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Titolo:
Coexpression of guanylate kinase with thymidine kinase enhances prodrug cell killing in vitro and suppresses vascular smooth muscle cell proliferation in vivo
Autore:
Akyurek, LM; Nallamshetty, S; Aoki, K; San, H; Yang, ZY; Nabel, GJ; Nabel, EG;
Indirizzi:
NHLBI, Vasc Biol Branch, NIH, Bethesda, MD 20892 USA NHLBI Bethesda MD USA 20892 Vasc Biol Branch, NIH, Bethesda, MD 20892 USA NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA NIAID Bethesda MD USA20892 Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 5, volume: 3, anno: 2001,
parte:, 1
pagine: 779 - 786
SICI:
1525-0016(200105)3:5<779:COGKWT>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VIVO; GENE-THERAPY; EXPRESSION; TUMOR; INJURY; COMBINATION; GENERATION; RESTENOSIS; VACCINES; VECTOR;
Keywords:
thymidine kinase; ganciclovir; acyclovir; vascular smooth muscle cells;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Nabel, EG NHLBI, Vasc Biol Branch, NIH, Bldg 10,Room 8C103, Bethesda, MD 20892 USA NHLBI Bldg 10,Room 8C103 Bethesda MD USA 20892 sda, MD 20892 USA
Citazione:
L.M. Akyurek et al., "Coexpression of guanylate kinase with thymidine kinase enhances prodrug cell killing in vitro and suppresses vascular smooth muscle cell proliferation in vivo", MOL THER, 3(5), 2001, pp. 779-786

Abstract

Herpes simplex virus-thymidine kinase (HSV-TK) phosphorylates the prodrugsganciclovir (GCV) and acyclovir (ACV), leading to disruption of DNA synthesis and inhibition of cell proliferation. HSV-TK vectors have been successfully employed in cardiovascular and cancer gene therapy. Activation of GCV and ACV, after an initial phosphorylation step by the viral thymidine kinase, is carried out by guanylate kinase. We reasoned that coexpression of guanylate kinase (CK) with HSV-TK would augment phosphorylation of CCV or ACV,leading to increased cell killing. To test this hypothesis, a vector expressing TK with CK (TKciteGK) was developed and tested on vascular smooth muscle cells (vsmcs) in vitro and in vivo. Compared to HSV-TK vectors, killingof vascular cells transduced with TKciteGK and exposed to GCV was significantly increased (P = 0.03). The TKciteGK construct was evaluated with threepromoters: CMV, EF1 alpha, and SM22 alpha. TKciteGK expression driven by aCMV promoter induced cell killing more effectively than SM22 alpha or EF1 alpha promoters in primary vsmcs. Based upon these in vitro findings, TKciteGK vectors with a CMV promoter were tested in two animal models of cardiovascular disease: balloon angioplasty and stent deployment in pig arteries. Following vascular injury, expression of CMV-TKciteGK with GCV significantly reduced vsmc proliferation and intimal lesion formation compared to control vectors with GCV, In the angioplasty model, there was an 80% reduction in intima-to-media area ratio (P = 0.0002). These findings were paralleled in a stent model with 66% reduction in intimal lesions (P = 0.006). Coexpression of GK with TK increases cell killing and permits administration of CCVat lower doses. These modifications in TKciteGK vectors and GCV showed enhanced efficacy at lower prodrug doses, leading to improved safety for cardiovascular gene therapy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/21 alle ore 16:22:22