Potential effect of chloroquine and propranolol combination to treat colorectal and triple-negative breast cancers

Drug repositioning explores the reuse of non-cancer drugs to treat tumors. In this work, we evaluated the effect of the combination of chloroquine and propranolol on colorectal and triple-negative breast cancers. Using as in vitro models the colorectal cancer cell lines HCT116, HT29, and CT26, and as triple-negative breast cancer models the 4T1, M-406, and MDA-MB-231 cell lines, we evaluated the effect of the drugs combination on the viability, apoptosis, clonogenicity, and cellular migratory capacity. To explore the in vivo effects of the combination on tumor growth and metastasis development we employed graft models in BALB/c, nude, and CBi mice. In vitro studies showed that combined treatment decreased cell viability in a dose-dependent manner and increased apoptosis. Also, we demonstrated that these drugs act synergically and that it affects clonogenicity and migration. In vivo studies indicated that this drug combination was effective on colorectal models but only partially on breast cancer. These results contributed to the search for new and safe treatments for colorectal and triple-negative carcinomas.Fil: Anselmino, L. E.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Baglioni, María Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Reynoso, G.. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Rozados, Viviana Rosa. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Scharovsky, Olga Graciela. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Rico, Maria Jose. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Menacho Márquez, Mauricio Ariel. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin

Immunotherapy for liver tumors: present status and future prospects

Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field

Nonclassical roles for IFN-γand IL-10 in a murine model of immunoedition

Aims: to characterize, by means of univariate and multivariate approaches, the Th1 and Th2 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 & Conclusions: 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. Lay abstract: Breast cancer is a complex, multifactor disease that affects about 10% of women in industrialized countries. The immune system has the ability to monitor the appearance of tumors, but the tumors have the ability to escape such rejection. For this reason, in order to design different therapeutic strategies, it is important to know the different mechanisms that take place when a tumor grows or when it is rejected. Here we sought to elucidate some of these mechanismsFil: del Giúdice, Antonela. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Pagura, Lucas. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Capitani, María Celeste. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; ArgentinaFil: Mainetti, Leandro Ernesto. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Scharovsky, Olga Graciela. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Universidad Nacional de Rosario. Consejo de Investigaciones de la Universidad de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Di Masso, Ricardo Jose. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Universidad Nacional de Rosario. Consejo de Investigaciones de la Universidad de Rosario; ArgentinaFil: Rico, Maria Jose. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Rozados, Viviana Rosa. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genética Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin

Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

Background Preclinical results showing therapeutic effect and low toxicity of metronomic chemotherapy with cyclophosphamide (Cy) + celecoxib (Cel) for mammary tumors encouraged its translation to the clinic for treating advanced breast cancer patients (ABCP). Patients and methods A single-arm, mono-institutional, non-randomized, phase II, two-step clinical trial (approved by Bioethics Committee and Argentine Regulatory Authority) was designed. Patients received Cy (50 mg po.d) + Cel (200 mg p.o.bid). Patient eligibility criteria included: ABCP who progressed to anthracyclines, taxanes and capecitabine, ≤4 chemotherapy schemes, with good performance status. Several pro- and anti-angiogenic molecules and cells were determined as biomarkers. Informed consent was signed by all patients. Primary endpoint was clinical benefit (CB). Results Twenty patients were enrolled. Main clinical outcomes were prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively. CB was 55 %, and time to progression (TTP) was 21.1 weeks. Median TTP in patients who achieved CB was 35.6 weeks, and mean overall survival was 44.20 weeks. There were no grade 3/4 toxicities associated with treatment. Circulating endothelial cells (CECs) increased at the time of progression in patients who showed CB (P = 0.014). Baseline CECs and circulating endothelial progenitor cells showed marginal associations with TTP. Serum VEGF decreased (P = 0.050), sVEGFR-2 increased (P = 0.005) and VEGF/sVEGFR-2 ratio decreased during treatment (P = 0.041); baseline VEGF and VEGF/sVEGFR-2 were associated with TTP (P = 0.035 and P = 0.030, respectively), while sVEGFR-2 did not. Conclusions Treatment was effective, showing low toxicity profile and excellent tolerability. The combination had anti-angiogenic effect. Increased levels of CEC could be useful for detecting progression. Baseline VEGF and VEGF/sVEGFR-2 values could be useful as early predictors of response. Trial registration ANMAT#4596/09.Fil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Alasino, Carlos María. Institute of Oncology of Rosario; ArgentinaFil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Mainetti, Leandro Ernesto. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; ArgentinaFil: Queralt, Francisco. Institute of Oncology of Rosario; ArgentinaFil: Pezzotto, Stella Maris. Research Council of the National University of Rosario (CIUNR); ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, O. Graciela. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; Argentin

Efecto protector de los componentes de la yerba mate sobre células óseas

El consumo de yerba mate (Ilex paraguariensis) es muy frecuente en varios países de América Latina. Varios fitoquímicos activos como xantinas (cafeína) y polifenoles (ácido clorogénico, quercetina, rutina) han sido identificados en extractos acuosos de Ilex paraguariensis. Entre los componentes de la yerba mate con efecto sobre el tejido óseo se destaca que la cafeína en altas concentraciones tendría un impacto negativo sobre la densidad mineral ósea (DMO) sobre todo cuando se asocia con dietas con bajo contenido de calcio. Contrariamente, los polifenoles han demostrado efectos beneficiosos a nivel del tejido óseo por su acción antioxidante. Se halló asociación entre la pérdida ósea con la edad y el estrés oxidativo por la determinación de productos avanzados de oxidación de proteínas, malondialdehído y superóxido dismutasa en fémures de ratas jóvenes, adultas y de edad avanzada.Una publicación previa mostró mayor DMO de columna lumbar (+9.7%) y cuello femoral (+6.2%) en mujeres postmenopáusicas que tomaban al menos 1 litro de mate/día en comparación con controles que no bebían mate. Nuestro grupo llevó a cabo un trabajo en ratas donde se evaluó el efecto de la yerba mate sobre el tejido óseo a través de estudios de densitometría, morfometría, histomorfometría, conectividad trabecular y biomecánica ósea. Se observó un efecto positivo sobre la DMO y el volumen de hueso trabecular en el grupo de animales que fue alimentado con una dieta con bajo contenido de calcio. Esto podría indicar que el efecto negativo de la baja ingesta de calcio en el volumen óseo se revierte, al menos en parte, por la yerba mate

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

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.Fil: Mainetti, Leandro Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Rico, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Kaufman, Cintia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Grillo, Monica Carolina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Guercetti, Julian. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Baglioni, María Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: del Giúdice, Antonela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Capitani, María Celeste. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Fusini, Matías. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Rozados, Viviana Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Scharovsky, Olga Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; Argentina. Metronomics Global Health Initiative; Franci

Highlights from the 1st Latin American meeting on metronomic chemotherapy and drug repositioning in oncology, 27–28 May, 2016, Rosario, Argentina

Following previous metronomic meetings in Marseille (2011), Milano (2014), and Mumbai (2016), the first Latin American metronomic meeting was held in the School of Medical Sciences, National University of Rosario, Rosario, Argentina on 27 and 28 of May, 2016. For the first time, clinicians and researchers with experience in the field of metronomics, coming from different countries in Latin America, had the opportunity of presenting and discussing their work. The talks were organised in three main sessions related to experience in the pre-clinical, and clinical (paediatric and adult) areas. The different presentations demonstrated that the fields of metronomic chemotherapy and repurposing drugs in oncology, known as metronomics, constitute a branch of cancer therapy in permanent evolution, which have strong groups working in LatinAmerica, both in the preclinical and the clinical settings including large, adequately designed randomised studies. It was shown that metronomics offers treatments, which, whether they are combined or not with the standard therapeutic approaches, are not only effective but also minimally toxic, with the consequent improvement of the patient’s quality of life, and inexpensive, a feature very important in low resource clinical settings. The potential use of metronomic chemotherapy was proposed as a cost/effective treatment in low-/middle-income countries, for adjuvant therapy in selected tumours. The fundamental role of the governmental agencies and non-governmental alliances, as the Metronomic Global Health Initiative, in supporting this research with public interest was underlined

Clinical response in patients with ovarian cancer treated with metronomic chemotherapy

Ovarian cancer (OC) is the leading cause of death from gynaecological cancer. It is extremely hard to diagnose in the early stages and around 70% of patients present with advanced disease. Metronomic chemotherapy (MCT) is described as the chronic administration of, generally low, equally spaced, doses of chemotherapeutic drugs with therapeutic efficacy and low toxicity. This is an effective and low-cost way to treat several types of tumours, including ovarian cancer. Here, we present six cases of advanced ovarian cancer treated with MCT with low doses of cyclophosphamide, which showed clinical response and stable disease.Fil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, Graciela Olga. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Alasino, Carlos María. Institute of Oncology of Rosario; Argentin

Comparative Effectiveness of Two Metronomic Chemotherapy Schedules. Our Experience in the Preclinical Field

Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of chemotherapeutic drugs, without extended interruptions. Previously, we developed two combined metronomic schemes for the treatment of murine mammary tumors. The aim of this study was to compare their effects on tumor and metastasis growth, survival, and toxicity. Metronomic chemotherapy with Cyclophosphamide + Celecoxib (Cy + Cel) showed higher antimetastatic power than Cyclophosphamide + Doxorubicin (Cy + Dox), while being similar in other aspects. That difference, plus the advantage that represents its oral administration, suggests that the Cy + Cel combination is more suitable than Cy + Dox for metronomic chemotherapy of mammary tumors and could be proposed to the translation to the clinic.Fil: Rico, María José. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Perroud, Herman A. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Mainetti, Leandro Ernesto. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; ArgentinaFil: Rozados, Viviana R. Institute of Experimental Genetics. School of Medical Sciences. National University of Rosario; Rosario; ArgentinaFil: Scharovsky, Graciela Olga. Universidad Nacional de Rosario. Consejo de Investigaciones UNR, Facultad de Ciencias Médicas; Argentin