Artikel
The orally available hedgehog inhibitor cyclopamine is a new effective chemotherapeutic agent in transgenic Rip1Tag2 mice
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Autoren
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Dominik Wiese
- Universitätsklinikum Marburg, Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Marburg
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Johannes Rehm
- Universitätsklinikum Marburg, Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Marburg
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Jens Waldmann
- Universitätsklinik Marburg, Visceral-, Thorax- und Gefaesschirurgie, Marburg
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Emily P. Slater
- Universitätsklinikum Marburg, Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Marburg
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Detlef K. Bartsch
- Universitätsklinikum Marburg, Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Marburg
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Volker Fendrich
- Universitätsklinik Marburg, Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Marburg
| Veröffentlicht: | 20. Mai 2011 |
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Gliederung
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Introduction: This study was designed to evaluate the role of the Hedgehog (Hh) pathway in tumor progression of murine islet cell tumors. Blockade of aberrant Hh activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with a new orally available agent have not been examined.
Materials and methods: To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or orally available cyclopamine (25 mg/kg/d). Treatment started at 5 weeks of age and was continued until death. The resected pancreata were evaluated macroscopically and microscopically. Furthermore, the tumor surface, tumor cell proliferation and apoptosis were evaluated.
Results: Hh-inhibition was confirmed by downregulation of Hh-target genes. Cyclopamine response was associated with increased apoptosis, decreased tumor cell proliferation and reduced tumor volume. Furthermore, hedgehog inhibition with cyclopamine significantly prolonged median survival in the used transgenic mouse model (105 vs. 115 days; p<0.05). Quantitative real-time PCR for Gli1 demonstrated significant down-regulation in the islet cell tumors of Rip1Tag2 mice treated with cyclopamine, confirming our ability to achieve effective pharmacologic levels of cyclopamine within the desired tissue site, in vivo.
Conclusion: This is the first study to show that the new orally available Hh inhibitor cyclopamine may provide a new paradigm for therapy of islet cell tumors, particularly their use in conjunction with conventional anti-metabolites should be further evaluated.
