Vascular normalization of triple negative mammary adenocarcinomas treated metronomically with cyclophosphamide (Cy) and losartan (Los)

RICO, MARÍA J.; GUERCETTI, J.; CAPITANI, MARÍA C.; FUSINI, MATÍAS E.; KAUFMAN, CINTIA D.; BAGLIONI, MARÍA VIRGINIA.; ROZADOS, VIVIANA R.; MAINETTI, LEANDRO E.; GRILLO, M. CAROLINA; DEL GIÚDICE, ANTONELA; SCHAROVSKY, O. GRACIELA

Congreso; Reunión Anual de Sociedades de Biociencia; 2020

Sociedad Argentina de Investigaciones Clínicas

CY is an alkylating drug with toxic action on proliferating cells. LOS is an antagonist of angiotensin II receptor, used to treat hypertension. It was postulated that the antiangiogenic effect of metronomic chemotherapy (MCT) could be obtained through a normalization of the abnormal tumor vasculature. Previously, we demonstrated that MCT with CY+LOS, in M-234p and M-406 tumor models, caused inhibition of tumor growth, increase of survival rate and was devoid of toxicity. We aimed to analyze the structural and morphologic changes in M-234p and M-406 vasculature after MCT with CY+LOS. Mice were challenged with each tumor (Day 0). On days 31 (M-234p) and 22 (M-406) tumor samples were taken from: 1) CONTROL: with tumor and no treatment, 2) TREATED: with tumor and treated in the drinking water, from days 5 and 8, respectively, with 2a) CY (25mg/kg/day), 2b) LOS (200mg/kg/day) and 2c) CY+LOS as 2a+2b. Samples were fixed, paraffin embedded, cut in 5μm slices and stained with H&E. The capillaries in CONTROL group showed a circumferentially incomplete inner lining layer of small cells, flattened nuclei, marked intercellular gaps and an underlying sheet of very thin and interrupted connective tissue. No pericytes were observed around the capillaries. Samples from CY+LOS group showed intra and peritumoral capillaries with structure and morphology similar to normal patterns in tissues without tumor. Endothelial cells provided a continuous and uninterrupted linning, with a well-defined basal membrane covered by pericytes. Samples from 2a and 2b tumors were similar to CONTROL group. Results were similar for M-234p and M-406 tumors. The CY+LOS treatment produced modifications of tumor vasculature consisting of normalization of tumor vessels that showed a morphology similar to normal mammary tissue. This changes may reduce hypoxia, increase tumor oxygenation, leading to a better delivery of drugs and a better therapeutic outcome for triple negative mammary tumors.