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Titolo:
Transactivation of the metallothionein promoter in cisplatin-resistant cancer cells: a specific gene therapy strategy
Autore:
Vandier, D; Calvez, V; Massade, L; Gouyette, A; Mickley, L; Fojo, T; Rixe, O;
Indirizzi:
NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 anch, Div Clin Sci, NIH, Bethesda, MD 20892 USA Hop La Pitie Salpetriere, Serv Virol, Paris, France Hop La Pitie Salpetriere Paris France triere, Serv Virol, Paris, France INSERM, U490, Mol Toxicol Lab, Paris, France INSERM Paris FranceINSERM, U490, Mol Toxicol Lab, Paris, France Inst Gustave Roussy, Lab Pharmacotoxicol & Pharmacogenet, CNRS, UMR 8532, Villejuif, France Inst Gustave Roussy Villejuif France CNRS, UMR 8532, Villejuif, France Clin Claude Bernard, Dept Oncol, Metz, France Clin Claude Bernard Metz France laude Bernard, Dept Oncol, Metz, France
Titolo Testata:
JOURNAL OF THE NATIONAL CANCER INSTITUTE
fascicolo: 8, volume: 92, anno: 2000,
pagine: 642 - 647
Fonte:
ISI
Lingua:
ENG
Soggetto:
THYMIDINE KINASE GENE; CIS-DIAMMINEDICHLOROPLATINUM(II) RESISTANCE; OVARIAN-CANCER; EXPRESSION; LINES; CARCINOMA; DNA; GANCICLOVIR; MECHANISM; DELIVERY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Fojo, T NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,Rm 12C428, Bethesda, MD 20892 USA NCI Bldg 10,Rm 12C428 Bethesda MD USA 20892 Bethesda, MD 20892 USA
Citazione:
D. Vandier et al., "Transactivation of the metallothionein promoter in cisplatin-resistant cancer cells: a specific gene therapy strategy", J NAT CANC, 92(8), 2000, pp. 642-647

Abstract

Background: Cisplatin (cis-diammine-dichloroplatinum) is one of the most active agents against a broad range of malignancies, including ovarian cancer. Cisplatin resistance appears to be associated with several molecular alterations, including overexpression of metallothionein, a metal-binding protein. In the present study, we attempted to take advantage of metallothionein overexpression to overcome cisplatin resistance. Methods: Using a virus-free system (liposomes), we sought to express the suicide gene, thymidine kinase (TK), driven by the promoter of the human metallothionein IIa (hMTIIa)gene using the pMT-TK plasmid, We used cisplatin-resistant human ovarian carcinoma cells as a model. Results: Ne first analyzed metallothionein expression using a ribonuclease protection assay, In comparison to parental cells, the cisplatin-resistant cells were found to have increased expression ofmetallothionein messenger RNA (mRNA). Metallothionein overexpression in these cells was not associated with an increased copy number of the hMTIIa gene or with different transfection efficiencies. Furthermore, we showed by reverse transcription-polymerase chain reaction analysis that transfection of the pMT-TK plasmid results in a 56-fold higher expression of thymidine kinase mRNA in cisplatin-resistant cells compared with parental cells, consistent with increased metallothionein promoter-mediated transactivation in the cisplatin-resistant cells, Transfection of resistant cells with pMT-TK; or a control plasmid (pCD3-TK) resulted in a marked sensitization to ganciclovir, wth a 50% cell growth-inhibitory concentration (IC50) of 20 mu g/mL and 9 mu g/mL, respectively. Transfections of the cisplatin-sensitive cells resulted in no sensitization to ganciclovir with pMT-TK; (IC50 200 mu g/ mL) and a high sensitization with pCD3-TK( (IC50 = 6 mu g/mL). Conclusion: These studies suggest that pMT-TK gene therapy may provide an alternative treatment for cisplatin-refractory ovarian tumors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 03:35:31