Telomerase-Dependent Gene Therapy

Wirth, Thomas; Kühnel, Florian; Kubicka, Stefan

doi:10.2174/1566524053586536

Cited by 32 publications

(31 citation statements)

References 45 publications

(52 reference statements)

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“…44 In the case of systemic delivery, to prevent detrimental expression of toxin in inappropriate tissues, SAP constructs could easily be improved with tissue and/or tumorspecific promoters. 7,9,[45][46][47][48][49] In addition, pharmacologically controlled gene expression could be ensured using inducible promoters such as the Tet-on system, which exhibits the best features for applications in patients because it permits rapid gene induction/silencing switch in vivo in a dose-dependent manner and its inducer doxycycline is widely used as an antibiotic and well tolerated in humans (Zabala et al 50 and references therein).…”

Section: Discussionmentioning

confidence: 99%

Saporin as a novel suicide gene in anticancer gene therapy

et al. 2006

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We used a non-viral gene delivery approach to explore the potential of the plant saporin (SAP) gene as an alternative to the currently employed suicide genes in cancer therapy. Plasmids expressing cytosolic SAP were generated by placing the region encoding the mature plant ribosome-inactivating protein under the control of cytomegalovirus (CMV) or simian virus 40 (SV40) promoters. Their ability to inhibit protein synthesis was first tested in cultured tumor cells co-transfected with a luciferase reporter gene. In particular, SAP expression driven by CMV promoter (pCI-SAP) demonstrated that only 10 ng of plasmid per 1.6 Â 10 4 B16 cells drastically reduced luciferase activity to 18% of that in control cells. Direct intratumoral injection of pCI-SAP complexed with either lipofectamine or N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate (DOTAP) in B16 melanoma-bearing mice resulted in a noteworthy attenuation of tumor growth. This antitumor effect was increased in mice that received repeated intratumoral injections. A SAP catalytic inactive mutant (SAP-KQ) failed to exert any antitumor effect demonstrating that this was specifically owing to the SAP N-glycosidase activity. Our overall data strongly suggest that the gene encoding SAP, owing to its rapid and effective action and its independence from the proliferative state of target cells might become a suitable candidate suicide gene for oncologic applications.

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Section: Discussionmentioning

confidence: 99%

Saporin as a novel suicide gene in anticancer gene therapy

et al. 2006

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“…Since the E1A protein has been identified and widely recognized to be essential for adenoviral replication and the production of progeny virions in human cells, a number of telomerase promoter-regulated adenoviral vectors retain E1A genes (17). Additionally, the catalytic component of hTERT is not expressed in the majority of primary somatic human cells, whereas major cancer cells are able to reactivate telomerase by transcriptional upregulation of hTERT (18).…”

Section: Discussionmentioning

confidence: 99%

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

Liu

Yang

et al. 2017

Oncol Lett

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Abstract. Gliomas are the most common type of primary brain tumor in adults, where more than half of the cases are malignant, and the prognosis is poor. The early viral 1A (E1A) protein has been widely recognized to be essential for adenoviral replication and production of progeny virions in human cells, a process that is regulated by human telomerase reverse transcriptase. The p53 gene, as a tumor suppressor, regulates diverse cellular processes, including cell cycle arrest, cell autophagy, senescence and apoptosis. Dysfunction of the p53 pathways is common in malignant gliomas. Exogenous expression of p53 during adenovirus replication in human cancer cells may accelerate cell death and improve the release of early virus progeny. In the present study, a conditionally replicative adenovirus (CRAd) Ad-Tp-E1A-Gp-p53, which expressed functional p53 protein when replicating in cancer cells, was constructed. Next, the level of p53 expression in U251 cells was determined by western blot analysis, and the inhibitory effect of Ad-Tp-E1A-Gp-p53 on U251 cells was detected via an MTT assay. The results indicated that p53 expression was upregulated with an increase in the multiplicity of infection (MOI) of Ad-Tp-E1A-Gp-p53. Additionally, the inhibitory effects of Ad-Tp-E1A-Gp-p53 in different groups were significantly different (P<0.05), with the inhibition ratio of the experimental groups being higher, compared with the control group (P<0.05). Furthermore, the inhibition ratio increased with increases in the MOI of Ad-Tp-E1A-Gp-p53. Therefore, the expression of functional p53 and that of E1A may increase the potency of CRAd, and overexpression of p53 through CRAd is a promising approach to more effective treatments in a number of human cancer types.

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“…Several therapeutic strategies have tried to exploit the fact that tumor cells have high levels of telomerase activity. Telomerase-based therapies include using gene promoters of the various components of telomerase for gene-therapy "suicide" strategies and using telomerase peptides, proteins, or RNA as vaccines for immunotherapy [174]. Other approaches have been examined to inhibit telomerase activity directly.…”

Section: Targeting Senescencementioning

confidence: 99%

Chemotherapeutic Approaches for Targeting Cell Death Pathways

2006

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Learning Objectives After completing this course, the reader will be able to: List the multiple cell death pathways that are activated in response to chemotherapeutic agents. Identify signaling molecules involved and morphological changes that occur in the different types of cell death pathways. Describe mechanisms targeted by novel chemotherapeutic agents. Access and take the CME test online and receive 1 AMA PRA category 1 credit at http://CME.TheOncologist.com For several decades, apoptosis has taken center stage as the principal mechanism of programmed cell death in mammalian tissues. It also has been increasingly noted that conventional chemotherapeutic agents not only elicit apoptosis but other forms of nonapoptotic death such as necrosis, autophagy, mitotic catastrophe, and senescence. This review presents background on the signaling pathways involved in the different cell death outcomes. A re‐examination of what we know about chemotherapy‐induced death is vitally important in light of new understanding of nonapoptotic cell death signaling pathways. If we can precisely activate or inhibit molecules that mediate the diversity of cell death outcomes, perhaps we can succeed in more effective and less toxic chemotherapeutic regimens.

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Telomerase-Dependent Gene Therapy

Cited by 32 publications

References 45 publications

Saporin as a novel suicide gene in anticancer gene therapy

Saporin as a novel suicide gene in anticancer gene therapy

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters

Chemotherapeutic Approaches for Targeting Cell Death Pathways

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