Therapeutic potential of Mdm2 inhibition in malignant germ cell tumours.
Eur Urol
; 57(4): 679-87, 2010 Apr.
Article
em En
| MEDLINE
| ID: mdl-19560254
ABSTRACT
BACKGROUND:
Inadequate response to cisplatin-based chemotherapy is associated with poor prognosis in patients with advanced malignant testicular germ cell tumours (TGCTs), especially of the nonseminomatous type. Novel chemotherapeutic agents have failed so far to significantly improve the outcome of such patients. The majority of these tumours express low levels of p53, and TP53 mutations are rarely observed. Murine double minute 2 (Mdm2) inhibitors enhance apoptosis in tumours harbouring wild-type p53.OBJECTIVE:
We sought to investigate the potential therapeutic value of Mdm2 in TGCT-derived cell lines with the histology of nonseminoma. DESIGN, SETTING, ANDPARTICIPANTS:
The Mdm2 inhibitor nutlin-3 was evaluated alone and in combination with cisplatin in a panel of germ cell tumour (GCT)-derived cell lines (embryonal carcinomas, being the nonseminomatous stem-cell component) with wild-type (NT2 and 2102EP cells) and mutant (NCCIT cells) p53 status. MEASUREMENTS Biological consequences of Mdm2 inhibition were determined by analysis of the p53 pathway, cell proliferation, and apoptosis. RESULTS ANDLIMITATIONS:
Nutlin-3 exhibited significant activity (IC50 2.8 µM) in NT2 and 2102EP (wild-type p53) but not in p53-mutant NCCIT cells (<10% inhibition at 10 µM). At concentrations beyond 500 nM, additive effects were seen for the combination of nutlin-3 and cisplatin in NT2 and 2102EP cells but not in NCCIT cells. This correlated with the induction of p53 and its target p21, suggesting an on-target effect of nutlin-3. Moreover, nutlin-3 (5 µM) and cisplatin (0.5 µM) additively induced caspase cleavage and apoptosis in NT2 cells and 2102-EP cells but not in p53-mutant NCCIT cells.CONCLUSIONS:
These results provide strong evidence for further development of pharmacologic Mdm2 inhibition for the treatment of patients suffering from high-risk nonseminomatous TGCT with wild-type p53 status.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Testiculares
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Protocolos de Quimioterapia Combinada Antineoplásica
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Carcinoma Embrionário
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Proteínas Proto-Oncogênicas c-mdm2
Limite:
Humans
/
Male
Idioma:
En
Revista:
Eur Urol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Alemanha