 status of cells. Flow cytometry revealed that the potent anti-tumor effect induced by the mixture of Ad5CMV-p53 and Ad5¢24 adenoviruses was due to a combination of apoptosis and cell lysis. Our results indicate that Ad5CMV-p53 enhances the oncolytic effect of the Ad5¢24 adenovirus, and the combination of adenovirus Ad5¢24 and Ad5CMV-p53 may thus be a potential therapeutic tool for gliomas. IntroductionMalignant gliomas are the most common primary brain tumors in humans, and highly resistant to all current therapies, including widely investigated approaches to gene therapy. At the molecular level, glioblastomas are highly heterogeneous tumors, as several populations of cells with different gene abnormalities co-exist within a given tumor (1). Secondary glioblastomas that develop from pre-existing low-grade astrocytomas frequently contain p53 mutations (1), and abnormalities of the p16/Rb/E2F pathway are present in most gliomas (2,3).Previous studies have demonstrated that the transfer of exogenous wild-type p53 cDNA causes apoptosis in glioma cells expressing endogenous mutant p53, but not in cells expressing endogenous wild-type p53 (4,5). However, only 50% of gliomas exhibit mutant p53, and the mutant cell population usually constitutes <30% of tumor mass (6).More than 90% of malignant gliomas exhibit abnormalities in the p16/Rb/E2F pathway (7). The adenovirus Ad5¢24 carries a 24-bp deletion in the E1 region corresponding to amino acids 122-129 specific for binding the Rb protein. This virus produces an anti-glioma effect in vitro and in vivo in tumors with altered p16/Rb/E2F pathway (8). The conditionally replicative adenoviruses (e.g. Ad5¢24 and ONYX-15) kill tumor cells selectively, and their replication leads to amplification of their oncolytic potential. Considerable preclinical data support this notion (8)(9)(10)(11). In this study, we tested if the combination of an apoptotic molecule (p53) with an oncolytic adenovirus (Ad5¢24) could have an additive effect on cell death in malignant glioma cells. Materials and methodsCell lines, adenoviral vectors, and infection conditions. The human glioma cell line U-251 MG was obtained from Dr W.K. Alfred Yung (Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX). U-87 MG was obtained from ATCC (Manassas, VA) and HFK (human kidney fibroblasts) from Dr T. Fotsis (Laboratory of Biological Chemistry, University of Ioannina Medical School, Ioannina, Greece). The conditionally replic...

show abstract

Section: Resultssupporting

confidence: 90%

p53 enhances the Δ-24 conditionally replicative adenovirus anti-glioma effect

Mitlianga

Sioka²,

Vartholomatos³

et al. 2006

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…Interestingly, D24 adenovirus induced cell death even in mutant-p53 cells such as U-251 MG glioma cells (Gomez-Manzano et al, 1996) and Saos-2 (Masuda et al, 1987). These results indicated that although p53 can cooperate with other viral and cell proteins to enhance adenovirallymediated cell death (Ridgway et al, 1997), wild-type p53 status was not a major determinant of ecient D24 replication and thus its oncolytic eect.…”

Section: Treatment With D24 Induces Entry Of Cells Into S Phase and Cmentioning

confidence: 96%

A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo

et al. 2000

View full text Add to dashboard Cite

Eective anti cancer strategies necessitate the use of agents that target tumor cells rather than normal tissues. In this study, we constructed a tumor-selective adenovirus, D24, that carries a 24-bp deletion in the E1A region responsible for binding Rb protein. Immunoprecipitation analyses veri®ed that this deletion rendered D24 unable to bind the Rb protein. However, titration experiments in 293 cells demonstrated that the D24 adenovirus could replicate in and lyse cancer cells with great eciency. Lysis of most human glioma cells was observed within 10 ± 14 days after infection with D24 at 10 PFU/cell. In vivo, a single dose of the D24 virus induced a 66.3% inhibition (P50.005) and multiple injections, an 83.8% inhibition (P50.01) of tumor growth in nude mice. However, normal ®broblasts or cancer cells with restored Rb activity were resistant to the D24 adenovirus. These results suggest that the E1A-mutant D24 adenovirus may be clinically and therapeutically useful against gliomas and possibly other cancers with disrupted Rb pathway. Oncogene (2000) 19, 2 ± 12.

show abstract

“…4,[6][7][8] However, these studies have produced considerable controversy. Using matched colon cancer cell lines Bischoff et al 4 reported reduced replication of ONYX-015 virus in the p53 transfectant cell line using burst assays as the measure of replication.…”

Section: Resultsmentioning

confidence: 99%

“…5 However, others have investigated the association between ONYX-015 viral replication and p53 status in a variety of cell lines and have reported no association. 6,7 Indeed, Hall et al 8 suggested that ONYX-015 induces cell death more efficiently in wildtype p53 containing cells, thus questioning the proposed selectivity of ONYX-015 for p53 deficient tumour cells. However, this study did not determine whether the mechanism of cell death was due to cytolysis induced by viral replication or virus-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis

Ganly¹,

Kim²,

Hann

et al. 2001

Gene Ther

View full text Add to dashboard Cite

Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic

show abstract

p53/E1b58kDa Complex Regulates Adenovirus Replication

Cited by 31 publications

References 45 publications

p53 enhances the Δ-24 conditionally replicative adenovirus anti-glioma effect

p53 enhances the Δ-24 conditionally replicative adenovirus anti-glioma effect

A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo

Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis

Contact Info

Product

Resources

About