Abstract 1125: Altered therapeutic response to metronomic chemotherapy in a metabolic syndrome model of mice bearing a mammary adenocarcinoma: Implication of intestinal ABC transporters
Authors: María Manuela Barranco, Martín Habib, Bianca Di Carlo, Nicolás Sigal, María Sylvestre Begnis, Felipe Zechinatti, Antonela Del Giudice, María Jose Rico, Viviana Rosa Rosados, O. Graciela Scharovsky, Silvina Stella Maris Villanueva, Fabiana García, Leandro E Mainetti
Journal: Cancer Research (2021)

Abstract Breast cancer is one of the most prevalent and deadly cancers worldwide. Its prognosis depends on the cell type, as well as the age and comorbidities of each patient. A novel therapeutic approach is metronomic chemotherapy (MCT) characterized by chronic, low dose drug administration with therapeutic efficacy andlow or null toxicity as majoradvantages. The comorbidity that worsens cancer prognosis is metabolic syndrome (MS) characterized by obesity, insulinresistance, hyperglycemia, hypertriglyceridemia and hypercholesterolemia, and a chronic systemic inflammatory state. These conditions influence the intestinal biochemical barrier, altering the multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp activities. Significantly, these two efflux pumps transport chemotherapeutics drugs such as cyclophosphamide (Cy). Our aim was to evaluate the effectiveness and toxicity of MCT with Cy in mice with metabolic syndrome bearing a mammary adenocarcinoma. Simultaneously, the activities of the intestinal efflux transporters were assessed. CBi male mice (5 weeks n=20/group), were fed with a chow diet (C) and a diet with 40% calories of fat (HFD) throughout the experiment. At 16 weeks, the development of MS was confirmed by biochemical and morphological parameters. The Mrp2 and P-gp activities were evaluated using the in vitro model of everted intestinal sacs. Once the MS features were settled, mice werechallenged s.c. with triple negative M-406 mammary adenocarcinoma (day 0); when the tumor was palpable, mice were distributed into 4 groups (n=8/group):GI: C no treatment, GII:C+Cy (30 mg/kg/day in drinking water), GIII: HFD no treatment and GIV: HFD+Cy. Efflux of Mrp2 substrate DNP-SG decreased 64% in HFD respect to C (P&amp;lt;0.05); transport rate of rhodamine 123 by P-gp decreased 55% in HFD vs C (P&amp;lt;0.05). At the end of the experiment (day 22), the tumor volume was lower in GIIvsGI and in GIVvsGIII (P&amp;lt;0.0001).The % inhibition of tumor growth in GII was higher than thatof GIV (P=0.052). The activity of Mrp2 or P-gpit was not modified by the tumor or MCT and remained decreased. It was observed a 30% decrease in body weight and leukopenia in GIV, indicating toxicity. We conclude that the induction of MS impairs the intestinal Mrp2 and P-gp activities bringing about differences in Cy absorption, leading to toxicity; in addition, MCT has lower antitumor effectiveness in animals with MS. The age-related changes and metabolic syndrome comorbid conditions urge to reconsider the therapeutics. Citation Format: María Manuela Barranco, Martín Habib, Bianca Di Carlo, Nicolás Sigal, María Sylvestre Begnis, Felipe Zechinatti, Antonela Del Giudice, María Jose Rico, Viviana Rosa Rosados, O. Graciela Scharovsky, Silvina Stella Maris Villanueva, Fabiana García, Leandro E Mainetti. Altered therapeutic response to metronomic chemotherapy in a metabolic syndrome model of mice bearing a mammary adenocarcinoma: Implication of intestinal ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1125.