2008
DOI: 10.1158/0008-5472.can-08-1145
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Bioselection of a Gain of Function Mutation that Enhances Adenovirus 5 Release and Improves Its Antitumoral Potency

Abstract: Genetic bioselection of a mutagenized Ad5wt stock in human tumor xenografts led us to isolate AdT1, a mutant displaying a large-plaque phenotype in vitro and an enhanced systemic antitumor activity in vivo. AdT1 phenotype correlates with an increased progeny release without affecting total viral yield in different human tumors and cancer-associated fibroblasts. An approach combining hybrid Ad5/AdT1 recombinants and sequencing identified a truncating insertion in the endoplasmic reticulum retention domain of th… Show more

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Cited by 57 publications
(62 citation statements)
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“…In this regard, we have previously demonstrated that a C-terminal mutation in the E3/19K protein enhances the release of adenovirus from the infected cell and improves its antitumoral efficacy. 30 Also, in a previous work, we demonstrated that the calcium channel blocker verapamil can improve the rate of adenovirus release and spread, enhancing the therapeutic activity of oncolytic adenoviruses. 6 We are currently analyzing whether the combination of these strategies with the expression of GALV will further enhance the antitumoral efficacy of the fusogenic adenovirus.…”
Section: Discussionmentioning
confidence: 86%
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“…In this regard, we have previously demonstrated that a C-terminal mutation in the E3/19K protein enhances the release of adenovirus from the infected cell and improves its antitumoral efficacy. 30 Also, in a previous work, we demonstrated that the calcium channel blocker verapamil can improve the rate of adenovirus release and spread, enhancing the therapeutic activity of oncolytic adenoviruses. 6 We are currently analyzing whether the combination of these strategies with the expression of GALV will further enhance the antitumoral efficacy of the fusogenic adenovirus.…”
Section: Discussionmentioning
confidence: 86%
“…Both viruses were amplified in A549 cells, purified on CsCl gradients according to standard techniques and quantified using the antihexon staining-based method using 293 cells. 30 Production assays A549 cells were infected with 25 TU per cell of each virus to allow for 80% to 100% infection. Four hours later, infection medium was removed; cells were washed twice with PBS and incubated with fresh medium.…”
Section: Methodsmentioning
confidence: 99%
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“…As viruses can manipulate or make use of the cytoskeletal network of actin filaments during their life cycles, (virus-induced) Rac1 activity has been linked to viral infection or protein trafficking processes as well as the spread of several viruses causing severe human diseases, for example, HIV (Lu et al, 1996), Ebola (Saeed et al, 2008), HSV-1 (Hoppe et al, 2006), HBV (Gros et al, 2008) and paramyxoviruses, for example, Hendra virus (Schowalter et al, 2006). From rodent experiments Rac1 is known to have oncogenic activity and to be involved in tumorigenesis (Kissil et al, 2007).…”
Section: Discussionmentioning
confidence: 99%
“…33 To more thoroughly evaluate the potential therapeutic benefit of M5, we compared it in parallel to its parental generation Adv5/dE1A and Adv5/dE1A/6.7K-gp19K. Although deletion of the E3 6.7K/gp19K region, which have antiapoptotic and immunity-evading function as reported, 35,36 could enhance antitumor efficacy versus Adv5/dE1A (Figure 4a), the tumoricidal effect of M5, characterized by apoptosis rate and cell viability, is still superior to that of Adv5/dE1A/6.7K-gp19K. Most strikingly, the tumoricidal effect of M5 exhibited not only in SiHa and HeLa cells, but also in HPV-negative CC cell lines C33A apparently.…”
Section: Discussionmentioning
confidence: 99%