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dc.contributor.authorBauer, Sebastian
dc.contributor.authorMühlenberg, Thomas
dc.contributor.authorLeahy, Michael G
dc.contributor.authorHoiczyk, Mathias
dc.contributor.authorGauler, Thomas
dc.contributor.authorSchuler, Martin
dc.contributor.authorLooijenga, Leendert
dc.date.accessioned2010-08-04T14:03:19Z
dc.date.available2010-08-04T14:03:19Z
dc.date.issued2010-06-21
dc.identifier.citationTherapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumours. 2009: Eur Urolen
dc.identifier.issn1873-7560
dc.identifier.pmid19560254
dc.identifier.doi10.1016/j.eururo.2009.06.014
dc.identifier.urihttp://hdl.handle.net/10541/109061
dc.description.abstractBACKGROUND: 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, AND PARTICIPANTS: 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 AND LIMITATIONS: Nutlin-3 exhibited significant activity (IC50 2.8muM) in NT2 and 2102EP (wild-type p53) but not in p53-mutant NCCIT cells (<10% inhibition at 10muM). At concentrations beyond 500nM, 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 (5muM) and cisplatin (0.5muM) 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.
dc.languageENG
dc.language.isoenen
dc.subjectMdm2en
dc.subjectNutlin-3en
dc.subjectp53en
dc.subjectMalignant Germ Cell Tumoursen
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols
dc.subject.meshCarcinoma, Embryonal
dc.subject.meshProto-Oncogene Proteins c-mdm2
dc.subject.meshTesticular Neoplasms
dc.subject.meshTumor Suppressor Protein p53
dc.titleTherapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumoursen
dc.typeArticleen
dc.contributor.departmentSarcoma Centre, West German Cancer Centre, University Hospital Essen, Essen, Germany; Department of Medicine (Cancer Research), West German Cancer Centre, University Duisburg-Essen, Essen, Germany.en
dc.identifier.journalEuropean Urologyen
html.description.abstractBACKGROUND: 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, AND PARTICIPANTS: 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 AND LIMITATIONS: Nutlin-3 exhibited significant activity (IC50 2.8muM) in NT2 and 2102EP (wild-type p53) but not in p53-mutant NCCIT cells (<10% inhibition at 10muM). At concentrations beyond 500nM, 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 (5muM) and cisplatin (0.5muM) 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.


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