Metronomic chemotherapy: changing the paradigm that more is better

The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in the design of therapeutic protocols against cancer

Regulatory T cells but not NKT I cells are modulated by a single low-dose Cyclophosphamide in a B cell lymphoma tumor-model

Aim: Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low doses leads to an enhancement of the antitumor immune response. Our objective was to study the modulation, if any, by low dose Cy, of T regulatory (Treg) and natural killer T (NKT) I cells, two cell populations of the innate immune response with opposing effects on the tumors, in a rat B cell lymphoma model. Methods: Inbred e rats were challenged s.c. with L-TACB lymphoma and on day 14 animals were distributed in two groups. Treated: injected i.p. with cyclophosphamide (10mg/kg of body weight) and Control: injected i.p. with saline. Blood samples were taken from days 0 to 21 and the percentage of T regulatory and natural killer T I cells were determined by flow cytometry. Results: We found that the increase of natural and inducible T regulatory cells of peripheral blood achieved during tumor growth was significantly downregulated by cyclophosphamide. On the contrary, natural killer T I cells were not modulated by the treatment. Conclusion: The antimetastatic effect of a single low dose of Cy would be due, at least in part, to downregulation of natural and inducible T regulatory cells

Reposicionamiento de drogas efectos de la combinación de metformina y propanolol sobre modelos de cáncer colorrectal

El reposicionamiento de drogas en oncología se refiere al uso de fármacos originalmente formulados para otras indicaciones que mostraron potencial antitumoral. En este trabajo, se seleccionó un grupo de drogas en reposicionamiento que incluyen metformina (M, utilizada en el tratamiento de la diabetes), propranolol (P, indicado para tratar la hipertensión), cloroquina (CQ, se usa en el tratamiento o prevención de la malaria), DHEA (un precursor de hormonas sexuales), orlistat (empleado en el tratamiento de la obesidad), atorvastatina (utilizado para tratar niveles altos de colesterol) y dicloroacetato (un inhibidor de la piruvato deshidrogenasa cinasa). El potencial antitumoral de estos fármacos se evaluó in vitro en células de cáncer de colon humano HCT116 y HT29 a través de ensayos de viabilidad estándar, individualmente o de forma combinada. Todos los fármacos probados inhibieron significativamente la proliferación de células HCT116 y HT29 de una manera dependiente de la dosis. De las combinaciones probadas, M+P resultó la más atractiva en ambas líneas celulares, ya que mostró una fuerte inhibición del crecimiento incluso combinando dosis bajas de ambos fármacos (P <0,001). Adicionalmente, el tratamiento mostro efectos significativos tanto sobre la capacidad migratoria celular, aumentando el número de adhesiones focales en células tratadas, como en los niveles de apoptosis que también se vieron incrementados por el tratamiento. Los datos preliminares de un modelo in vivo con ratones BALB/c bajo un protocolo de carcinogénesis estándar de azoximetano (carcinógeno iniciador)/sulfato de dextrano (agente promotor) indicaron un beneficio potencial de la combinación M+P en la prevención del desarrollo de tumores de colon, sin síntomas asociados de toxicidad. A través de la tinción inmunohistoquímica para el antígeno Ki67 se detectó un menor número de células proliferativas en tumores tratados, lo que confirmó el efecto del tratamiento in vivo. En conjunto, nuestros resultados sugieren que la terapia con medicamentos reposicionados podría ser de interés para el tratamiento del cáncer de colon y, en particular, la combinación de M+P podría inhibir su desarrollo y potencialmente el desarrollo de metástasisFil: Anselmino L.E.. Universidad Nacional de RosarioFil: Baglioni M.V.. Universidad Nacional de RosarioFil: Rico M.J.. Universidad Nacional de RosarioFil: Rozados V.R.. Universidad Nacional de RosarioFil: Scharovsky O.G.. Universidad Nacional de RosarioFil: Fernández C.O.. Universidad Nacional de RosarioFil: Martínez-Marignac V.. Universidad Nacional de RosarioFil: Menacho-Márquez M.. Universidad Nacional de Rosari

Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan

International audienceThe Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy