Preclinical combination therapy of the investigational drug NAMI-A+ with doxorubicin for mammary cancer
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Aim of the study The tumor metastases targeting ruthenium complex NAMI-A synergistically improves the activity of gemcitabine in combination therapies. High-throughput screening was used to identify other potential drug combinations from a library of FDA approved drugs. Doxorubicin was identified as a hit compound and was therefore evaluated in combination with NAMI-A in vitro and in a preclinical in vivo model. Results High-throughput screening identified eight structurally diverse compounds that synergize with NAMI-A including doxorubicin. The combination index on MCF-7 cells showed synergism as the concentration of NAMI-A increases independent of the doxorubicin concentration. In MCa mammary carcinoma of CBA mice, NAMI-A (35 mg/kg/day i.p. on days 7–12) followed by doxorubicin (10 mg/kg i.p. on day 16), significantly increased the effects of the individual drugs on metastases with 70 % animals resulting free of macroscopically detectable tumor nodules in the lungs at sacrifice. NAMI-A, unlike doxorubicin, cured 60 % of the treated mice but the combination therapy was toxic to the animals. Conclusions The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses.
KeywordsCombination therapy Mammary cancer Doxorubicin NAMI-A In vitro In vivo
Contributions by Ms. L. Macrì and Mr. G. Flego are gratefully appreciated. Dr. G. Turcatti at the Biomolecular Screening Facility (EPFL), Dr. C. Casarsa who performed the histological examinations and Dr. M. Cocchietto who determined ruthenium content are thanked for their help.
Financial support by: Callerio Foundation Onlus and Swiss National Science Foundation, National Centre of Competence in Research Chemical Biology2Visualisation and Control of Biological Processes Using Chemistry.
Conflict of Interest
No conflict of interest are declared by the authors.
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