Therapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumours

2.50
Hdl Handle:
http://hdl.handle.net/10541/109061
Title:
Therapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumours
Authors:
Bauer, Sebastian; Mühlenberg, Thomas; Leahy, Michael G; Hoiczyk, Mathias; Gauler, Thomas; Schuler, Martin; Looijenga, Leendert
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, 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.
Affiliation:
Sarcoma Centre, West German Cancer Centre, University Hospital Essen, Essen, Germany; Department of Medicine (Cancer Research), West German Cancer Centre, University Duisburg-Essen, Essen, Germany.
Citation:
Therapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumours. 2009: Eur Urol
Journal:
European Urology
Issue Date:
21-Jun-2010
URI:
http://hdl.handle.net/10541/109061
DOI:
10.1016/j.eururo.2009.06.014
PubMed ID:
19560254
Type:
Article
Language:
en
ISSN:
1873-7560
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorBauer, Sebastianen
dc.contributor.authorMühlenberg, Thomasen
dc.contributor.authorLeahy, Michael Gen
dc.contributor.authorHoiczyk, Mathiasen
dc.contributor.authorGauler, Thomasen
dc.contributor.authorSchuler, Martinen
dc.contributor.authorLooijenga, Leenderten
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.en
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

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