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Titolo:
Evaluation of an E1E4-deleted adenovirus expressing the herpes simplex thymidine kinase suicide gene in cancer gene therapy
Autore:
Lanuti, M; Gao, GP; Force, SD; Chang, MY; El Kouri, C; Amin, KM; Hughes, JV; Wilson, JM; Kaiser, LR; Albelda, SM;
Indirizzi:
Univ Penn, Med Ctr, Dept Surg, Thorac Oncol Res Lab, Philadelphia, PA 19104 Univ Penn Philadelphia PA USA 19104 Oncol Res Lab, Philadelphia, PA 19104 Univ Penn, Med Ctr, Inst Human Gene Therapy, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 e Therapy, Philadelphia, PA 19104 USA Univ Penn, Med Ctr, Wistar Inst, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 star Inst, Philadelphia, PA 19104 USA UnivAPenn, Med Ctr, Dept Med, Div Pulm Crit Care, Philadelphia, PA 19104 US Univ Penn Philadelphia PA USA 19104 Crit Care, Philadelphia, PA 19104 US
Titolo Testata:
HUMAN GENE THERAPY
fascicolo: 3, volume: 10, anno: 1999,
pagine: 463 - 475
SICI:
1043-0342(19990210)10:3<463:EOAEAE>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VIVO; RECOMBINANT ADENOVIRUS; TRANSGENE EXPRESSION; CYSTIC-FIBROSIS; E1-DELETED ADENOVIRUSES; MALIGNANT MESOTHELIOMA; DNA-REPLICATION; MOUSE-LIVER; CELL-LINE; VECTORS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Albelda, SM Hosp Univ Penn, 3600 Spruce St,809 Maloney Bldg, Philadelphia,PA 19104 USA Hosp Univ Penn 3600 Spruce St,809 Maloney Bldg Philadelphia PA USA 19104
Citazione:
M. Lanuti et al., "Evaluation of an E1E4-deleted adenovirus expressing the herpes simplex thymidine kinase suicide gene in cancer gene therapy", HUM GENE TH, 10(3), 1999, pp. 463-475

Abstract

Studies with first-generation adenoviral vectors have uncovered limitations that include finite transgene persistence, potential hepatotoxicity, and contamination with replication-competent adenovirus (RCA). To address theselimitations within the context of cancer suicide gene therapy, a new adenoviral vector was developed containing the herpes simplex virus type 1 thymidine kinase (HSV tk) gene inserted in the Fl region of a recombinant vectorcontaining deletions in the E-1 and E-4 regions of the Ads genome. The HSVtk minigene was placed under transcriptional control of a Rous sarcoma virus (RSV) promoter. This new E1E4-deleted vector was compared with the first-generation E1E3-deleted Ad.RSVtk vector. Generation of replication-competent adenovirus during production was eliminated. Using semiquantitative immunoblotting, the two vectors produced equivalent amounts of the expected 44-kDa tk-encoded protein in three different cell lines tested. The ability ofthe E1E4-deleted vector to sensitize tumor cells to ganciclovir (GCV) using in vitro assays and mixing studies was comparable to that of the E1E3-deleted vector. In vivo bystander effects were investigated using mixing studies in a syngeneic flank tumor model and demonstrated no difference between vectors in either immunocompetent or immunodeficient mice. To test the efficiency of these vectors in treating tumors in clinically relevant models, virus was injected intraperitoneally into tumor-bearing SCID mice and intrapleurally in a syngeneic rat mesothelioma model. After treatment of animals with ganciclovir, both vectors were roughly equivalent in their ability to increase mean survival (from similar to 40 to similar to 70 days) and markedly reduce tumor burden. Finally, formal toxicology studies were performed and showed similar amounts of local inflammation without systemic toxicity. In summary, this series of in vitro and in vivo experiments indicates thatthe performance of the recombinant E1E4-deleted adenoviral vector was virtually identical to that of the E1E3-deleted vector. Since the E1E4 vector has a much lower rate of recombination during production and has been shown to be less hepatotoxic in animal models, this new vector should prove superior to the first-generation Ad.HSVtk vectors in clinical cancer gene therapy trials.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 23:54:07