Triplex formation inhibits HER-2/neu transcription in vitro.

Ebbinghaus, Scot; Gee, Jay E.; Rodu, Brad; Mayfield, Charles A.; Sanders, Glenn M.; Miller, Donald M.

doi:10.1172/jci116850

Cited by 83 publications

(62 citation statements)

References 32 publications

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“…Our goal was to understand how this transmembrane receptor impinges on the cell cycle, allowing tumour cells with multiple molecular alterations to progress in an orderly manner through the cell cycle. Our results, and data from other studies employing di erent methods to inhibit ErbB2 Ebbinghaus et al, 1993;Juhl et al, 1997), show that ErbB2 plays a central role in the proliferation of these tumour cells. We show here the mechanism underlying this growth inhibition.…”

Section: Discussionsupporting

confidence: 79%

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

et al. 2000

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The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human tumours. In order to understand the mechanism by which ErbB2 mediates tumour proliferation we have functionally inactivated the receptor using an intracellularly expressed, ER-targeted single-chain antibody (scFV-5R). Inducible expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cell line leads to loss of plasma membrane localized ErbB2. Simultaneously, the activity of ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggesting that active ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of functional ErbB2 caused the SKBr3 tumour cells to accumulate in the G1 phase of the cell cycle. This was a result of reduction in CDK2 activity, which was mediated by a re-distribution of p27 Kip1 from sequestering complexes to cyclin E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27 Kip1 sequestration, decreased in the absence of functional ErbB2. Ectopic expression of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a partial G1 rescue. We propose that c-Myc is a primary e ector of ErbB2-mediated oncogenicity and functions to prevent normal p27 Kip1 control of cyclinE/CDK2.

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Section: Discussionsupporting

confidence: 79%

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

et al. 2000

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“…[2][3][4][5][6] Based on this concept, a number of methods have been endeavored to achieve selective gene product abrogation as a means to revert the transformed phenotype. These interventions have included antisense molecules and ribozymes designed to interrupt oncogene expression at the transcriptional level, as well as dominant-negative molecules and intrabodies to achieve direct oncoprotein knockout.…”

Section: Discussionmentioning

confidence: 99%

“…1 For the context of dominant oncogenes, methods have been developed to achieve abrogation of the dysregulated cellular pathways. [2][3][4][5][6] Such interventions have been endeavored at the transcriptional level of gene expression by using triplex, antisense, or ribozyme approaches. 4 -8 In addition, functional knockout at the level of protein expression has been achieved via dominant-negative mutation, as well as intrabody methods.…”

mentioning

confidence: 99%

Antineoplastic effect of anti-erbB-2 intrabody is not correlated with scFv affinity for its target

et al. 2000

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Intracellular single-chain antibodies (scFvs) have emerged as a powerful method to knock out expression of oncoproteins. We have demonstrated previously that scFvs directed against a variety of molecular targets induce specific toxicity in tumor cells. Recently, the utility of an anti-erbB-2 scFv has predicated its evaluation in a phase I gene therapy clinical trial. The utility of scFv as an intrabody is closely linked to its interaction with a target, limiting the contribution of the latter to the neoplastic phenotype. In this study, we sought to determine whether improvement in the affinity of the scFv for its cognate target could improve the efficiency of intrabody-mediated oncoprotein knockout. We compared in erbB-2-positive and -negative tumor cells the function of plasmids encoding a newly developed C6.5 anti-erbB-2 scFv, which has a 1000-fold higher affinity, with our original e23 anti-erbB-2 scFv. Intracellular scFv expression, target binding, and tumor cell cytotoxicity were found to be similar in all conditions tested, including dose-response studies with limiting dilutions of the scFv. On this basis, we have concluded that the antineoplastic effect of anti-erbB-2 intrabody is not correlated with scFv affinity for its target.

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“…Por mutaciones, pueden transformarse en oncogenes y contribuir al desarrollo de cáncer. Por lo tanto, una de las estrategias de TG consiste en inactivar oncogenes mediante el uso de oligonucleótidos que se unen directamente al ADN y forman un triplex (estructura tricatenaria compuesta por la doble cadena del ADN nativo asociada a la simple cadena del oligonucleótido) 35 o actuar sobre el ARN mensajero del oncogén vía oligonucleótidos antisentido 36 o ribozimas, 37 e impedir así su expresión.…”

Section: Inhibición De Oncogenesunclassified

Terapia génica: opción terapéutica para neoplasias, infecciones y enfermedades monogénicas

Cavagnari

2011

Arch Argent Pediat

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Arch Argent Pediatr 2011;109(4):326-332 / 326 RESUMEN Durante las últimas dos décadas, los resultados de varios protocolos de terapia génica llevaron al descreimiento de la comunidad médica. Sin embargo, en años recientes se obtuvieron resultados muy exitosos que la reposicionaron como una opción prometedora para el tratamiento de muchas enfermedades. Frente a este resurgimiento del interés de la comunidad científica internacional en la terapia génica, resulta apropiado que el médico generalista comprenda sus fortalezas y limitaciones. El objetivo de este artículo es comentar la forma en que la terapia génica encara actualmente el tratamiento de patologías tan diversas como neoplasias, infecciones y enfermedades monogénicas.

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Triplex formation inhibits HER-2/neu transcription in vitro.

Abstract: Triplex-forming oligonucleotides (TFOs) Invest. 1993Invest. .92:2433Invest. -2439

Cited by 83 publications

References 32 publications

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

Antineoplastic effect of anti-erbB-2 intrabody is not correlated with scFv affinity for its target

Terapia génica: opción terapéutica para neoplasias, infecciones y enfermedades monogénicas

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