Comparative Effect of Oncolytic Adenoviruses with E1 A or E113-55 kDa Deletions in Malignant Gliomas

Jiang, Hong; Gomez-Manzano, Candelaria; Alemany, Ramón; Medrano, Diana; Alonso, Marta M.; Bekele, B. Nebiyou; Lin, Eric W.; Conrad, Charles; Yung, W. K. Alfred; Fueyo, Juan

doi:10.1593/neo.04391

Cited by 32 publications

(20 citation statements)

References 22 publications

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“…Accordingly, we showed that infection of cancer cells with a mutant E1A adenovirus (D-39; ref. 19) unable to bind to and inactivate p300 did not modify the level of expression of MGMT (Fig. 4A).…”

Section: Resultsmentioning

confidence: 89%

Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter

Alonso¹,

Gomez-Manzano²,

et al. 2007

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Currently, the most efficacious treatment for malignant gliomas is temozolomide; however, gliomas expressing the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) are resistant to this drug. Strong clinical evidence shows that gliomas with methylation and subsequent silencing of the MGMT promoter are sensitive to temozolomide. Based on the fact that adenoviral proteins directly target and inactivate key DNA repair genes, we hypothesized that the oncolytic adenovirus #-24-RGD could be successfully combined with temozolomide to overcome the reported MGMTmediated resistance. Our studies showed that the combination of #-24-RGD and temozolomide induces a profound therapeutic synergy in glioma cells. We observed that #-24-RGD treatment overrides the temozolomide-mediated G 2 -M arrest. Furthermore, #-24-RGD infection was followed by downmodulation of the RNA levels of MGMT. Chromatin immunoprecipitation assays showed that #-24-RGD prevented the recruitment of p300 to the MGMT promoter. Importantly, using mutant adenoviruses and wild-type and dominantnegative forms of the p300 protein, we showed that #-24-RGD interaction with p300 was required to induce silencing of the MGMT gene. Of further clinical relevance, the combination of #-24-RGD and temozolomide significantly improved the survival of glioma-bearing mice. Collectively, our data provide a strong mechanistic rationale for the combination of oncolytic adenoviruses and temozolomide, and should propel the clinical testing of this therapy approach in patients with malignant gliomas. [Cancer Res 2007;67(24):11499-504]

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Section: Resultsmentioning

confidence: 89%

Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter

Alonso¹,

Gomez-Manzano²,

et al. 2007

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“…Nevertheless, dl1520 is a prototype agent which is rather attenuated even in tumor cells, when compared with wild-type adenovirus (25,40). In contrast, the 24-bp deletion in D24-based agents does not attenuate but may in fact increase replication of the virus (21), which could predict superior efficacy versus H101/dl1520, as already shown preclinically (21,42). The oncolytic potency of the viruses used here is further increased by capsid modification -mediated infectivity enhancement (40,43).…”

Section: Discussionmentioning

confidence: 99%

Infectivity-Enhanced Adenoviruses Deliver Efficacy in Clinical Samples and Orthotopic Models of Disseminated Gastric Cancer

Kangasniemi

Kiviluoto²,

Kanerva

et al. 2006

Clinical Cancer Research

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Purpose: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective and safe modality for the treatment of cancer. However, expression of the primary coxsackie-adenovirus receptor is variable in advanced cancers, and therefore, the use of heterologous receptors could be advantageous. Experimental Design: Here, we used capsid-modified adenoviruses for increasing the transduction and subsequent antitumor efficacy. 5/3 chimeric viruses have a serotype 3 knob which allows binding to a receptor distinct from coxsackie-adenovirus receptor.The fiber of Ad5lucRGD is modified with an integrin-targeted motif. Polylysine motifs, pK7 and pK21, bind to heparan sulfates. Oncolytic adenoviruses replicate in and kill tumor cells selectively. Gastric cancer cell lines and fresh clinical samples from patients were infected with transductionally targeted viruses. Capsid-modified oncolytic adenoviruses were used in cell killing experiments. To test viral transduction and therapeutic efficacy in vivo, we developed orthotopic mouse models featuring i.p. disseminated human gastric cancer, which allowed the evaluation of biodistribution and antitumor efficacy in a system similar to humans. Results: Capsid modifications benefited gene transfer efficiency and cell killing in gastric cancer cell lines and clinical samples in vitro and in vivo. Modified oncolytic adenoviruses significantly increased the survival of mice with orthotopic gastric cancer. Conclusions:These preclinical data set the stage for the clinical evaluation of safety and efficacy in patients with disease refractory to current modalities.

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“…They were then grown in serum-free medium for 24 h followed by transfection with 250 ng of a E2F-1-Luciferase reporter plasmid and 1 ng of pRL-CMV (expressing Renilla luciferase, Promega Life Science, Madison, MI) for normalization of transfection efficiency. 12 FuGENE 6 (Roche Molecular Biochemicals, Indianapolis, IN) was used for plasmid transfection. The cells were kept in serum-free medium for another 24 h and then harvested for luciferase activity assay, using Dual-Glot Luciferase Assay System (Promega Life Sceince) as instructed by the manufacturer.…”

Section: Western Blot Analysismentioning

confidence: 99%

Combination effect of oncolytic adenovirotherapy and TRAIL gene therapy in syngeneic murine breast cancer models

et al. 2005

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and oncolytic adenovirotherapy have been investigated extensively in xenografic human tumor models established in immunocompromised nude mice. However, the effects of these therapies on syngeneic murine tumors in immunocompetent settings were not well documented. We hypothesized that TRAIL gene therapy used with an oncolytic adenovirus would overcome the weaknesses of the two therapies used individually. In this study, we evaluated the antitumor effects of an oncolytic adenovirus, Delta24, in both human and murine breast cancer cell lines. We also analyzed the effects of TRAIL gene therapy combined with oncolytic virotherapy in these cancer cells. Our results showed that Delta24 can replicate and help the E1-deleted adenovector replicate in murine cancer cells. We also found that these two therapies combined had greater antitumor activity than either one alone in both human and murine breast cancer cells lines and in the syngeneic breast cancer models established in immunocompetent mice. Moreover, Delta24 virotherapy alone and combined with TRAIL gene therapy dramatically reduced the spontaneous liver metastasis that originated in the subcutaneous 4T1 tumor established in Balb/c mice. These findings provide important considerations in the development and preclinical assessments of oncolytic virotherapy.

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Comparative Effect of Oncolytic Adenoviruses with E1 A or E113-55 kDa Deletions in Malignant Gliomas

Cited by 32 publications

References 22 publications

Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter

Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter

Infectivity-Enhanced Adenoviruses Deliver Efficacy in Clinical Samples and Orthotopic Models of Disseminated Gastric Cancer

Combination effect of oncolytic adenovirotherapy and TRAIL gene therapy in syngeneic murine breast cancer models

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