Document Detail


Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies.
MedLine Citation:
PMID:  12855656     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The purpose of the following study was to investigate the safety and efficacy of the novel multitargeted indolinone receptor tyrosine kinase (RTK) inhibitor, SU11654, using a canine model of spontaneous tumors. This p.o. bioavailable compound exhibits potent inhibitory activity against members of the split kinase family of RTKs, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Kit, and Flt-3, resulting in both direct antitumor and antiangiogenic activity. EXPERIMENTAL DESIGN: This was a Phase I trial in which successive cohorts of dogs with spontaneous tumors that had failed standard treatment regimens received escalating doses of SU11654 as oral therapy. Pharmacokinetics, toxicity, and tumor response were assessed. RESULTS: Fifty-seven dogs with a variety of cancers were enrolled; of these, 10 experienced progressive disease within the first 3 weeks. Measurable objective responses were observed in 16 dogs (including 6 complete responses), primarily in mast cell tumors (n = 11), mixed mammary carcinomas (n = 2), soft tissue sarcomas (n = 2), and multiple myeloma (n = 1), for an overall response rate of 28% (16 of 57). Stable disease of sufficient duration to be considered clinically meaningful (>10 weeks) was seen in an additional 15 dogs, for a resultant overall biological activity of 54% (31 of 57). CONCLUSIONS: This study provides the first evidence that p.o. administered kinase inhibitors can exhibit activity against a variety of spontaneous malignancies. Given the similarities of canine and human cancers with regard to tumor biology and the presence of analogous RTK dysregulation, it is likely that such agents will demonstrate comparable antineoplastic activity in people.
Authors:
Cheryl A London; Alison L Hannah; Regina Zadovoskaya; May B Chien; Cynthia Kollias-Baker; Mona Rosenberg; Sue Downing; Gerald Post; Joseph Boucher; Narmada Shenoy; Dirk B Mendel; Gerald McMahon; Julie M Cherrington
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Publication Detail:
Type:  Clinical Trial; Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  9     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-07-11     Completed Date:  2004-04-20     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2755-68     Citation Subset:  IM    
Affiliation:
School of Veterinary Medicine, University of California, Davis, Davis, California 95616, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology
Dog Diseases / drug therapy*
Dogs
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Female
Indoles / administration & dosage,  therapeutic use*
Inhibitory Concentration 50
Male
Models, Chemical
Mutation
Neoplasms / drug therapy*,  veterinary*
Proto-Oncogene Proteins c-kit / genetics
Pyrroles / administration & dosage,  therapeutic use*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptors, Vascular Endothelial Growth Factor / metabolism
Time Factors
Tomography, X-Ray Computed
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Indoles; 0/Pyrroles; 0/SU 11654; EC 2.7.10.1/Proto-Oncogene Proteins c-kit; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.10.1/Receptors, Vascular Endothelial Growth Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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