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Suominen et al. J Cancer Metastasis Treat 2019;5:14 Journal of Cancer
DOI: 10.20517/2394-4722.2018.64 Metastasis and Treatment

Original Article Open Access

Sequential treatment with doxorubicin and
zoledronic acid has no additive effects in an

aggressive model of established bone metastases

Mari I. Suominen , Rami Käkönen , Jukka P. Rissanen , Jussi M. Halleen , Pirkko Härkönen , Sanna-Maria
3
2
1
4
1
Käkönen 2,4
1 Pharmatest Services Ltd., Turku FI-20520, Finland.
2 Aurexel Life Sciences Ltd., Askainen FI-21240, Finland.
3 PreclinApps Ltd., Raisio FI-21200, Finland.
4 Institute of Biomedicine, University of Turku, Turku 20520, Finland.
Correspondence to: Dr. Mari I. Suominen, Pharmatest Services Ltd., Itäinen Pitkäkatu 4C, Turku, FI-20520, Finland.
E-mail: mari.suominen@pharmatest.com

How to cite this article: Suominen MI, Käkönen R, Rissanen JP, Halleen JM, Härkönen P, Käkönen SM. Sequential treatment
with doxorubicin and zoledronic acid has no additive effects in an aggressive model of established bone metastases. J Cancer
Metastasis Treat 2019;5:14. http://dx.doi.org/10.20517/2394-4722.2018.64

Received: 29 Sep 2018 First Decision: 16 Nov 2018 Revised: 3 Jan 2019 Accepted: 14 Jan 2019 Published: 28 Feb 2019

Science Editor: Andrea Nicolini Copy Editor: Cui Yu Production Editor: Huan-Liang Wu

Abstract
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

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
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