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Titolo:
Systemic production of IL-12 by naked DNA mediated gene transfer: toxicityand attenuation of transgene expression in vivo
Autore:
Lui, VWY; Falo, LD; Huang, L;
Indirizzi:
Univ Pittsburgh, Sch Pharm, Ctr Pharmacogenet, Pittsburgh, PA 15213 USA Univ Pittsburgh Pittsburgh PA USA 15213 cogenet, Pittsburgh, PA 15213 USA Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA Univ Pittsburgh Pittsburgh PA USA 15261 armacol, Pittsburgh, PA 15261 USA Univ Pittsburgh, Sch Med, Dept Dermatol, Pittsburgh, PA 15261 USA Univ Pittsburgh Pittsburgh PA USA 15261 ermatol, Pittsburgh, PA 15261 USA
Titolo Testata:
JOURNAL OF GENE MEDICINE
fascicolo: 4, volume: 3, anno: 2001,
pagine: 384 - 393
SICI:
1099-498X(200107/08)3:4<384:SPOIBN>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECOMBINANT HUMAN INTERLEUKIN-12; RENAL-CELL CARCINOMA; ANTITUMOR-ACTIVITY; INTERFERON-GAMMA; IN-VIVO; INTRAVENOUS-INJECTION; TUMOR-GROWTH; THERAPY; MODEL; IMMUNITY;
Keywords:
gene therapy; IL-12 toxicity; IFN-gamma;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Huang, L Univ Pittsburgh, Sch Pharm, Ctr Pharmacogenet, 633 Salk Hall, Pittsburgh, PA 15213 USA Univ Pittsburgh 633 Salk Hall Pittsburgh PA USA 15213A 15213 USA
Citazione:
V.W.Y. Lui et al., "Systemic production of IL-12 by naked DNA mediated gene transfer: toxicityand attenuation of transgene expression in vivo", J GENE MED, 3(4), 2001, pp. 384-393

Abstract

Background IL-12 is a potent antitumor cytokine for cancer gene therapy. Previously, we demonstrated that single systemic administration of naked DNA(encoding IL-12) could serve as a good model for in vivo evaluation of theantitumor effect of a candidate gene (unpublished data). In the present study, we propose that this gene delivery method could be a very useful modelfor in vivo evaluation of the toxicity of a given therapeutic gene (using IL-12 as an example). By comparing the toxicities and the effects of initial IL-12 administration on subsequent transgene expression, both IL-12 gene delivery and recombinant murine IL-12 protein (rmIL-12) administration showed similar toxicity profiles. Methods Naked DNA encoding murine IL-12 (mIL-12) was delivered into mice by systemic administration. Toxicity profiles of mice treated with DNA or rmIL-12 were compared. Results Systemic administration of naked DNA encoding mIL-12 resulted in very similar toxicity as rmIL-12 with respect to liver enzyme, hematologicaland immunological profiles. Repeated injection of mIL-12 gene did not recover a high level of mIL-12 production as the first injection. Moreover, initial mIL-12 administration resulted in inhibition of subsequent reporter gene expression with both viral and non-viral promoters (CMV, human alpha -antitrypsin or chicken beta -actin promoter). This transgene inhibition effect was entirely mediated by IFN-gamma as the transgene expression was fully recovered in IFN-gamma knockout mice. Conclusions Systemic IL-12 therapy, with either a protein or gene therapy approach, resulted in comparable liver and systemic toxicities. Refractoriness of mIL-12 production by subsequent administration of mIL-12 gene was observed. The transgene attenuation effect of IL-12 pre-dosing (either by IL-12 or rmIL-12), mediated by IFN-gamma, provided important insights for the design of IL-12 combination gene therapy and the improvement of gene vectors for IL-12 therapy. The present results show that simple injection of naked DNA could serve as a good model for in vivo evaluation of the toxicity ofa candidate therapeutic gene. Copyright (C) 2001 John Wiley & Sons, Ltd.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 19:02:27