The Effect of a Monoclonal Antibody Coupled to Ricin A Chain-Derived Peptides on Endothelial Cells in Vitro: Insights into Toxin-Mediated Vascular Damage

Baluna, Roxana; Coleman, Elaine J.; Jones, Chandria D.; Gheţie, Victor; Vitetta, Ellen S.

doi:10.1006/excr.2000.4954

Cited by 69 publications

(48 citation statements)

References 45 publications

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“…Apoptosis of endothelial cells could result from protein synthesis inhibition, inhibition of integrins, or other toxic actions of A chains of internalized RCA I, as indicated by multiple mechanisms of endothelial cell death mediated by ricin. 27,47 Tumor vessels that regressed after RCA I left behind empty sleeves of basement membrane, as found in the same tumor model after inhibition of VEGF signaling. [32][33][34] The appearance of blobs that had RCA I fluorescence and VEGFR-2 immunoreactivity within F4/80-positive macrophages indicates a fate of some apoptotic endothelial cells of regressing tumor vessels in this model.…”

Section: Discussionsupporting

confidence: 52%

Ricinus communis Agglutinin I Leads to Rapid Down-Regulation of VEGFR-2 and Endothelial Cell Apoptosis in Tumor Blood Vessels

You

Kasman

Hu-Lowe

et al. 2010

The American Journal of Pathology

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Ricinus communis agglutinin I (RCA I), a galactosebinding lectin from castor beans, binds to endothelial cells at sites of plasma leakage, but little is known about the amount and functional consequences of binding to tumor endothelial cells. We addressed this issue by examining the effects of RCA I on blood vessels of spontaneous pancreatic islet-cell tumors in RIP-Tag2 transgenic mice. After intravenous injection, RCA I bound strongly to tumor vessels but not to normal blood vessels. At 6 minutes, RCA I fluorescence of tumor vessels was largely diffuse, but over the next hour, brightly fluorescent dots appeared as the lectin was internalized by endothelial cells. RCA I injection led to a dose-and time-dependent decrease in vascular endothelial growth factor receptor-2 (VEGFR-2) immunoreactivity in tumor endothelial cells, with 95% loss over 6 hours. By comparison, VEGFR-3 , CD31 , and CD105 had decreases in the range of 21% to 33%. Loss of VEGFR-2 was followed by increased activated caspase-3 in tumor vessels. Prior inhibition of VEGF signaling by AG-028262 decreased RCA I binding and internalization into tumor vessels. These findings indicate RCA I preferentially binds to and is internalized by tumor endothelial cells , which leads to VEGFR-2 downregulation , endothelial cell apoptosis , and tumor vessel regression. Together , the results illustrate the selective impact of RCA I on VEGF signaling in tumor blood vessels.

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Section: Discussionsupporting

confidence: 52%

Ricinus communis Agglutinin I Leads to Rapid Down-Regulation of VEGFR-2 and Endothelial Cell Apoptosis in Tumor Blood Vessels

You

Kasman

Hu-Lowe

et al. 2010

The American Journal of Pathology

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“…The stress caused by the inhibition of protein synthesis partially contributes to ABR-triggered apoptosis. It has recently been demonstrated that the segment of the ricin A-chain (SVTLALDVTNAY) linked to antibodies can induce the apoptosis of human vein endothelial cells (7). The data suggested that the ricin A-chain-mediated inhibition of protein synthesis and apoptosis might be exerted by different motifs of the ricin A-chain molecule.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their ability to inhibit protein synthesis, recent studies have shown that these toxins are able to induce apoptosis (3)(4)(5). Baluna and colleagues (6,7) have suggested that inhibition of protein synthesis and apoptosis may be mediated by different segments of the ricin A-chain molecule. Besides the inhibition of protein synthesis, it is an attractive hypothesis that ABRA adopts alternative molecular mechanisms to trigger apoptotic programs.…”

mentioning

confidence: 99%

Abrin Triggers Cell Death by Inactivating a Thiol-specific Antioxidant Protein

Shih

Hung³

et al. 2001

Journal of Biological Chemistry

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“…[14][15][16] In contrast, vascular leak syndrome secondary to vascular injury may be due to selective receptors for peptide toxins on endothelial cells. 20,21 A modification of the endothelial binding residues on toxins may reduce this toxicity. Reaction of immunotoxins with macrophages and lymphocytes leads to the release of cytokines such as IL-6 and TNFa with constitutional symptoms.…”

Section: Lessons From Immunotoxinsmentioning

confidence: 99%

Protein toxins: intracellular trafficking for targeted therapy

2005

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The immunotoxin approach is based on the use of tumortargeting ligands or antibodies that are linked to the catalytic (toxic) moieties of bacterial or plant protein toxins. In this review, we first discuss the current state of clinical development of immunotoxin approaches describing the results obtained with the two toxins most frequently used: diphtheria and Pseudomonas toxin-derived proteins. In the second part of the review, a novel concept will be presented in which the roles are inverted: nontoxic receptor-binding toxin moieties are used for the targeting of therapeutic and diagnostic compounds to cancer or immune cells. The cell biological basis of these novel types of toxin-based therapeutics will be discussed, and we will summarize ongoing preclinical and clinical testing.

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The Effect of a Monoclonal Antibody Coupled to Ricin A Chain-Derived Peptides on Endothelial Cells in Vitro: Insights into Toxin-Mediated Vascular Damage

Cited by 69 publications

References 45 publications

Ricinus communis Agglutinin I Leads to Rapid Down-Regulation of VEGFR-2 and Endothelial Cell Apoptosis in Tumor Blood Vessels

Ricinus communis Agglutinin I Leads to Rapid Down-Regulation of VEGFR-2 and Endothelial Cell Apoptosis in Tumor Blood Vessels

Abrin Triggers Cell Death by Inactivating a Thiol-specific Antioxidant Protein

Protein toxins: intracellular trafficking for targeted therapy

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