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Titolo:
Trans-complementation of vector replication versus Coxsackie-adenovirus-receptor overexpression to improve transgene expression in poorly permissive cancer cells
Autore:
Fechner, H; Wang, X; Wang, H; Jansen, A; Pauschinger, M; Scherubl, H; Bergelson, JM; Schultheiss, HP; Poller, W;
Indirizzi:
Free Univ Berlin, Hosp Benjamin Franklin, Dept Cardiol & Pneumol, D-12200 Berlin, Germany Free Univ Berlin Berlin Germany D-12200 Pneumol, D-12200 Berlin, Germany Free Univ Berlin, Hosp Benjamin Franklin, Dept Gastroenterol, D-12200 Berlin, Germany Free Univ Berlin Berlin Germany D-12200 enterol, D-12200 Berlin, Germany Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA Childrens Hosp Philadelphia Philadelphia PA USA 19104 lphia, PA 19104 USA
Titolo Testata:
GENE THERAPY
fascicolo: 22, volume: 7, anno: 2000,
pagine: 1954 - 1968
SICI:
0969-7128(200011)7:22<1954:TOVRVC>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEDIATED GENE-TRANSFER; HUMAN TUMOR-CELLS; IMMEDIATE-EARLY PROMOTER; THYMIDINE KINASE GENE; IN-VIVO; COLORECTAL-CANCER; HEPATOCELLULAR-CARCINOMA; RECOMBINANT ADENOVIRUS; DEFECTIVE ADENOVIRUS; THERAPY;
Keywords:
Coxsackie-adenovirus-receptor; alpha(v)-integrins; recombinant adenovectors; cancer gene therapy; replication-competent adenovirus; trans-complementation of vector replication;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Fechner, H Free Univ Berlin, Hosp Benjamin Franklin, Dept Cardiol & Pneumol, Hindenburgdamm 30, D-12200 Berlin, Germany Free Univ Berlin Hindenburgdamm 30 Berlin Germany D-12200 many
Citazione:
H. Fechner et al., "Trans-complementation of vector replication versus Coxsackie-adenovirus-receptor overexpression to improve transgene expression in poorly permissive cancer cells", GENE THER, 7(22), 2000, pp. 1954-1968

Abstract

Gene therapy of cancer requires high-level expression of therapeutic transgenes in the target cells. Poor gene transfer is an important limitation toadenovector-mediated cancer gene therapy. We investigated two fundamentally different approaches to improve transgene expression in poorly permissivecancer cells. First, overexpression of the adenovirus attachment receptor CAR to facilitate receptor-mediated adenovector (AdV) uptake into the target cells; second, coinfection of this vector together with traces of replication competent adenovirus (RCA) accidentally arising by back-recombination during large-scale vector preparation. Among eight gastrointestinal cancer cell lines, the colorectal cancer lines showed particularly poor vector-mediated transgene expression (down to 67-fold lower than in HeLa cells). Expression of the adenovirus receptors CAR, alpha (v)beta (5)- and alpha (v)beta (3)-integrin were highly variable between cell lines. AdV uptake was significantly associated with CAR levels on the cell surface, but not with those of the integrins. AdV-mediated CAR overexpression increased CAR density on the surface of all investigated tumor cells and led to enhancement of transgene expression by 1.8- to 6.7-fold. The other principle to enhance transgene expression was 'trans-complementation' of the therapeutic vector, ie induction of ifs replication within the target cells. Traces of RCA in a vector preparation, as well as purified RCA were found to provide sufficient E1-region transcripts to induce replication of the therapeutic vector genome. The number of adenovector-based transgene expression cassettes was greatly amplified by this principle, notably without any influence on the rate ofvector entry. Co-infection of four colorectal cancer cell lines with marker vector plus RCA (at around 240:1 particle ratio) resulted in far strongerenhancement of transgene expression (up to 46-fold) as compared with CAR overexpression, even in cancers almost refractory to standard adenovector-mediated gene transfer. Whereas RCAs need to be strictly avoided in gene therapy of non-malignant diseases for safety reasons, the magnitude of helper virus-induced therapeutic transgene expression could possibly warrant application of this principle to overcome the resistance of highly malignant cancers against gene therapy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 10:30:45