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Titolo:
Use of protamine to augment adenovirus-mediated cancer gene therapy
Autore:
Lanuti, M; El Kouri, C; Force, SD; Chang, MY; Amin, K; Xu, K; Blair, IA; Kaiser, LR; Albelda, SM;
Indirizzi:
Univ Penn, Med Ctr, Dept Surg, Thorac Oncol Res Lab, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 l Res Lab, Philadelphia, PA 19104 USA Univ Penn, Med Ctr, Dept Med, Div Pulm Crit Care, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Crit Care, Philadelphia, PA 19104 USA Univ Penn, Med Ctr, Dept Pharmacol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Pharmacol, Philadelphia, PA 19104 USA
Titolo Testata:
GENE THERAPY
fascicolo: 9, volume: 6, anno: 1999,
pagine: 1600 - 1610
SICI:
0969-7128(199909)6:9<1600:UOPTAA>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
THYMIDINE KINASE GENE; HUMAN-MALIGNANT MESOTHELIOMA; COLONY-STIMULATING FACTOR; TRANSFER IN-VIVO; MOUSE MODEL; OVARIAN-CANCER; DRUG-THERAPY; CELLS; VECTORS; GANCICLOVIR;
Keywords:
gene therapy; protamine; mesothelioma; herpes thymidine kinase; cytosine deaminase; coxsackievirus and adenovirus receptor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Albelda, SM 809 Maloney Bldg HUP,3600 Spruce St, Philadelphia, PA 19104 USA 809 Maloney Bldg HUP,3600 Spruce St Philadelphia PA USA 19104
Citazione:
M. Lanuti et al., "Use of protamine to augment adenovirus-mediated cancer gene therapy", GENE THER, 6(9), 1999, pp. 1600-1610

Abstract

Improving the therapeutic potential of adenoviral (Ad) suicide gene therapy has become an area of intense investigation since the inception of gene therapy strategies for cancer treatment. Poor efficiency of gene transfer totarget tissues has become one of the most important limitations to Ad-based gene therapy. Since polycations have been shown to enhance adenovirus-mediated gene transfer in epithelial cells both in vitro and in vivo, we hypothesized that polycations could augment treatment efficacy in animals with established tumor. To address this hypothesis, protamine sulfate, a polycation already safely administered in humans, was complexed with a recombinant Ad (E(1)E(3-)deleted) vector containing the herpes simplex I thymidine kinase (HSVtk) suicide gene to treat cancer cell lines in vitro and in animals bearing intraperitoneal tumor. In the presence of 5 mu g/ml protamine, the efficiency of gene transfer to a number of cancer cell lines normally resistant to adenovirus was significantly enhanced. Protamine's effect in vitro was found to be inversely proportional to the level of expression of the high affinity Ad binding site, coxsackievirus and adenovirus receptor(CAR), on the sur-face of the various cell lines tested. Ad.tk infected tumor cellswere rendered 2.5- to three-fold more sensitive to 20 mu M ganciclovir (GCV) in the presence of protamine. Protamine also augmented the in vivo transfer efficiency of the marker gene, LacZ (contained in an Ad vector), on thesurface of tumors derived from an intraperitoneal mouse model. Quantitative imaging revealed 50% tumor surface transduced with LacZ when treatment was performed in the presence of 50 mu g/ml protamine compared with 12% tumorsurface in controls. However, experiments performed utilizing intraperitoneal administration of Ad. tk/GCV in the presence or absence of 50 mu g/ml protamine demonstrated no significantly improved median survival in mice bearing established intraperitoneal tumors. Similarly, in Fischer rats bearingintrapleural tumor, no improvement in anti-tumor response was observed when Ad treatment was performed intrapleurally in the presence of protamine. Thus, although protamine induced an enhancement of Admediated gene transfer in vitro and in vivo, its use as an adjunct to intracavitary Ad-based cancer gene therapy in vivo appears to be limited.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/09/20 alle ore 00:03:01