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Titolo:
Restricted expression of an adenoviral vector encoding Fas ligand (CD95L) enhances safety for cancer gene therapy
Autore:
Aoki, K; Akyurek, LM; San, H; Leung, K; Parmacek, MS; Nabel, EG; Nabel, GJ;
Indirizzi:
NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA NIH Bethesda MD USA 20892NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 nternal Med, Ann Arbor, MI 48109 USA Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 t Biol Chem, Ann Arbor, MI 48109 USA NHLBI, NIH, Bethesda, MD 20892 USA NHLBI Bethesda MD USA 20892NHLBI, NIH, Bethesda, MD 20892 USA Univ Penn Hlth Syst, Philadelphia, PA 19104 USA Univ Penn Hlth Syst Philadelphia PA USA 19104 Philadelphia, PA 19104 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 6, volume: 1, anno: 2000,
pagine: 555 - 565
SICI:
1525-0016(200006)1:6<555:REOAAV>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
TRANSFORMING GROWTH FACTOR-BETA-1; SMOOTH-MUSCLE CELLS; INDUCED APOPTOSIS; DOWN-REGULATION; TUMOR-CELLS; IN-VIVO; MYOBLASTS; LIVER; DEATH; REPLICATION;
Keywords:
cancer gene therapy; Fas ligand; CD95L; adenoviral vectors; leiomyosarcoma; SM22 alpha promoter; cleavage mutant; smooth muscle cell;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Nabel, GJ NIH, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA NIH 40 Convent Dr Bethesda MD USA 20892 , Bethesda, MD 20892 USA
Citazione:
K. Aoki et al., "Restricted expression of an adenoviral vector encoding Fas ligand (CD95L) enhances safety for cancer gene therapy", MOL THER, 1(6), 2000, pp. 555-565

Abstract

Gene transfer of Fas ligand (CD95L) using adenoviral vectors has been shown to generate apoptotic responses and potent inflammatory reactions that earn be used to induce the regression of malignancies in vivo, but these vectors also cause significant hepatotoxicity that may limit their clinical utility. Here we describe an adenoviral vector encoding CD95L with restricted gene expression that reduces its toxicity in vivo. Preclinical efficacy andgene expression studies of lineage-restricted CD95L adenoviral vectors were performed. To enhance its cytotoxicity and reduce potential systemic effects, a noncleavable CD95L was made by deleting a segment containing the cleavage site (CD95L Delta QP). Higher CD95L expression of this mutant was observed on the tumor cell surface, together with a reduction in the release of soluble CD95L. This CD95L cleavage mutant was then expressed under control of a smooth muscle-specific promoter, SM22 alpha, and analyzed for its ability to suppress the growth of tumors of smooth muscle origin in vivo. Growth of human leiomyosarcomas but not gliomas was inhibited after ADV gene transfer into tumor-bearing immunodeficient mice. In contrast to viral promoters, in which mortality was uniformly seen after injection of 10(12) particles, no significant hepatic injury or systemic toxicity was observed in mice, and the maximum tolerated dose was increased greater than or equal to 10- to 100-fold. These findings suggest that restricted specificity of adenoviral CD95L gene expression enhances the safety of this approach for cancergene therapy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/09/20 alle ore 09:03:57