Distinct pathways of apoptosis triggered by FTY720, etoposide, and anti-Fas antibody in human T-lymphoma cell line (Jurkat cells).
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2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diol hydrochloride (FTY720), a synthetic product derived from a metabolite of Isaria sinclairii, has been demonstrated to have a potent immunosuppressive activity that induces apoptotic cell death in T cells and several other cell lines. In this study, using the human T-lymphoma cell line, Jurkat cells, we investigated the apoptotic signal transduction mediated by FTY720, in particular comparing its role on the cleavage of caspases, with that mediated by etoposide or anti-Fas antibody. All of these agents cleaved caspases, inducing their active form in the affected cells. Pretreatment with a broad caspase inhibitor [benzyloxycarbonyl-Val-Ala-Asp-(Ome) fluoromethyl ketone] markedly decreased the incidence of apoptotic cells induced by FTY720, etoposide, and anti-Fas antibody, through the abrogation of cleavage of Bid, poly(ADP-ribose) polymerase, and caspases 3, 8, and 9. The overexpression of Bcl-2 gene prevented FTY720- and etoposide-mediated apoptosis, but not Fas-mediated apoptosis. In addition, mitochondria were demonstrated to play a critical role in FTY720-triggered cell death, suggesting that this drug has a potent anticancer activity. (+info)
Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models.
(34/714)
FTY720 is a unique immunosuppressive agent that exerts its activity by inducing apoptosis in lymphocytes. We conducted the present study to investigate the effects of FTY720 on cancer growth and metastasis, as well as its mechanism of action. In vitro treatment with FTY720 induced dramatic cancer cell apoptosis in a mouse breast cancer cell line, JygMC(A). Electron microscopy revealed distinct changes on the cell surface with decreased filopodias and microvilli in cancer cells treated with FTY720 at 2 microM and clear evidence of apoptosis at 10 microM. Interestingly, the effect of FTY720 was significantly less in the normal fibroblasts than in the cancer cells, indicating greater susceptibility of cancer cells to the agent. We then tested the in vivo effect of FTY720 in a mouse breast cancer model created by inoculating JygMC(A) cells (s.c.) in the flank region of BALB/c-nu/nu mice at three different dosages (2, 5, and 10 mg/kg/day; n = 30/group). Tumor growth was markedly suppressed at a dosage of 5 mg/kg or more without notable side effects. In addition, tumor metastasis, which was dramatically evident in control mice, was significantly prevented even at a low dose (2 mg/kg/day), resulting in a significant prolongation of animal survival. These data led us to additionally investigate the mechanism of action, especially the prevention of metastasis at a low dose. FTY720 treatment at 2 microM caused a remarkable cytoskeletal change with deformed and decreased filopodias in cancer cells. In addition, it significantly decreased the ability of cancer cells to adhere and migrate to extracellular matrix components, and markedly reduced the expression of integrins on the cancer cell surface. These results indicate that FTY720 is a potent anticancer agent that induces cancer cell apoptosis and is markedly effective for prevention of metastasis. The changes of cellular structure with reduction of integrin expression may be one of its underlying mechanisms of action. (+info)
Efficacy of the inactivation of bacterial spores in white petrolatum and a hydrophilic ointment by gamma irradiation.
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To evaluate the possibilities of using gamma irradiation for the sterilization of ointments, the effect of irradiation on spores of Bacillus pumilus and Bacillus sphaericus in dry material and in two different kinds of ointments was studied. The results indicate that for sterilization purposes irradiation was less effective in white petrolatum as compared to irradiation in the dry state. No such protective effect was found in a hydrophilic ointment. Accordingly, the sterilization dose needed for the sterilization of an ointment can be decided upon only after inactivation experiments with suitable test organisms in the actual preparation. (+info)
First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients.
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FTY720 is a novel immunomodulator to be developed for use in organ transplantation. The primary objective of this study was to measure safety, single-dose pharmacokinetics, and pharmacodynamics in stable renal transplant patients-the first human use of FTY720. This study used a randomized, double-blind, placebo-controlled design that explored single oral doses of FTY720 from 0.25 to 3.5 mg in 20 stable renal transplant patients on a cyclosporine-based regimen. Safety assessments and blood samples were taken predose and at multiple time points during a 96-h period postdose. Standard pharmacokinetic parameters were derived from the FTY720 whole blood concentrations, measured by HPLC/MS/MS. FTY720 was well tolerated, with no serious adverse events. Transient, asymptomatic bradycardia occurred after administration in 10 of 24 doses of FTY720. Pharmacokinetics are characterized by a prolonged absorption phase; the terminal elimination phase started 36 h after the administration, with elimination half-life (t(1/2)) ranging from 89 to 157 h independent of dose. Maximum plasma concentration and AUC were proportional to dose with low intersubject variability, the apparent volume of distribution (V(d)/F) ranged from 1116 to 1737 L. FTY pharmacodynamics were characterized by a reversible transient lymphopenia within 6 h, the nadir being 42% of baseline. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Single oral doses of FTY720 ranging from 0.25 to 3.5 mg were well tolerated and caused a reversible selective lymphopenia. Transient, but asymptomatic bradycardia was the most common adverse event. The long t(1/2) suggests less frequent dosing intervals. The size of V(d)/F is in excess of blood volume, consistent with widespread tissue distribution (+info)
Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
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Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression. (+info)
Pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720) in cynomolgus monkeys after single oral and intravenous doses.
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The pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720), a novel immunosuppressive agent, were examined in cynomolgus monkeys (three males and three females). After single doses of 0.1 mg/kg p.o. or i.v. bolus and 1 mg/kg p.o. were administered to the animals, the concentrations of FTY720, and the numbers of lymphocytes, CD20+CD2-B cells, and CD2+CD20-T cells in blood were measured over 23 days. A linear three-compartment model characterized the time course of FTY720 concentrations with a terminal half-life of about 31 h, clearance of about 0.53 l/h/kg, and bioavailability of about 38%. The dynamic responses were not area under the curve (or dose) proportional for either males or females. An indirect response model with a distribution pool captured the cell trafficking data for all doses for each cell type, where initial blood counts (R(0)) were about 7650, 2100, and 5250 cells/microl; maximum fractional inhibition (I(max)) about 0.88, 0.85, and 0.91; influx (k(in)) about 6014, 1312, and 5662 cells/microl/h; efflux (k(out)) about 0.798, 0.555, and 1.08 h(-1); intercompartmental k(cp) about 0.134, 0.192, and 0.082 h(-1); and intercompartmental k(pc) rate constants about 3.9 x 10(-4), and 0.016 and 8.9 x 10(-6) h(-1) for lymphocytes, B cells, and T cells, respectively. The inhibition concentration IC(50) was about 0.48 microg/l for all cells, which was remarkably low. The apparent distribution volumes of peripheral pool (V(p)) were markedly larger than blood volume (V(b)) for all cells. The I(max) for cell trafficking was achieved at doses smaller than that producing graft protection, indicating stronger central than peripheral effects of this drug. The profound cell trafficking effects of FTY720 can be readily captured and interpreted with an extended indirect response model. (+info)
The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
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Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking. (+info)
The Spanish toxic oil syndrome 20 years after its onset: a multidisciplinary review of scientific knowledge.
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In 1981, in Spain, the ingestion of an oil fraudulently sold as olive oil caused an outbreak of a previously unrecorded condition, later known as toxic oil syndrome (TOS), clinically characterized by intense incapacitating myalgias, marked peripheral eosinophilia, and pulmonary infiltrates. Of the 20,000 persons affected, approximately 300 died shortly after the onset of the disease and a larger number developed chronic disease. For more than 15 years, a scientific committee supported by the World Health Organization's Regional Office for Europe and by the Institute of Health Carlos III in Madrid has guided investigation intended to identify the causal agent(s), to assess toxicity and mode of action, to establish the pathogenesis of the disease, and to detect late consequences. This report summarizes advances in research on this front. No late mortality excess has been detected. Among survivors, the prevalence of some chronic conditions (e.g., sclerodermia, neurologic changes) is high. Attempts to reproduce the condition in laboratory animals have been unsuccessful, and no condition similar to TOS has been reported in the scientific literature. Laboratory findings suggest an autoimmune mechanism for TOS, such as high levels of seric soluble interleukin-2 receptor. Epidemiologic studies integrated with chemical analyses of case-related oils have shown that the disease is strongly associated with the consumption of oils containing fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP). These chemicals have also been found in oils synthesized under conditions simulating those hypothesized to have occurred when the toxic oil was produced in 1981. Whether PAP esters are simply markers of toxicity of oils or have the capability to induce the disease remains to be elucidated. (+info)