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2-aminopurine enhances the oncolytic activity of an E1b-deleted adenovirus in hepatocellular carcinoma cells.

Sharon D, Schümann M, MacLeod S, McPherson R, Chaurasiya S, Shaw A, Hitt MM - PLoS ONE (2013)

Bottom Line: Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells.We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines.Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.

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Related in: MedlinePlus

2′AP increases the replication of an adenovirus with an E1b-55K deletion but not with a VA-RNA deletion.Cells were infected in duplicate with (A) Ad-dl309ΔVA, (B) Ad-dl1520, or (A and B) Ad-dl309 at a multiplicity of infection (MOI) of 1 plaque forming unit per cell (PFU/cell) 1 hour prior to treatment with medium containing no drug or 2.5 mM 2′AP. Cells and media were harvested at 1 hr (day 0) as well as 1, 2, 3 and 4 days post-infection. Virus yields were determined using plaques assays on HEK293 cells. Error bars correspond to +/−SD.
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pone-0065222-g002: 2′AP increases the replication of an adenovirus with an E1b-55K deletion but not with a VA-RNA deletion.Cells were infected in duplicate with (A) Ad-dl309ΔVA, (B) Ad-dl1520, or (A and B) Ad-dl309 at a multiplicity of infection (MOI) of 1 plaque forming unit per cell (PFU/cell) 1 hour prior to treatment with medium containing no drug or 2.5 mM 2′AP. Cells and media were harvested at 1 hr (day 0) as well as 1, 2, 3 and 4 days post-infection. Virus yields were determined using plaques assays on HEK293 cells. Error bars correspond to +/−SD.

Mentions: In order to determine the effect of deletions of VA-RNA genes and/or E1b-55K on adenovirus growth, we generated a series of time-courses of virus production in a panel of hepatocellular carcinoma (HCC) and normal cell lines (for clarity, these data are presented in Figures 2 and 3). Ad-dl309 was used as a VA-RNA and E1b positive control (Figure 1), and therefore, its production time-course was plotted in both figures 2 and 3.


2-aminopurine enhances the oncolytic activity of an E1b-deleted adenovirus in hepatocellular carcinoma cells.

Sharon D, Schümann M, MacLeod S, McPherson R, Chaurasiya S, Shaw A, Hitt MM - PLoS ONE (2013)

2′AP increases the replication of an adenovirus with an E1b-55K deletion but not with a VA-RNA deletion.Cells were infected in duplicate with (A) Ad-dl309ΔVA, (B) Ad-dl1520, or (A and B) Ad-dl309 at a multiplicity of infection (MOI) of 1 plaque forming unit per cell (PFU/cell) 1 hour prior to treatment with medium containing no drug or 2.5 mM 2′AP. Cells and media were harvested at 1 hr (day 0) as well as 1, 2, 3 and 4 days post-infection. Virus yields were determined using plaques assays on HEK293 cells. Error bars correspond to +/−SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672087&req=5

pone-0065222-g002: 2′AP increases the replication of an adenovirus with an E1b-55K deletion but not with a VA-RNA deletion.Cells were infected in duplicate with (A) Ad-dl309ΔVA, (B) Ad-dl1520, or (A and B) Ad-dl309 at a multiplicity of infection (MOI) of 1 plaque forming unit per cell (PFU/cell) 1 hour prior to treatment with medium containing no drug or 2.5 mM 2′AP. Cells and media were harvested at 1 hr (day 0) as well as 1, 2, 3 and 4 days post-infection. Virus yields were determined using plaques assays on HEK293 cells. Error bars correspond to +/−SD.
Mentions: In order to determine the effect of deletions of VA-RNA genes and/or E1b-55K on adenovirus growth, we generated a series of time-courses of virus production in a panel of hepatocellular carcinoma (HCC) and normal cell lines (for clarity, these data are presented in Figures 2 and 3). Ad-dl309 was used as a VA-RNA and E1b positive control (Figure 1), and therefore, its production time-course was plotted in both figures 2 and 3.

Bottom Line: Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells.We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines.Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co-administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdΔE1bΔVA without reducing its selectivity for HCC cells.

Show MeSH
Related in: MedlinePlus