Document Detail


Sagopilone inhibits breast cancer bone metastasis and bone destruction due to simultaneous inhibition of both tumor growth and bone resorption.
MedLine Citation:
PMID:  19470728     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a "vicious cycle" of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo, and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model. EXPERIMENTAL DESIGN: The potency of sagopilone was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic. RESULTS: We showed that sagopilone inhibited tumor burden and bone destruction, in addition to reducing tumor-induced cachexia and paraplegia. The reduction in osteolytic lesions, tumor growth in bone, and weight loss was statistically significant in the preventive model compared with the vehicle group. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts and significantly reduced the osteolytic lesion area, bone volume loss, and bone resorption compared with vehicle treatment while simultaneously inhibiting tumor burden. An in vitro assay confirmed that sagopilone inhibited osteoclast activation without cytotoxic effects, whereas paclitaxel resulted in lower inhibition and high levels of cytotoxicity. CONCLUSIONS: Sagopilone seems to inhibit the vicious cycle at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment of patients with breast cancer at risk from bone metastases or with bone lesions already present. Phase II clinical trials with sagopilone in patients with breast cancer are ongoing.
Authors:
Anne Strube; Jens Hoffmann; Elizaveta Stepina; Peter Hauff; Ulrich Klar; Sanna-Maria Käkönen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-26
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  15     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-02     Completed Date:  2009-07-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3751-9     Citation Subset:  IM    
Affiliation:
Global Drug Discovery, Bayer Schering Pharma AG, Free University Berlin, Berlin, Germany.
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MeSH Terms
Descriptor/Qualifier:
Acid Phosphatase / blood,  metabolism
Animals
Antineoplastic Agents, Phytogenic / pharmacology
Benzothiazoles / pharmacology*
Bone Neoplasms / prevention & control*,  secondary
Bone Resorption / blood,  pathology,  prevention & control*
Bone and Bones / drug effects*,  metabolism,  pathology
Cachexia / etiology,  prevention & control
Cell Line, Tumor
Dose-Response Relationship, Drug
Epothilones / pharmacology*
Female
Humans
Isoenzymes / blood,  metabolism
Mammary Neoplasms, Experimental / complications,  drug therapy*,  pathology
Mice
Mice, Nude
Osteoclasts / drug effects,  metabolism,  pathology
Osteolysis / etiology,  prevention & control
Paclitaxel / pharmacology
Tumor Burden / drug effects
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Benzothiazoles; 0/Epothilones; 0/Isoenzymes; 0/sagopilone; 33069-62-4/Paclitaxel; EC 3.1.3.-/tartrate-resistant acid phosphatase; EC 3.1.3.2/Acid Phosphatase

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


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