A triple regulated oncolytic adenovirus armed with IL-24
A triple regulated oncolytic adenovirus armed with IL-24
Name of the Drug: Ad·sp·E1A(∆24)·E1B(∆55)·IL-24
Adenoviruses carry proteins with them, which change cellular mechanisms inside the host cell, in a way that makes it possible for the virus to be reproduced by the host and to induce cell lysis at the end of the viral replication cycle. These alterations of the host cell share some characteristics with cancer cells, namely extended stimulation of the cell cycle and inhibition of apoptosis. Since this cancer like conditions are required, a virus without the ability to create this conditions on it self, would only replicate in cancer cells and could therefore have oncolytic effects.
Oncolytic adenoviruses present a recent approach to achieve virus induced cell lysis in cancer cells but not in other healthy cells. The first presented oncolytic virus ONYX-15 consisted of an Adenovirus that was deleted in its 55kDa gene for E1B. E1B was believed to be involved in degradation of p53. Therefore ONYX-15 would only be replicated by cells with impaired p53-function. Most human cancers include mutations in p53 or its downstream players. Unfortunately ONYX-15 was slightly capable of infecting normal replicating cells and normal non-replicating cells (Xiao et al., 2010). This may be due to E1B having another function than previously believed. E1B has more recently been shown to be responsible for late viral RNA-export rather than breakdown of p53. Therefore an altered mechanism of RNA-export in cancer cells may be responsible for the selectivity of E1B restricted adenoviruses (O 'Shea et al., 2004).
Figure 1 Schematic structure of the genomes of all viruses discussed (Adapted from Xiao et al., 2010): Promoters or genes, which have not been changed in any of the viruses, are not shown. (ITR: inverted terminal repeat; hSurP: human Survivin promoter; E1B∆55: deletion of the complete gene for the 55kDa E1B protein; E1A∆24: deletion of 24bp form the E1A gene; CMV:
Name of the Drug: Ad·sp·E1A(∆24)·E1B(∆55)·IL-24
Adenoviruses carry proteins with them, which change cellular mechanisms inside the host cell, in a way that makes it possible for the virus to be reproduced by the host and to induce cell lysis at the end of the viral replication cycle. These alterations of the host cell share some characteristics with cancer cells, namely extended stimulation of the cell cycle and inhibition of apoptosis. Since this cancer like conditions are required, a virus without the ability to create this conditions on it self, would only replicate in cancer cells and could therefore have oncolytic effects.
Oncolytic adenoviruses present a recent approach to achieve virus induced cell lysis in cancer cells but not in other healthy cells. The first presented oncolytic virus ONYX-15 consisted of an Adenovirus that was deleted in its 55kDa gene for E1B. E1B was believed to be involved in degradation of p53. Therefore ONYX-15 would only be replicated by cells with impaired p53-function. Most human cancers include mutations in p53 or its downstream players. Unfortunately ONYX-15 was slightly capable of infecting normal replicating cells and normal non-replicating cells (Xiao et al., 2010). This may be due to E1B having another function than previously believed. E1B has more recently been shown to be responsible for late viral RNA-export rather than breakdown of p53. Therefore an altered mechanism of RNA-export in cancer cells may be responsible for the selectivity of E1B restricted adenoviruses (O 'Shea et al., 2004).
Figure 1 Schematic structure of the genomes of all viruses discussed (Adapted from Xiao et al., 2010): Promoters or genes, which have not been changed in any of the viruses, are not shown. (ITR: inverted terminal repeat; hSurP: human Survivin promoter; E1B∆55: deletion of the complete gene for the 55kDa E1B protein; E1A∆24: deletion of 24bp form the E1A gene; CMV:
References: See references for pictures or see https://www.dropbox.com/s/boazfx8wvp84fcr/XEROX.Oncolytic_adenovirus_layout.pdf Xiao, L. L., Wu, Y. M., Qian, J., et al. (2010) The antitumor efficacy of IL-24 mediated by E1A and E1B triple regulated oncolytic adenovirus. Cancer Biol Ther vol. 10 pp. 242-50 O 'Shea, C. C., Johnson, L., Bagus, B., et al. (2004) Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell vol. 6 pp. 611-23 Cory, A. H., Owen, T. C., Barltrop, J. A. and Cory, J. G. (1991) Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun vol. 3 pp. 207-12