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Titolo:
The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: Insights into toxin-mediated vascular damage
Autore:
Baluna, R; Coleman, E; Jones, C; Ghetie, V; Vitetta, ES;
Indirizzi:
Univ Texas, SW Med Ctr, Canc Immunol Ctr, Dallas, TX 75235 USA Univ TexasDallas TX USA 75235 tr, Canc Immunol Ctr, Dallas, TX 75235 USA Univ Texas, SW Med Ctr, Grad Program Immunol, Dallas, TX 75235 USA Univ Texas Dallas TX USA 75235 Grad Program Immunol, Dallas, TX 75235 USA Univ Texas, SW Med Ctr, Canc Educ Summer Program, Dallas, TX 75235 USA Univ Texas Dallas TX USA 75235 Educ Summer Program, Dallas, TX 75235 USA
Titolo Testata:
EXPERIMENTAL CELL RESEARCH
fascicolo: 2, volume: 258, anno: 2000,
pagine: 417 - 424
SICI:
0014-4827(20000801)258:2<417:TEOAMA>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
DISINTEGRIN-LIKE DOMAIN; III CONNECTING SEGMENT; INDUCED BINDING-SITE; PHASE-I; A-CHAIN; CONTINUOUS-INFUSION; DIPHTHERIA-TOXIN; LEAK SYNDROME; ALPHA-V-BETA-3 INTEGRINS; CASPASE ACTIVATION;
Keywords:
immunotoxins; disintegrins; endothelial cells; vascular leak syndrome;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Vitetta, ES Univ Texas, SW Med Ctr, Canc Immunol Ctr, 5323 Harry Hines Blvd, Dallas, TX 75235 USA Univ Texas 5323 Harry Hines Blvd Dallas TX USA 75235 75235 USA
Citazione:
R. Baluna et al., "The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: Insights into toxin-mediated vascular damage", EXP CELL RE, 258(2), 2000, pp. 417-424

Abstract

Immunotoxins (ITs) containing plant or bacterial toxins have a dose-limiting toxicity of vascular leak syndrome (VLS) in humans. The active A chain of ricin toxin (RTA), other toxins, ribosome-inactivating proteins, and the VLS-inducing cytokine IL-2 contain the conserved sequence motif (x)D(y) where x = L, I, G, or V and y = V,L, or S. RTA-derived LDV-containing peptidesattached to a monoclonal antibody, RFB4, induce endothelial cell (EC) damage in vitro and vascular leak in two animal models in vivo. We have now investigated the mechanism(s) by which this occurs and have found that (1) theexposed D75 in the LDV sequence in RTA and the C-terminal flanking threonine play critical roles in the ability of RFB4-conjugated RTA peptide to bind to and damage ECs and (2) the LDV sequence in RTA induces early manifestations of apoptosis in HUVECs by activating caspase-3. These data suggest that RTA-mediated inhibition of protein synthesis (due to its active site) and apoptosis (due to LDV) may be mediated by different portions of the RTA molecule. These results suggest that ITs prepared with RTA mutants containing alterations in LDVT may kill tumor cells in vivo in the absence of EC-mediated VLS. (C) 2000 Academic Press.

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Documento generato il 10/07/20 alle ore 15:59:54