Clinical Trials of Adenoviruses in Brain Tumors: A Review of Ad-p53 and Oncolytic Adenoviruses

Vecil, Giacomo G.; Lang, Frederick F.

doi:10.1023/b:neon.0000003653.45635.32

Cited by 85 publications

(54 citation statements)

References 65 publications

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“…Clinical trials of adenovirus in brain tumours were reviewed by Vecil et al [27]. The therapy strategies differ between the genes used something which might influence the possible course of events if normal cells "by mistake" become the target cells.…”

Section: Discussionmentioning

confidence: 99%

Cell type- and region- dependent coxsackie adenovirus receptor expression in the central nervous system

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Cell type- and region- dependent coxsackie adenovirus receptor expression in the central nervous system

et al. 2005

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“…1 Unfortunately, despite its potential, the efficacy of CRAd virotherapy as a monotherapeutic agent in clinical trials has so far been limited. 2,3 Combination treatment with chemotherapy has been explored, and it has been shown to be significantly more effective [4][5][6] However, conventional chemotherapy is always limited by its associated toxicity. As an alternative, the tumour cell activation of non-toxic prodrugs to produce cytotoxic derivatives by suicide systems has the potential to overcome the dose-limiting toxicity of chemotherapy and achieve a superior antitumoural effect when combined with virotherapy.…”

Section: Introductionmentioning

confidence: 99%

GCV modulates the antitumoural efficacy of a replicative adenovirus expressing the TAT8-TK as a late gene in a pancreatic tumour model

et al. 2007

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Replication-competent adenoviruses carrying the herpes simplex thymidine kinase (TK) gene have shown contradictory evidence with regard to their antitumoural efficacy in combination with ganciclovir (GCV) treatment. We generated a replication-competent adenovirus carrying Tat8-TK, a modified form of the TK gene, under the control of the adenoviral major late promoter (AdRGDTat8-TK-L). Pancreatic cancer cell lines with different sensitivity to the TK/ GCV system were infected with AdRGDTat8-TK-L, both in the presence and absence of GCV, and tested for treatment efficacy. We observed that, although the presence of GCV reduced viral replication in all infected cell lines, in three out of four GCV significantly enhanced the efficacy of the virotherapy. Interestingly, the cytotoxicity of the AdRGDTat8-TK-L/GCV was found more potent than that of a first generation AdTK/GCV system. In tumour xenografts from BxPC-3 and NP-18 pancreatic cells, both AdRGDTat8-TK-L and AdRGDTat8-TK-L/GCV treatment showed antitumoural activity. In BxPC-3 tumours scheduling of virus and prodrug was a key factor to determine the outcome of the therapy. Importantly, the addition of GCV enhanced the antitumoural effect of AdRGDTat8-TK-L only when applied in two rounds of virus+GCV. Interestingly, in spite of interfering with viral replication in vitro, GCV treatment of NP-18 tumours did not compromise the antitumoural efficacy of the AdRGDTat8-TK-L adenovirus. Thus, our results show that the combination therapy of a replicative adenovirus and the Tat8-TK/GCV suicide system can prove beneficial, when the appropriate regimen of virus and GCV is applied.

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“…15 A phase I trial provided compelling evidence that re-establishment of wtp53 functions by introduction of exogenous wtp53 is a feasible approach. 7,10 However, expression of recombinant wtp53 in glioma cells effectively activates the p53-dependent cell cycle checkpoints, but fails to induce apoptosis, 10 which from a therapeutic point of view would be the most desired outcome. 16 An alternative approach to activate the p53-dependent apoptotic response is based on the ability of some agents to activate the endogenous p53 pathway either by DNA-damaging agents or by the agents that can stabilize p53 protein in the absense of DNA damage.…”

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confidence: 99%

Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

et al. 2010

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Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy.

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Clinical Trials of Adenoviruses in Brain Tumors: A Review of Ad-p53 and Oncolytic Adenoviruses

Cited by 85 publications

References 65 publications

Cell type- and region- dependent coxsackie adenovirus receptor expression in the central nervous system

Cell type- and region- dependent coxsackie adenovirus receptor expression in the central nervous system

GCV modulates the antitumoural efficacy of a replicative adenovirus expressing the TAT8-TK as a late gene in a pancreatic tumour model

Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

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