Highly specific antiangiogenic therapy is effective in suppressing growth of experimental Wilms tumors

Huang, Jianzhong; Moore, James T.; Soffer, Samuel Z.; Kim, Eugene; Rowe, Dorothy H.; Manley, Christina; O’Toole, Kathleen; Middlesworth, William; Stolar, Charles J.H.; Yamashiro, Darrell J.; Kandel, Jessica J.

doi:10.1053/jpsu.2001.20716

Cited by 55 publications

(42 citation statements)

References 7 publications

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“…Moreover, they can be synthesized efficiently and reliably by using established phosphoramidite chemistry. Thus far, many aptamers have been identified, and some of them are very close to becoming marketable drugs (9)(10)(11)(12)(13). Nevertheless, engineering these aptamers for enhanced performance or new functions remains virtually unexplored.…”

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confidence: 99%

Molecular assembly for high-performance bivalent nucleic acid inhibitor

Kim

Cao

Tan

2008

Proc. Natl. Acad. Sci. U.S.A.

167

147

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It is theorized that multivalent interaction can result in better affinity and selectivity than monovalent interaction in the design of high-performance ligands. Accordingly, biomolecular engineers are increasingly taking advantage of multivalent interactions to fabricate novel molecular assemblies, resulting in new functions for ligands or enhanced performance of existing ligands. Substantial efforts have been expended in using small molecules or epitopes of antibodies for designing multifunctional or betterperforming ligands. However, few attempts to use nucleic acid aptamers as functional domains have been reported. In this study, we explore the design of bivalent nucleic acid ligands by using thrombin and its aptamers as the model by which to evaluate its functions. By assembling two thrombin-binding aptamers with optimized design parameters, this assembly has resulted in the successful development of a nucleic acid-based high-performance bivalent protein inhibitor. Our experimentation proved (i) that the simultaneous binding of two aptamers after linkage achieved 16.6-fold better inhibition efficiency than binding of the monovalent ligand and (ii) that such an improvement originated from changes in the kinetics of the binding interactions, with a k off rate Ϸ1/50 as fast. In addition, the newly generated aptamer assembly is an excellent anticoagulant reagent when tested with different samples. Because this optimized ligand design offers a simple and noninvasive means of accomplishing higher performance from known functional aptamers, it holds promise as a potent antithrombin agent in the treatment of various diseases related to abnormal thrombin activities.anticogulation ͉ aptamers ͉ multivalent binding ͉ thrombin I n contrast to monovalent interaction, multivalent, or polyvalent, interactions involve the binding of multiple ligands of a biological entity, such as small molecules, oligosaccharides, proteins, nucleic acids (NAs), lipids, or aggregates of these molecules, to multiple binding pockets or receptors of a target, e.g., a protein, virus, bacterium, or cell (1). Polyvalency is ubiquitous in biology and has a number of benefits over monovalent interactions. For instance, polyvalent interactions collectively possess higher binding affinity than the corresponding monovalent interactions. That is, polyvalency results in a ''cooperative'' configuration in which the probability of rebinding of a dissociated monomer to the target is increased by the presence of other monomers bound to the same target. A classical example of this is demonstrated by the binding of galactoseterminated oligosaccharides to C-type mammalian hepatic lectins (2). In addition to increased binding affinity, polyvalent interactions also stand a better chance of providing higher selectivity in target recognition. Noticeably, a multivalent binder, despite being composed of weak homo-or heterogeneous ligands, can still have stronger binding property because of multiple binding events. A well known example of this phenomenon is taken fro...

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confidence: 99%

Molecular assembly for high-performance bivalent nucleic acid inhibitor

Kim

Cao

Tan

2008

Proc. Natl. Acad. Sci. U.S.A.

167

147

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“…Platelet-derived growth factor (PDGF)-specific aptamers ARC126 and ARC127, developed for the treatment of pathogenesis of proliferative retinopathies, have been successfully tested in a transgenic mouse disease model. Inhibition of PDGF receptor binding by aptamers led to reduction of Lewia lung carcinoma vascularity (12) as was observed for VEGF-binding aptamers in an experimental Wilms tumor model (13). An anticancer aptamer binding to cell surface nucleolin followed by internalization and induction of S-phase arrest was studied in dose escalation Phase I studies in patients with advanced tumors.…”

Section: The Selex Technologymentioning

confidence: 83%

Disease‐specific biomarker discovery by aptamers

Ulrich

Wrenger

2009

Cytometry Pt A

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RNA and DNA aptamers developed by an in vitro selection process, Systematic Evolution of Ligands by EXponential enrichment (SELEX), comprise a novel class of highaffinity and specific capture agents, which can be easily modified for cytometry and in vivo applications. A novel application of this technique (Cell SELEX) explores the expression of cell surface epitopes that differ between two given cell types or between healthy and diseased cells. Using whole cells as targets, aptamer libraries can be identified that bind to biomarkers expressed by target cells and not by any other cells. Aptamers have been developed that specifically interact with cell surface epitopes of trypanosomes or distinguish between the differences in molecular signature of somatic and cancer cells. Aside from its use for target cell identification by image and flow cytometry and laser-scanning microscopy, aptamers can be used for ligand-mediated purification and identification of their binding proteins in target cell membranes. In this review, we discuss an approach for the development of aptamers targeting parasitederived surface proteins of Trypanosoma and Plasmodium. ' 2009 International Society for Advancement of CytometryKey terms aptamers; Plasmodium falciparum; deconvolution SELEX; cell and target protein identification; fluorescence-labeled aptamers for clinical and cytomics application THE SELEX TECHNOLOGYThe SELEX technique (Systematic Evolution of Ligands by EXponential enrichment) initially developed by the laboratories of Larry Gold (1) and Jack Szostak (2) uses iterative in vitro selection of combinatorial RNA or DNA pools against a target molecule for the identification of high-affinity oligonucleotide ligands, known as aptamers. This methodology has been extensively used to isolate aptamers for a wide variety of peptides and proteins of therapeutic importance, including growth and coagulation factors (3). This novel class of oligonucleotide-based ligands recognizes their targets with binding specificities and affinities comparable to those of monoclonal antibodies. Moreover, aptamers are able to distinguish between protein isoforms and different conformational forms of the same protein (4,5). In most cases, aptamer binding to its target protein inhibits its biological activity, either resulting from aptamer interference with the catalytic site of an enzyme or with sites involved in ligandreceptor recognition. However, it is also possible that aptamer-target protein binding induces allosteric effects, such as changes in conformational states resulting in loss of biological activity of the target protein.Aptamers can be identified by in vitro selection against almost any target, including toxins and antigens which do not induce immune responses in host animals for antibody production. As a result, this novel class of ligands is highly promising for the development of therapeutics and biotechnological tools. The potential utility of aptamers for in vivo applications and as therapeutic agents is considerably enhanced ...

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“…Опухоль имплантировали в почку мыши и поддерживали её рост неделю. Группа мышей получала ежедневную инъекцию 200 мкг аптамера к VEGF, а контрольная группа -фосфатно-солевой буфер в течение 5 недель [57]. После декапитации животных наблюдали уменьшение в весе опухоли на 84% у обработанных мышей в сравнении с контрольной группой.…”

Section: Vegfunclassified

“…Кроме того, метастазы в легких были видны только у 20%, в сравнении с 60% у контрольной группы. Аптамеры, тестированные на мышиной бластоме, показали уменьшение роста опухоли на 53% в сравнении с контролем [57].…”

Section: Vegfunclassified

Molecular recognition elements - DNA/RNA-aptamers to proteins

Спиридонова

2010

BIOMED KHIM

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In this review summarizes data on DNA/RNA aptamers - a novel class of molecular recognition elements. Special attention is paid to the aptamers to proteins involved into pathogenesis of wide spread human diseases. These include aptamers to serine protease, to cytokines/growth factors, to influenza viral protein, nucleic acid binding proteins. Strong and specific binding for a given protein target of aptamers make them an attractive class of direct protein inhibitors. They can inhibit pathogenic proteins and it is becoming clear that aptamers have the potential to be a new and effective class of therapeutic molecules.

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Highly specific antiangiogenic therapy is effective in suppressing growth of experimental Wilms tumors

Cited by 55 publications

References 7 publications

Molecular assembly for high-performance bivalent nucleic acid inhibitor

Molecular assembly for high-performance bivalent nucleic acid inhibitor

Disease‐specific biomarker discovery by aptamers

Molecular recognition elements - DNA/RNA-aptamers to proteins

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