| A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo. | |
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MedLine Citation:
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PMID: 21134556 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Most medullary thyroid carcinomas (MTC) recur or progress despite curative resection. Current targeted therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build on previous in vitro work and evaluate withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC. METHODS: A total of 5 million DRO-81-1 human MTC cells injected in the left posterior neck of nu/nu mice generated metastases uniformly to the liver, spleen, and/or lungs. Treatment with WA (8 mg/kg/day, intraperitoneally, for 21 days) was started for neoplasms > 100 mm(3). Endpoints were survival, neoplasm > 15,00 mm(3), decreased body weight, or body score (all measured three times/wk). RESULTS: All controls (saline; n = 5) died or deteriorated from metastatic disease by 7 weeks postinjection. All treated animals were alive (WA; n = 5), having tumor regression and growth delay without toxicity or weight loss at 6 weeks posttreatment (P < .01). Tumor cells treated with WA demonstrated inhibition of total and phospho-RET levels by Western blot analysis in a dose-dependent manner (almost complete inhibition with treatment of 5 μM WA) as well as potent inhibition of phospho-ERK and phospho-Akt levels. CONCLUSION: WA is a novel natural-product RET-inhibitor with efficacy in a metastatic murine model of MTC. Further long-term efficacy/toxicity studies are warranted to evaluate this compound for clinical translation. |
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Authors:
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Abbas K Samadi; Ridhwi Mukerji; Anuj Shah; Barbara N Timmermann; Mark S Cohen |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Surgery Volume: 148 ISSN: 1532-7361 ISO Abbreviation: Surgery Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-07 Completed Date: 2011-01-14 Revised Date: 2013-05-27 |
Medline Journal Info:
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Nlm Unique ID: 0417347 Medline TA: Surgery Country: United States |
Other Details:
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Languages: eng Pagination: 1228-36; discussion 1236 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2010 Mosby, Inc. All rights reserved. |
Affiliation:
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Department of Surgery, The University of Kansas Medical Center, Kansas City, KS, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / therapeutic use Biopsy, Fine-Needle Calcitonin / blood Humans Mice Mice, Nude Neural Crest / pathology Proto-Oncogene Proteins c-ret / antagonists & inhibitors* Thyroid Neoplasms / blood, drug therapy, pathology Transplantation, Heterologous / methods, pathology Withanolides / therapeutic use* |
| Grant Support | |
ID/Acronym/Agency:
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L30 CA136330-02/CA/NCI NIH HHS; P20 RR015563-105577/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Withanolides; 5119-48-2/withaferin A; 9007-12-9/Calcitonin; EC 2.7.10.1/Proto-Oncogene Proteins c-ret; EC 2.7.10.1/Ret protein, mouse |
| Comments/Corrections | |
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