Journal
ANNALS OF SURGERY
Volume 253, Issue 3, Pages 546-552Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SLA.0b013e31820a5bbe
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- University Medical Center Giessen and Marburg
- German Academic Exchange Service (DAAD)
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Background: Blockade of aberrant hedgehog (Hh) activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors have not been examined. In this study, we address the role of the Hh pathway in tumor progression of murine islet cell tumors. Methods: To assess in vivo effects, Rip1 Tag2 mice were treated with vehicle or cyclopamine (25 mg/kg/d) (n = 10 in each group). The effect of hedgehog pathway inhibition on survival was determined by continuous application of the small molecule smoothened antagonist cyclopamine. 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 (102 vs 124 days; P = 0.02). Conclusions: Thus, Hh inhibitors may provide a new paradigm for therapy of islet cell tumors in various stages, particularly their use in conjunction with conventional antimetabolites should be further evaluated.
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