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

LEANDRO E. MAINETTI; MARÍA JOSÉ RICO; CINTIA DANIELA KAUFMAN; MÓNICA CAROLINA GRILLO; JULIAN GUERCETTI; MARÍA VIRGINIA BAGLIONI; ANTONELA DEL GUÍDUCE ; MARÍA CELESTE CAPITANI; MATÍAS FUSINI; VIVIANA ROSA ROZADOS; O. GRACIELA SCHAROVSKY

Oncotarget

Albany, N.Y.

Año: 2020

1949-2553

Metronomic chemotherapy refers to the minimum biologically effective doses ofa 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 medicalindication, different from the original one. In oncology the combination of these twotherapeutic approaches is called ?Metronomics?.The aim of this work is to evaluate the therapeutic effect of cyclophosphamidein a metronomic schedule in combination with the repurposed drug losartan in twogenetically different mice models of triple negative breast cancer.Our findings showed that adding losartan to metronomic cyclophosphamidesignificantly improved the therapeutic outcome. In both models the combinedtreatment increased the mice?s survival without sings of toxicity. Moreover, weelucidated some of the mechanisms of action involved, which include a decrease ofintratumor hypoxia, stimulation of the immune response and remodeling of the tumormicroenvironment.The remarkable therapeutic effect, the lack of toxicity, the low cost of the drugsand its oral administration, strongly suggest its translation to the clinical setting inthe near future.