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Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma.

Buijs P, van Nieuwkoop S, Vaes V, Fouchier R, van Eijck C, van den Hoogen B - Viruses (2015)

Bottom Line: However, expression of interferon, but not NS1, resulted in loss of multicycle replication.Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F₃aa resulted in regression of tumors.We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. p.buijs@erasmusmc.nl.

ABSTRACT
Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F₀) or an IFN antagonistic protein (rNDV-NS1-F₀), as well as rNDV with increased virulence (rNDV-F₃aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F₃aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ -F₀, while inoculation with rNDV-NS1-F₀ resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F₃aa caused markedly more cytotoxicity compared to rNDV-F₀, while inoculation with rNDVβ-hIFN -F₀ and rNDV-NS1-F₀ induced cytotoxic effects comparable to those induced by the parental rNDV-F₀. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F₃aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.

No MeSH data available.


Related in: MedlinePlus

Replication kinetics of rNDVs in 6 different human pancreatic adenocarcinoma cell lines (HPACs). Cells were inoculated in triplo with m.o.i. 0.1 and samples were taken at indicated time points and titrated by end-point dilution assay in Vero-118 cells. Means and standard deviations of duplicate titrations are plotted. H.p.i.: hours post inoculation. * = p < 0.05 vs. rNDV-F0 (one-way ANOVA + Bonferroni post-test), tested for time points 24, 48 and 96 h.p.i.
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viruses-07-02756-f002: Replication kinetics of rNDVs in 6 different human pancreatic adenocarcinoma cell lines (HPACs). Cells were inoculated in triplo with m.o.i. 0.1 and samples were taken at indicated time points and titrated by end-point dilution assay in Vero-118 cells. Means and standard deviations of duplicate titrations are plotted. H.p.i.: hours post inoculation. * = p < 0.05 vs. rNDV-F0 (one-way ANOVA + Bonferroni post-test), tested for time points 24, 48 and 96 h.p.i.

Mentions: Upon inoculation, no significant differences were observed for replication of the lentogenic viruses rNDV-F0, rNDV-GFP-F0, and rNDV-NS1-F0 on all cellsSU.86.86 and PHPAF-II cells supported replication of these viruses to high titers, while replication was less efficient in the other four cell lines (Figure 2).


Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma.

Buijs P, van Nieuwkoop S, Vaes V, Fouchier R, van Eijck C, van den Hoogen B - Viruses (2015)

Replication kinetics of rNDVs in 6 different human pancreatic adenocarcinoma cell lines (HPACs). Cells were inoculated in triplo with m.o.i. 0.1 and samples were taken at indicated time points and titrated by end-point dilution assay in Vero-118 cells. Means and standard deviations of duplicate titrations are plotted. H.p.i.: hours post inoculation. * = p < 0.05 vs. rNDV-F0 (one-way ANOVA + Bonferroni post-test), tested for time points 24, 48 and 96 h.p.i.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4488723&req=5

viruses-07-02756-f002: Replication kinetics of rNDVs in 6 different human pancreatic adenocarcinoma cell lines (HPACs). Cells were inoculated in triplo with m.o.i. 0.1 and samples were taken at indicated time points and titrated by end-point dilution assay in Vero-118 cells. Means and standard deviations of duplicate titrations are plotted. H.p.i.: hours post inoculation. * = p < 0.05 vs. rNDV-F0 (one-way ANOVA + Bonferroni post-test), tested for time points 24, 48 and 96 h.p.i.
Mentions: Upon inoculation, no significant differences were observed for replication of the lentogenic viruses rNDV-F0, rNDV-GFP-F0, and rNDV-NS1-F0 on all cellsSU.86.86 and PHPAF-II cells supported replication of these viruses to high titers, while replication was less efficient in the other four cell lines (Figure 2).

Bottom Line: However, expression of interferon, but not NS1, resulted in loss of multicycle replication.Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F₃aa resulted in regression of tumors.We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. p.buijs@erasmusmc.nl.

ABSTRACT
Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F₀) or an IFN antagonistic protein (rNDV-NS1-F₀), as well as rNDV with increased virulence (rNDV-F₃aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F₃aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ -F₀, while inoculation with rNDV-NS1-F₀ resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F₃aa caused markedly more cytotoxicity compared to rNDV-F₀, while inoculation with rNDVβ-hIFN -F₀ and rNDV-NS1-F₀ induced cytotoxic effects comparable to those induced by the parental rNDV-F₀. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F₃aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.

No MeSH data available.


Related in: MedlinePlus