Electrotransfer of gene encoding endostatin into normal and neoplastic mouse tissues: Inhibition of primary tumor growth and metastatic spread

Cichoń, Tomasz; Jamroży, Laura; Głogowska, Joanna; Missol-Kolka, Ewa; Szala, Stanisław

doi:10.1038/sj.cgt.7700497

Cited by 42 publications

(25 citation statements)

References 36 publications

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“…In our experiments, low-voltage in vivo electroporation was applied, but to achieve the same quantity of heat, longer loading periods can be employed. Cichon et al 22 reported that the electrotransfer of the gene encoding endostatin into neoplastic mouse tissue resulted in the inhibition of primary tumor growth and metastatic spread. They reported that there was no improvement in the efficiency of gene transfers into tumors beyond a threshold voltage, and that distinct tissue damage could be seen at higher voltages, especially with combinations of high voltage and lengthy impulse time.…”

Section: Low-voltage Ep and Antiangiogenic Gene Therapy M Uesato Et Almentioning

confidence: 99%

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

et al. 2004

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Antiangiogenic factors are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vitro and tumor growth in mice. We have demonstrated the synergistic antitumor effect of antiangiogenic genes (mouse angiostatin: pBLASTmAngio; and mouse endostatin: p-BLAST42-mEndo XV) delivered to tumors by low-voltage electroporation in mouse colon 26 models. A synergistic antitumor effect was strongly suggested by in vivo tumor growth kinetics, as well as in survival studies with the mice. RT-PCR confirmed that the fragments of each gene were transferred by low-voltage electroporation in the tumor. Decreased microvessel density measurements in tumors also confirmed the efficacy of the synergistic antitumor effect of both genes. Significant growth inhibition was observed in mice treated with a 1:1 proportion of angiostatin and endostatin genes, and the order of the both genes transferred (first the endostatin gene, followed 1 week later by the angiostatin gene) had a profound inhibitory effect on tumor growth. These data suggest that in vivo delivery of antiangiogenic genes with low-voltage electroporation could be a possible therapeutic strategy for established solid tumors when both genes were applied in combination.

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Section: Low-voltage Ep and Antiangiogenic Gene Therapy M Uesato Et Almentioning

confidence: 99%

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

et al. 2004

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“…In hindsight, it would be preferable to deliver the angiogenic factors prior to surgical removal of a tumor in order to ensure that serum levels of angiostatin and endostatin have reached a maximum level. Our approach using naked plasmids could potentially be enhanced by electrotransfer of angiostatin and endostatin plasmids into muscle tissues as exemplified by Cichon et al 9 Antiangiogenic therapy is widely regarded as a promising treatment strategy to combat cancer based on the fact that most tumors are dependent on angiogenesis for survival. However, despite many successful animal experiments employing antiangiogenic therapies, disappointing reports have emerged recently, particular when antiangiogenic therapies have been applied to human beings.…”

Section: Discussionmentioning

confidence: 99%

“…They both inhibit endothelial cell migration and proliferation, and induce the regression of a wide variety of established tumors of mouse, rat and human origin, including metastases. [4][5][6][7][8][9] The tumor-suppressor activity of angiostatin may arise from its ability to inhibit the proliferation of endothelial cells by binding to the a/bsubunits of ATP synthase, 10 inducing apoptotic cell death, 5 by subverting adhesion plaque formation and thereby inhibiting the migration and tube formation of endothelial cells, and/or by downregulating vascular endothelial growth factor (VEGF) expression. 11,12 The latter feature of angiostatin is not retained in all tumor models, as it had no effect on VEGF expression in two reports, 13,14 and even slightly upregulated VEGF expression in EL-4 tumors.…”

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confidence: 99%

Intramuscular delivery of antiangiogenic genes suppresses secondary metastases after removal of primary tumors

et al. 2004

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The success of surgery to remove primary tumors can be compromised by the subsequent outgrowth of metastases. It is recognized that primary tumors secrete antiangiogenic factors that suppress the outgrowth of their daughter metastases. In accord we show here that surgical removal of primary EL-4 lymphomas led to a marked decrease in the levels of circulating angiostatin and endostatin, and promoted the growth of distant nodular tumors. Expression vectors encoding angiostatin and endostatin, formulated with poly-N-vinyl pyrrolidone (PVP), were injected into the tibialis and gastrocnemia muscles, leading to expression of angiostatin and endostatin in muscle fibers. High levels of biologically active exogenous proteins were secreted into the circulation. Intramuscular gene therapy with angiostatin and endostatin plasmids significantly inhibited tumor vascularity and induced tumor cell apoptosis, and thereby suppressed the growth of secondary subcutaneous and disseminated metastatic tumors in the lung and liver. Simultaneous intramuscular delivery of both angiostatin and endostatin plasmids significantly prolonged the survival of mice after removal of primary tumors. These results suggest that intramuscular gene transfer of angiostatin and endostatin might serve as a prophylactic cancer-prevention strategy to combat the recurrence of cancer after surgical resection of primary tumors.

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“…Several other studies have employed in vivo electroporation (direct electroporation of solid tumors) with some successes. For example, Cichon et al 23 used in vivo electroporation to administer the ES transgene into normal and neoplastic mouse tissues to treat RENCA as well as B16F10 melanoma. In that study, ES could similarly control primary and metastatic tumor development.…”

Section: Discussionmentioning

confidence: 99%

Rapid, in vivo, evaluation of antiangiogenic and antineoplastic gene products by nonviral transfection of tumor cells

et al. 2004

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Using a nonviral, electroporation-based gene transfection approach, we demonstrate the efficient and consistent transfection of two poorly immunogenic tumor cell lines: B16F10 melanoma and renal carcinoma (RENCA). Three genes, IL-12, angiostatin (AS), and an endostatin:angiostatin fusion protein (ES:AS) were subcloned into a DNA plasmid containing EBNA1-OriP, which was then transfected into B16F10 and RENCA cells. Significant levels of protein were secreted into the culture supernatants of transfected cells in vitro. Transfected tumor cells were injected subcutaneously into mice. All the three transgenes were capable of significantly delaying and reducing the formation of primary B16F10 and RENCA tumors, as well as B16F10 lung metastases. By day 11 postinjection, all control mice that received either mock-transfected or empty vector DNA-transfected B16F10 tumor cells had developed large primary tumors. In contrast, mice that received IL-12-transfected B16F10 cells did not develop appreciable tumors until day 17, and these were significantly smaller than controls. Similar results were observed for the RENCA model, in which only one of the IL-12 mice had developed tumors out to day 31. Expression of AS or ES:AS also significantly delayed and reduced primary tumors. Overall, ES:AS was more effective than AS alone. Furthermore, 25% of the AS mice and 33% of the ES:AS mice remained tumor-free at day 17, by which point all control mice had significant tumors. Mouse survival rates also correlated with the extent of tumor burden. Importantly, no lung metastases were detected in the lungs of mice that had received either AS or ES:AS-transfected B16F10 tumor cells and significantly fewer metastases were found in the IL-12 group. The consistency of our transfection results highlight the feasibility of directly electroporating tumor cells as a means to screen, identify, and validate in vivo potentially novel antiangiogenic and/or antineoplastic genes.

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Electrotransfer of gene encoding endostatin into normal and neoplastic mouse tissues: Inhibition of primary tumor growth and metastatic spread

Cited by 42 publications

References 36 publications

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

Intramuscular delivery of antiangiogenic genes suppresses secondary metastases after removal of primary tumors

Rapid, in vivo, evaluation of antiangiogenic and antineoplastic gene products by nonviral transfection of tumor cells

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