Research Papers:

Losartan improves the therapeutic effect of metronomic cyclophosphamide in triple negative mammary cancer models

Leandro E. Mainetti _, María José Rico, Cintia Daniela Kaufman, Monica Carolina Grillo, Julian Guercetti, María Virginia Baglioni, Antonela Del Giúdice, Maria Celeste Capitani, Matias Fusini, Viviana Rosa Rozados and O. Graciela Scharovsky

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Oncotarget. 2020; 11:3048-3060. https://doi.org/10.18632/oncotarget.27694

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Leandro E. Mainetti1,2,*, María José Rico1,2,*, Cintia Daniela Kaufman1,2, Monica Carolina Grillo1, Julian Guercetti1, María Virginia Baglioni1,2, Antonela Del Giúdice1,2, Maria Celeste Capitani1, Matias Fusini1, Viviana Rosa Rozados1,2,# and O. Graciela Scharovsky1,2,3,#

1 Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina

2 Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina

3 Metronomics Global Health Initiative, Marseille, France

* These authors contributed equally and are co-first authors

# These authors contributed equally and are co-senior authors

Correspondence to:

Leandro E. Mainetti,email: [email protected]

Keywords: mammary cancer; metronomic chemotherapy; drug repurposing; cyclophosphamide; losartan

Received: March 17, 2020     Accepted: May 25, 2020     Published: August 11, 2020


Metronomic chemotherapy refers to the minimum biologically effective doses of a chemotherapy agent given as a continuous regimen without extended rest periods. Drug repurposing is defined as the use of an already known drug for a new medical indication, different from the original one. In oncology the combination of these two therapeutic approaches is called “Metronomics”.

The aim of this work is to evaluate the therapeutic effect of cyclophosphamide in a metronomic schedule in combination with the repurposed drug losartan in two genetically different mice models of triple negative breast cancer.

Our findings showed that adding losartan to metronomic cyclophosphamide significantly improved the therapeutic outcome. In both models the combined treatment increased the mice’s survival without sings of toxicity. Moreover, we elucidated some of the mechanisms of action involved, which include a decrease of intratumor hypoxia, stimulation of the immune response and remodeling of the tumor microenvironment.

The remarkable therapeutic effect, the lack of toxicity, the low cost of the drugs and its oral administration, strongly suggest its translation to the clinical setting in the near future.

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