title: Sagopilone inhibits breast cancer bone metastasis and bone destruction due to simultaneous inhibition of both tumor growth and bone resorption.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Global Drug Discovery, Bayer Schering Pharma AG, Free University Berlin, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Strube
authors.forename: Jens
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Stepina
authors.forename: Peter
authors.initials: P
authors.lastname: Hauff
authors.forename: Ulrich
authors.initials: U
authors.lastname: Klar
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Käkönen
mesh_terms: D000135:Acid Phosphatase / Q000097:blood / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001862:Bone Resorption / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002100:Cachexia / Q000209:etiology / Q000517:prevention & control; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000097:blood / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control; D017239:Paclitaxel / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D052160:Benzothiazoles; D034261:Epothilones; D007527:Isoenzymes; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C530494:sagopilone; D017239:Paclitaxel