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.
Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of chemotherapeutic drugs, without extended interruptions. Drug repositioning in oncology refers to the use of drugs formulated for other indications that showed antitumor potential. Los is an antagonist of angiotensin II receptor used to treat hypertension. We aim to study the combined effect of metronomic Cy+Los on M-234p tumor. Female BALB/c mice were orthotopically challenged with M-234p (day 0) and distributed, on day 8, into 4 groups (n=5-6/group) treated as follows, GI: Control, without treatment; GII: Cy 25mg/kg/day in the drinking water; GIII: Los 200mg/kg/day in the drinking water; GIV: Treated as GII+GIII. Mice were weighted, and tumor volume measured 3 times/week. When tumors were exponentially growing, mice were euthanized, tumors excised, and blood samples taken for immunohistochemistry, western blot and flow cytometry. GIV showed tumor growth inhibition compared to GI, GII and GIII and, as a consequence, higher survival (P<0.005). Also, GIV showed 60% (3/5) of complete tumor regressions, without relapses. No weight losses or sings of toxicity were observed. IHC analysis showed a lower N° of Ki67+ cells in GIV (P<0.05). Moreover, a significant increase of apoptosis in GIV vs Control was shown by TUNEL assay (P<0.05). No differences in circulating CD4+, CD8+ and Treg cells were shown by flow cytometry but, a marginally significant increase in Th17 cells in GII and GIV was seen. To share some light on the effect of the therapy on the cancer associated fibroblasts, the protein αSMA was measured by western blot; the expression of this marker was significantly lower in GIV vs GI (P<0.05). To evaluate the anti-metastatic effect of the therapy, mice were inoculated i.v. with 5x105 M-234p cells. On day 3, mice were distributed in the same experimental groups. When the first mouse showed signs of metastatic disease, all of them were euthanized, lungs excised and stained to highlight metastasis. The N° of lung metastasis was significantly lower in GII and GIV. No weight losses or any other sing of toxicity were observed. These results clearly show that metronomic chemotherapy with a combination of Cyclophosphamide and Losartan, administered as an intervention strategy, can inhibit, not only the growth of a triple negative mammary adenocarcinoma, causing permanent regressions, but also its metastasis, while being devoid of toxicity. Those effects would be achieved, at least partially, by inhibition of tumor proliferation, increase of apoptosis and modification of tumor microenvironment through tumor fibroblasts. The characteristics and the efficacy of the therapeutic schedule herein utilized suggest its implementation at the clinical setting in the near future. Citation Format: Julian Guercetti, Leandro E. Mainetti, M.Carolina Grillo, Antonela Del Giúdice, Maria V. Baglioni, Juan M. Cáceres, Ainelén Arboatti, Daniel Francés, Viviana R. Rozados, Maria J. Rico, O.Graciela Scharovsky. Metronomic chemotherapy with cyclophosphamide (Cy) and the repositioned drug losartan (Los) for the treatment of M-234p triple negative murine mammary adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3.
To improve the specificity of breast cancer diagnosis SOLUS combines ultrasound, shear-wave elastography and time-domain diffuse optical tomography in a multimodal imaging system. An innovative compact device for time-domain multi-wavelength diffuse optics was also developed.
Aim: To characterize, by means of univariate and multivariate approaches, the T helper (Th)-1 and Th-2 responses during the different phases of tumor immunoediting. Materials & methods: We used a multivariate principal component analysis applied to analyze the joint behavior of serum concentrations of IFN-γ, IL-2, IL-10 and IL-4, during the different phases of tumor immunoediting, in CBi/L mice challenged with M-406 mammary adenocarcinoma. Results & conclusion: Animals in equilibrium phase showed the widest variations in values of the four cytokines. In this experimental model, the role of IFN-γ would be related to tumor growth and progression, while IL-10 would participate in the antitumor immune response.
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<0.05); transport rate of rhodamine 123 by P-gp decreased 55% in HFD vs C (P<0.05). At the end of the experiment (day 22), the tumor volume was lower in GIIvsGI and in GIVvsGIII (P<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.
Aim: According to the need for the development of new anticancer agents, we have synthetized novel bioactive compounds and aimed to determine their antitumor action. Materials & methods: We describe in vitro studies evaluating the effect of 35 novel chemical compounds on two triple negative murine mammary adenocarcinoma tumors. Results & conclusion: Three compounds were selected because of their high antitumor activity and their low toxicity to normal cells. Their effect on tumor cells apoptosis, clonogenicity and migratory capacity, were determined. We found that the selected compounds showed inhibition of viability and clonogenic capacity, and promotion of apoptosis. They also decreased the migratory capacity of tumor cells. The results obtained suggest the likelihood of their future use as antitumor and/or antimetastatic agents.
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