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Titolo:
Enhanced apoptotic activity of a p53 variant in tumors resistant to wild-type p53 treatment
Autore:
Atencio, IA; Avanzini, JB; Johnson, D; Neuteboom, S; Vaillancourt, MT; Nielsen, LL; Hajian, G; Sutjipto, S; Sugarman, BJ; Philopena, J; McAllister, DL; Beltran, JC; Nodelman, M; Ramachandra, M; Wills, KN;
Indirizzi:
Canji Inc, La Jolla, CA 92121 USA Canji Inc La Jolla CA USA 92121Canji Inc, La Jolla, CA 92121 USA NewBiot, San Diego, CA 92121 USA NewBiot San Diego CA USA 92121NewBiot, San Diego, CA 92121 USA Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA Schering Plough Corp Kenilworth NJ USA 07033 st, Kenilworth, NJ 07033 USA
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 1, volume: 4, anno: 2001,
pagine: 5 - 12
SICI:
1525-0016(200107)4:1<5:EAAOAP>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELL LUNG-CANCER; MDM2 GENE AMPLIFICATION; ENCODING HUMAN P53; BREAST-CANCER; GLIOBLASTOMA CELLS; GROWTH-INHIBITION; SUPPRESSOR GENE; IN-VIVO; THERAPY; OVEREXPRESSION;
Keywords:
adenovirus; p53; variant; MDM2; apoptosis; antitumor; efficacy; gene therapy; chemotherapeutics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Atencio, IA Canji Inc, 3525 John Hopkins Court, La Jolla, CA 92121 USA Canji Inc 3525 John Hopkins Court La Jolla CA USA 92121 21 USA
Citazione:
I.A. Atencio et al., "Enhanced apoptotic activity of a p53 variant in tumors resistant to wild-type p53 treatment", MOL THER, 4(1), 2001, pp. 5-12

Abstract

TP53 is the most commonly altered tumor-suppressor gene in cancer and is currently being tested in Phase II/III gene replacement trials. Many tumors contain wild-type TP53 sequence with elevated MDM2 protein levels, targeting p53 for degradation. These tumors are more refractory to treatment with exogenous wild-type p53. Here we generate a recombinant adenovirus expressing a p53 variant, rAd-p53 (d 13-19), that is deleted for the amino acid sequence necessary for MDM2 binding (amino acids 13-19). We compared the apoptotic activity of rAd-p53 (d 13-19) with that of a recombinant adenovirus expressing wild-type p53 (rAd-p53) in cell lines that differ in endogenous p53status, rAd-p53 (d 13-19) caused higher levels of apoptosis in p53 wild-type tumor lines compared with wild-type p53 treatment, as measured by annexin V-FITC staining. In p53-altered tumor lines, rAd-p53 (d 13-19) showed apoptotic activity similar to that seen with wild-type p53 treatment. In normal cells, no increase in cytopathicity was detected with rAd-p53 (d 13-19) compared with wild-type p53 treatment. This variant protein displayed synergy with chemotherapeutic agents to inhibit proliferation of ovarian and breast cell lines. The p53 variant showed greater antitumor activity in an established p53 wild-type tumor compared with treatment with wild-type p53. Thep53 variant represents a means of expanding TP53 gene therapy to tumors that are resistant to p53 treatment due to the cellular responses to wild-type p53.

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Documento generato il 19/01/20 alle ore 09:21:47