FTY720 – THE IMMUNE CELLS CONTROLLER

by Selleckchem | Apr 11 2012

FTY720:
One of the extensively used immunoregulatory drug is Fingolimod, FTY720 is the code for this drug and it is a product of Novartis. The properties like anti-tumor actions and immunosuppressant activities made FTY720 Fingolimod a new hope against the debilitating diseases such as Multiple Sclerosis. FTY720 price for 100mg is around $40. Like many other compounds it is not soluble in water but a reasonable solubility of concentration of 100mg/ml can be attained using organic solvents such as DMSO and ethanol. Structurally FTY720 is an analogue of sphingosine molecule due to which this molecule has the capability to act on sphingosine-1-phosphate receptor, this report has been confirmed by gene deletion and reverse pharmacology studies. Various chemical modifications have been made with FTY720 in order to enhance its efficiency and to take it in clinical trials based on different diseases. If anyone wants to purchase FTY720 for laboratory and clinical uses one can order FTY720 to any FTY720 suppliers. IC50 of this drug is about 0.13 nM.

FTY720 AS IMMUNOREGULATOR:
FTY720 pharmacological traits and pharmacokinetics are studied in detail on both healthy and kidney transplanted individuals to analyze its affects, dose and mechanism of action to explain clear cut ability of this molecule [1]. Clinical trials phase I of FTY720 showed about safety and pharmacokinetics profile in which 0.25mg to 3.5mg/kg body weight was given with Cyclosporine A and prednisone led to a decrease in T, B cell count and CD4 and CD8+ve present in peripheral blood in a dose dependent manner [2] and declared its appropriateness in kidney transplant regime. During phase III it was further confirmed when FTY720 and Mofetil were compared with Cyclosporin, this confirmed FTY720 suitability although with few side effects associated [3]. Almost ten years back the human trials where FTY720 was used as an immunomodulator and it proved its success [4], since then it’s being used extensively for the similar purpose and in 3 years 1st clinical trial phase II-A was carried out [5].
To analyze the properties of FTY720 as an anti-inflammatory agent in multiple sclerosis, in vivo studies about macrophages trafficking on rat models was done and it was reported that rat cells were lacking neurological symptoms and inflammations [6]. The studies of FTY720 with respect to cell cycle arrest and apoptosis in human cells was carried out and it was noticed that this compound targets the mitochondria due to which cell cycle ceases at G0/G1 stage and also the dephosphorylation of retinoblastoma protein’s presence was noted, thus presenting its function in two entirely independent ways [7]. More recently a research on anti-cancer assessment of FTY720 was done which stated in ovarian cancer autophagic cell death was noticed when treated Cisplatin-resistant ovarian cancer of humans [8] for further demonstrating its good performance, in vivo preclinical evaluations are compulsory to analyze its ability in treating ovarian cancers during clinical evaluations.

FTY720 INHIBITS BCR/ABL:
FTY720 has been used as regulator for the control of lymphocytic traffic while transplantation of an allograft [9]. FTY720 S1P Receptor inhibitor and agonist [10] controls the lymphocytes movement listed as its main function and targeting these specific receptors and can reduce airway inflammations by acting as potent S1PR agonist [11] therefore also a hope for the treatment of asthma. Human progenitor cells are resisted by the CXCR4 and this is induced by FTY720 both in vivo and in vitro cases [12]. Similarly, FTY720 checked transendothelial human dendritic cell movement and enhanced their life in in vivo conditions [13], this is an additional property to immunosuppressive effect of this compound. The inhibiting ability for BCR/ABL a tyrosine kinase is very high of this molecule and soon after FTY720 remarkable actions on leukemogenesis during in vitro environment [14], it has also been applied for its actions on CML or Chronic Myelogenous Leukemia patients due to property of BCR/ABL inhibition [15-18].

REFERENCES:
1. Kovarik, J.e.a., Overview of FTY720 Clinical Pharmacokinetics and Pharmacology. Therapeutic Drug Monitoring, 2004. 26(6): p. 585-587.
2. Kahan, B.e.a., Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation, 2003. 76(7): p. 1079-1084.
3. Salvadori, M.e.a., FTY720 versus MMF with Cyclosporine in de novo Renal Transplantation: A 1-Year, Randomized Controlled Trial in Europe and Australia. American Journal of Transplantation, 2006. 6(12): p. 2912-2921.
4. Budde, K.e.a., First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients. J Am Soc Nephrol, 2002. 13: p. 1073-1083.
5. Silva, H.e.a., FTY720, A Novel Immunomodulator: Efficacy and Safety Results from the First Phase 2A Study in de novo Renal Transplantation. Transplantation, 2005. 79(11): p. 1553-1560.
6. Rausch, M.e.a., Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: Clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. Journal of Magnetic Resonance Imaging, 2004. 20(1): p. 16-24.
7. Nagahara, Y.e.a., Coordinate Involvement of Cell Cycle Arrest and Apoptosis Strengthen the Effect of FTY720. Cancer Science, 2001. 92(6): p. 680-687.
8. Zhang, N.e.a., FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: a protective role of autophagy. Autophagy, 2010. 6(8): p. 1157-67.
9. Brinkmann, V.e.a., FTY720: Altered Lymphocyte Traffic Results in Allograft Protection. Transplantation, 2001. 72(5): p. 764-769.
10. Brinkmann, V.a.L., K.R., FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Current Opinion in Immunology, 2002. 14(5): p. 569-575.
11. Sawicka, E.e.a., Inhibition of Th1- and Th2-Mediated Airway Inflammation by the Sphingosine 1-Phosphate Receptor Agonist FTY720. The Journal of Immunology, 2003. 171: p. 6206-6214.
12. Kimura, T., The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells. Blood, 2004. 103(12): p. 4478-4486.
13. Lan, Y.Y.e.a., The Sphingosine-1-Phosphate Receptor Agonist FTY720 Modulates Dendritic Cell Trafficking In Vivo. American Journal of Transplantation, 2005. 5(11): p. 2649-2659.
14. Neviani, P.e.a., FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest., 2007. 117(9): p. 2408-2421.
15. Tanaka, R.a.K., S., Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation. Expert Review of Anticancer Therapy, 2008. 8(9): p. 1387-1398.
16. Noronha, G.e.a., Inhibitors of ABL and the ABL-T315I Mutation. Current Topics in Medicinal Chemistry, 2008. 8(10): p. 905-921.
17. Cardama, A.Q.a.C., J., Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia. Clin Cancer Res, 2008. 14: p. 4392.
18. Druker, B.J.e.a., Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia Chromosome. N Engl J Med, 2001. 344: p. 1038-1042.