Tat8-TK/GCV Suicide Gene Therapy Induces Pancreatic Tumor Regression In Vivo

Cascante, Anna; Rodriguez, Laura Garcia; Gonzalez, J.R.; Costantini, Lauren C.; Fillat, Cristina

doi:10.1089/hum.2005.16.ft-147

Cited by 2 publications

(3 citation statements)

References 32 publications

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“…Reversible electroporation has been exploited to deliver chemotherapeutic drugs into the cells of solid tumors in a process termed electrochemotherapy [6] and to transfect tissues with DNA plasmids in a process termed electrogenetherapy [7]. In fact, our group has previously shown that the intratumoral electrogene delivery of the Herpes Simplex Thymidine Kinase gene followed by intraperitoneal ganciclovir administration reduces pancreatic tumor growth in mouse models [8]. Recently, irreversible electroporation (IRE) has been proposed as a method for solid tumor ablation and it is now being assayed clinically [9].…”

Section: Introductionmentioning

confidence: 99%

Irreversible electroporation shows efficacy against pancreatic carcinoma without systemic toxicity in mouse models

et al. 2012

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Pancreatic ductal adenocarcinoma (PDAC) therapies show limited success. Irreversible electroporation (IRE) is an innovative loco-regional therapy in which high-voltage pulses are applied to induce plasma membrane defects leading to cellular death. In the present study we evaluated the feasibility of IRE against PDAC. IRE treatment exhibited significant antitumor effects and prolonged survival in mice with orthotopic xenografts. Extensive tumor necrosis, reduced tumor cell proliferation and disruption of microvessels were observed at different days post-IRE. Animals had transient increases in transaminases, amylase and lipase enzymes that normalized at 24h post-IRE. These results suggest that IRE could be an effective treatment for locally advanced pancreatic tumors.

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Section: Introductionmentioning

confidence: 99%

Irreversible electroporation shows efficacy against pancreatic carcinoma without systemic toxicity in mouse models

et al. 2012

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“…Tat fused to TK has been shown to increase a bystander effect and therapeutic efficacy of the TK/ganciclovir system. 13,14 Although cellular export of Tat-TK was suggested in one study, 13 significant amounts of Tat-TK were detected in the supernatant of Tat-TK-expressing cells only in the presence of ganciclovir, 14 which induces cell lysis. Full-length Tat is released from infected cells via a nonclassical export mechanism.…”

Section: Discussionmentioning

confidence: 98%

“…12 The basic domain of Tat fused to thymidine kinase (TK) resulted in an enhanced bystander effect serving as indirect evidence for intercellular trafficking. 13,14 Tat-fusion of β-glucoronidase, expressed with an adenovirus, has been shown to facilitate significant intercellular trafficking and improved biodistribution of the functional protein. 15 In this context, it is important to note that β-glucoronidase contains a strong secretory signal peptide (SP), and other more recent publications support the concept that secreted Tat-fusion proteins can mediate intercellular trafficking.…”

Section: Introductionmentioning

confidence: 99%

Expressed Cell-penetrating Peptides Can Induce a Bystander Effect, but Passage Through the Secretory Pathway Reduces Protein Transduction Activity

Shen

Hay

et al. 2011

Molecular Therapy

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Despite advances in vector technology, inefficient gene transfer still limits clinical efficacy of cancer gene therapy. Cell-penetrating peptides (CPPs), such as the basic domain of the transactivator of transcription (Tat) protein of HIV-1, are internalized by intact cells and have been used to deliver purified recombinant proteins. A combination of gene therapy with protein transduction technology could induce a strong bystander effect and represent a platform to deliver proteins to target cells. However, whether expressed CPP can facilitate intercellular trafficking, i.e., a bystander effect, is controversial. Our data suggest that expressed fusion proteins that contain the basic domain of Tat do not induce a detectable bystander effect. However, Tat-fusion proteins that also contain a secretory signal peptide (SP) can induce a bystander effect in vitro, although the in vivo effect is small. Surprisingly, despite the presence of a SP, the bystander effect does not seem to be related to secretion of the fusion protein. In fact, Tat-fusion proteins are secreted very inefficiently, and protein transduction seems largely mediated by fusion proteins that are released by cell lysis. Modification of Tat can improve secretion efficacy and prevent cleavage by the endoprotease furin, but passage through the secretory pathway is associated with reduced transduction activity of Tat-fusion proteins.

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Tat8-TK/GCV Suicide Gene Therapy Induces Pancreatic Tumor Regression In Vivo

Cited by 2 publications

References 32 publications

Irreversible electroporation shows efficacy against pancreatic carcinoma without systemic toxicity in mouse models

Irreversible electroporation shows efficacy against pancreatic carcinoma without systemic toxicity in mouse models

Expressed Cell-penetrating Peptides Can Induce a Bystander Effect, but Passage Through the Secretory Pathway Reduces Protein Transduction Activity

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