Adenoviral TNF-α gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft

Staba, M J; Mauceri, Helena J.; Küfe, Donald; Hallahan, Dennis E.; Weichselbaum, Ralph R.

doi:10.1038/sj.gt.3300594

Cited by 114 publications

(56 citation statements)

References 33 publications

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“…It is still unclear if the response is mediated by the binding of a transcription factor, if it is due to a variation of DNA conformation after cellular redox change, or if DNA damage per se is the initiating signal. DNA vectors based on the Egr-1 promoter have been used for cancer gene therapy and shown efficacy when controlling the tumoricidal cytokine tumor necrosis factor (TNF)-a (Weichselbaum et al, 1994;Hallahan et al, 1995;Staba et al, 1998) or HSVtk/GCV GDEPT (Joki et al, 1995;Marples et al, 2000;Scott et al, 2002). We have shown for the first time that the combination of HREs and CArG elements can act as gene enhancers, responding to hypoxic and radiation stimuli, and can effectively control experimental suicide gene therapy (Greco et al, 2002a).…”

Section: Combined Hypoxia-and Radiation-targeted Gene Therapymentioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

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Section: Combined Hypoxia-and Radiation-targeted Gene Therapymentioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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“…34 We also reported significant tumor regression following treatment with TNF-a delivered using a replication-deficient adenoviral vector (Ad.Egr.TNF) combined with IR. [35][36][37] The Ad.Egr.TNF vector used in our studies contained the radiation-responsive DNA sequences of the EGR1 promoter ligated upstream of the cDNA for human TNF-a. The use of the radiationinducible promoter permitted spatial and temporal control of TNF-a expression within the tumor volume.…”

Section: Discussionmentioning

confidence: 99%

Selective gene expression using a DF3/MUC1 promoter in a human esophageal adenocarcinoma model

et al. 2003

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“…Previous studies by us and others have shown that local TNFa production provides multiple benefits to cancer gene therapy and include the recruitment of nonspecific antitumor cellular responses and increased the effectiveness of radiation therapy and GKR. [20][21][22] The expression of TNFa was vigorous during the initial phase of the study and rapidly declined to undetectable levels at 4 weeks postinoculation as documented by RT-PCR. We did not determine whether increased levels of TNF were present in the blood; however, the injected animals showed no behavioral changes or weight loss.…”

Section: Biodistributionmentioning

confidence: 99%

“…The synergistic effect of radiation and TNFa on a variety of tumors provides an additional combinatorial approach to increasing the effectiveness of experimental therapies. [17][18][19] Chung et al, 20 Rasmussen et al, 21 and Staba et al 22 found inducible TNF expression (TNFerade) combined with radiation was superior to either treatment alone. Similarly, the response to GKR was enhanced by sensitizing experimental tumors with vector-expressed TNFa using our HSV vector system in combination with GKR.…”

Section: Introductionmentioning

confidence: 99%

Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates

et al. 2004

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Malignant glioma is a fatal human cancer in which surgery, chemo-and radiation therapies are ineffective. Therapeutic gene transfer used in combination with current treatment methods may augment their effectiveness with improved clinical outcome. We have shown that NUREL-C2, a replication-defective multigene HSV-based vector, is effective in treating animal models of glioma. Here, we report safety and biodistribution studies of NUREL-C2 using rhesus macaques as a model host. Increasing total doses (1 Â 10 7 to 1 Â 10 9 plaque forming units (PFU)) of NUREL-C2 were delivered into the cortex with concomitant delivery of ganciclovir (GCV). The animals were evaluated for changes in behavior, alterations in blood cell counts and chemistry. The results showed that animal behavior was generally unchanged, although the chronic intermediate dose animal became slightly ataxic on day 12 postinjection, a condition resolved by treatment with aspirin. The blood chemistries were unremarkable for all doses. At 4 days following vector injections, magnetic resonance imaging showed inflammatory changes at sites of vector injections concomitant with HSV-TK and TNFa expression. The inflammatory response was reduced at 14 days, resolving by 1 month postinjection, a time point when transgene expression also became undetectable. Immunohistochemical staining following animal killing showed the presence of a diffuse low-grade gliosis with infiltrating macrophages localized to the injection site, which also resolved by 1 month postinoculation. Viral antigens were not detected and injected animals did not develop HSV-neutralizing antibodies. Biodistribution studies revealed that vector genomes remained at the site of injection and were not detected in other tissues including contralateral brain. We concluded that intracranial delivery of 1 Â 10 9 PFU NUREL-C2, the highest anticipated patient dose, was well tolerated and should be suitable for safety testing in humans.

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Adenoviral TNF-α gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft

Cited by 114 publications

References 33 publications

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Selective gene expression using a DF3/MUC1 promoter in a human esophageal adenocarcinoma model

Safety and biodistribution studies of an HSV multigene vector following intracranial delivery to non-human primates

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