Sagopilone inhibits breast cancer bone metastasis and bone destruction due to simultaneous inhibition of both tumor growth and bone resorption.
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.
Strube
Anne
A
Global Drug Discovery, Bayer Schering Pharma AG, Free University Berlin, Berlin, Germany.
Hoffmann
Jens
J
Stepina
Elizaveta
E
Hauff
Peter
P
Klar
Ulrich
U
Käkönen
Sanna-Maria
SM
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
D000972:Antineoplastic Agents, Phytogenic; D052160:Benzothiazoles; D034261:Epothilones; D007527:Isoenzymes; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; C530494:sagopilone; D017239:Paclitaxel