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Sequential treatment with doxorubicin and zoledronic acid has no additive effects in an aggressive model of established bone metastases

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Journal of Cancer Metastasis and Treatment 2019年第2期4卷 87-99页

作者： Mari I.Suominen Rami Käkönen Jukka P.Rissanen Jussi M.HaIIeen Pirkko Härkönen Sanna-Maria Käkönen Pharmatest Services ltd. Turku FI-20520Finland aurexel life sciences ltd. Askainen FI-21240Finland PreclinApps ltd. Raisio FI-21200Finland Institute of Biomedicine University of TurkuTurku 20520Finland

Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. We studied the effects of doxorubicin (DOX) and zoledronic acid (ZOL) and their combination on established bone metastases in the MDA-MB-231(SA) GFP bone metastasis model. Methods: Tumor burden and osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively. The mice were randomized in four groups receiving vehicle, DOX, ZOL or both DOX and ZOL in a sequential combination on day 14. Serum marker of osteoclast number was followed weekly, and blood ionized calcium was measured at sacrifice. Bone and tumor area, apoptosis and proliferation of tumor cells were analyzed from histological sections. Results: ZOL prevented hypercalcemia and osteolytic lesion progression, whereas DOX induced apoptosis in the MDA-MB-231(SA)GFP cells. However, neither of the treatments alone nor in sequential combination were able to reduce tumor burden in bone. Furthermore, no additive effects on tumor cell apoptosis were observed in the ;combination group. Conclusion: No additive effects in combination of DOX and ZOL were observed in this aggressive model of breast cancer bone metastasis.

关键词： Combination treatment breast cancer bone metastasis MDA-MB-231(SA) doxorubicin zoledronic acid

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