FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system

OBJECTIVE: Available chemotherapy presents poor control over the development of metastatic melanoma. FTY720 is a compound already approved by the Food and Drug Administration for the treatment of patients with multiple sclerosis. It has also been observed that FTY720 inhibits tumor growth in vivo (experimental models) and in vitro (animal and human tumor cells). The aim of this study was to evaluate the effects of FTY720 on a metastatic melanoma model and in tumor cell lines. METHODS: We analyzed FTY720 efficacy in vivo in a syngeneic murine metastatic melanoma model, in which we injected tumor cells intravenously into C57BL/6 mice and then treated the mice orally with the compound for 7 days. We also treated mice and human tumor cell lines with FTY720 in vitro, and cell viability and death pathways were analyzed. RESULTS: FTY720 treatment limited metastatic melanoma growth in vivo and promoted a dose-dependent decrease in the viability of murine and human tumor cells in vitro. Melanoma cells treated with FTY720 exhibited characteristics of programmed cell death, reactive oxygen species generation, and increased β-catenin expression. In addition, FTY720 treatment resulted in an immunomodulatory effect in vivo by decreasing the percentage of Foxp3+ cells, without interfering with CD8+ T cells or lymphocyte-producing interferon-gamma. CONCLUSION: Further studies are needed using FTY720 as a monotherapy or in combined therapy, as different types of cancer cells would require a variety of signaling pathways to be extinguished. .

The imbalance between Treg and Th17 cells caused by FTY720 treatment in skin allograft rejection

OBJECTIVES: FTY720 modulates CD4+T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4+ graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.

FTY720: Mechanism of Action and Potential Benefit in Organ Transplantation

FTY720 is a novel immunomodulator that has proven effective in animal models of transplantation and autoimmunity, has achieved promising results in Phase I and Phase II studies of renal transplantation in humans, and is currently undergoing phase III studies. FTY720 acts as a high-affinity agonist at the sphingosine 1-phosphate receptor-1 (S1P1), where it internalises the receptor and causes alterations to the normal circulation of lymphocytes between the blood and lymphoid tissue. Unlike conventional immunosuppressants, FTY720 does not impair the activation, proliferation or effector functions of T- and B-cells. Further development of FTY720 is in progress, including trials in autoimmune disorders as well as transplantation. This review summarises the mechanism of action of FTY720, its effects in models of transplantation and autoimmunity, and results from clinical trials in humans.

Castración no quirúrgica por inyección intratesticular con una preparación de epinefrina-propilenglicol en lechones / Non-chirurgical castration with an intratesticular injection of epinephrine-propyleclycol in piglets

Se evaluó un método de castración no quirúrgico por inyección intratesticular en lechones de 21 días de edad. Cinco grupos experimentales fueron tratados con diferentes mezclas. Un grupo fue inyectado con formaldehido, xilocaína, epinefrina y propilenglicol (FXEP), otro con xilocaína y propolenglicol (XP), otro con epinefrina y propilenglicol (EP), otro con propilenglicol (P) y otro con formaldehido en solución amortiguadora de fosfatos 0.1 M (F). Se inyectó 1.5 ml de cada mezcla experimental en cada testículo de los lechones según su grupo. El tratamiento EP luego de 30 Días causó necrosis completa, a 90 y 180 días postratamiento se observó fibrosis, lo cual revela probablemente atrofia irreversible de ambos testículos. Asimismo, dichoo tratamiento produjo severa reducción del peso testicular, sin embargo, no se observaron efectos colaterales indeseables. El tratamiento no afectó el peso somático. En los otros grupos experimentales no se obtuvieron resultados satisfactorios sobre la atrofia y reducción de peso testicular. La preparación experimental no es costosa, la técnica de inyección es sencilla y facíl de realizar, y podría ser un modelo rápido y efectivo de castración no quirúrgica. Sin embargo, se encuentra aún en fase experimental.

Tratamiento de dermatosis corticosusceptibles graves o resistentes con crema de dipropionato de betametasoma con glicol de propileno / Treatment of severe or resistant corticosusceptible dermatosis with cream betamethasone dipropionate with propylenglycol

En un estudio abierto se administró crema de dipropionato de betametasona con glicol de propileno a 50 pacientes con psoriasis severa o resistente, dermatitis atópica y otras dermatosis corticosusceptibles igualmente graves o resistentes. Durante un periodo de 14 días, los pacientes se aplicaron diariamente 3.5 gramos del medicamento, dos veces al día. La eficacia del agente se valoró en 46 sujetos, mientras que la tolerancia y seguridad fueron evaluadas en los 50 participantes. Al tercer día de tratamiento se observó una respuesta terapéutica en 41 de 46 pacientes. Al día 14 de tratamiento, la clasificación media de la severidad total de signos y síntomas en 21 pacientes con psoriasis se había reducido en 88%. De modo similar, 25 enfermos con otras dermatosis corticosusceptibles, graves o resistentes, mostraron una disminución del 99% en la clasificación media de la severidad total de signos y síntomas. Entre los sujetos evaluados por tolerancia y seguridad, 24 de 50 comunicaron una sensación pasajera de ardor leve a moderado, que ocurrió más a menudo al aplicarse el medicamento en estudio. En ninguno de estos sujetos fue suspendido el tratamiento, y nadie necesitó terapia adicional para alivio de la reacción local. Las concentraciones matutinas de cortisol plasmático en los enfermos vigilados permanecieron dentro de los límites normales durante el estudio