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LENALIDOMIDE – AN INHIBITOR OF INFLAMMATION

by Selleckchem | Aug 29 2012

LENALIDOMIDE
Tumor necrosis factor or TNF is amongst the pro-inflammatory cytokines, in varied forms of diseases associated with cancer, autoimmune diseases (like ankylosing spondylitis and Crohn's disease etc.) and skin diseases e: g refractory asthma and psoriasis high levels of TNF are being observed. From medical point of view due to this reality inhibitors of TNF-alpha are being given lots of value. Different inhibitors of tumor necrosis factor are being studied from numerous physiological and medical point of view these inhibitors include illusion inducing compounds, natural compounds comprising cannabis, curcumin and green tea whereas artificial include xanthine derivatives and most significantly monoclonal antibodies. Lots of emphasize is being placed on these inhibitors for cancer therapy [1].
Lenalidomide TNF-alpha Receptor inhibitor is amongst those inhibitors and it is marketed with the trade name of Revlimid and buy Lenalidomide from Lenalidomide supplier with Lenalidomide price of roughly $60 per 500mg however its value varies relying upon proportion purity of final product. Lenalidomide solubility is maximally around 100mg/ml of DMSO but it is incompletely soluble in ethanol and water. Lenalidomide structure revealed that it contained 4-amino-glutamyl structure that is analogous to Thalidomide but for the therapy of myeloma this drug was known to be the milestone because this specific disease is linked with the dismal prognosis.

MECHANISM OF ACTION OF LENALIDOMIDE

Since Lenalidomide Revlimidis analogous to Thalidomide it shows some similarities associated with mode of action however the compounds additionally share some variations [2]. Different research teams brought into light its mode of action and one reported the details regarding Lenalidomide efficiency which resulted in prevention of the mevalonate cascade in therapy of myeloma [3]. Another study revealed that for the therapy of lymphoma and multiple myeloma it found to begin a p21WAF-1 and epigenetic variation pathway when it was co-administered with Pomalidomide [4]. In in vitro studies leukemic cell were shown to have inhibited proliferation by the administration of Lenalidomide that ultimately blocks the Gab1 phosphorylation [5]. The anti-angiogenic impact was shown by Lenalidomide in in vivo studies whereas it had been found to cut back the cell proliferation and Akt phosphorylation in endothelial cells in in vitro studies [6].The studies that were conducted to judge Lenalidomide’s anti-angiogenic impact in case of blood cancers it was found to behave as immunomodulator [7].

CLINICAL ASSESSMENT OF LENALIDOMIDE
Extensive Lenalidomide clinical trials have been conducted but it showed promising results in case of chronic lymphocytic leukemia or CLL, Hodgkin's and non-Hodgkin's lymphoma as well as different types of solid tumor like cancer of pancreas. Discoid Lupus Erythematosus treatment is also the candidate of mentioned list [8]. A lot of clinical trial studies are being conducted for therapy of lymphoma and leukemia cancer in which Lenalidomide either administered alone or co-administered with other drugs. Above mentioned studies were continued in vitro on human CD34+ erythropoetic progenitor cells are being treated with co-administration of Pomalidomide and Lenalidomide [9].
Phase I trials of Lenalidomide were conducted on patients suffering from solid tumor cancer [10]. Promising results shown by Lenalidomide I trial it was also administered to patients of RCC in phase II trials [11] in which it showed outstanding results related to its efficiency. In phase II trials Lenalidomide was co-administered with different drugs for therapy of amyloidosis [12] as well as on myeloma patients [13-14] and fruitful results were obtained. Clinical trials phase II trials were also conducted on patients of chronic lymphocytic leukemia by administering Lenalidomide which is TNF-alpha inhibitor [15] and also on the patients suffering from MDSs or in myelodysplastic syndromes [16].Outstanding results were shown in phase III on relapsed/refractory patients of multiple myeloma [17]. On the basis of less toxicity profile Lenalidomide got approved for treatment of elderly patients of myeloma [18].

REFERENCES:
1. Zidi, I.e.a., TNF-α and its inhibitors in cancer. Medical Oncology, 2010. 27(2): p. 185-198.
2. Anderson, K.C.e.a., Lenalidomide and Thalidomide: Mechanisms of Action-Similarities and Differences. Seminars in Hematology, 2005. 42(4): p. S3-S8.
3. Spek, E.V.e.a., Inhibition of the mevalonate pathway potentiates the effects of lenalidomide in myeloma. Leukemia Research, 2009. 33(1): p. 100-108.
4. Lozach, L.E.e.a., Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism. Cancer Res, 2009. 69: p. 7347.
5. Gandhi, A.K.e.a., Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly. Leukemia Research, 2006. 30(7): p. 849-858.
6. Dredge, K.e.a., Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvascular Research, 2005. 69(1-2): p. 56-63.
7. Kotla, V.e.a., Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol., 2009. 2(36).
8. Shah, A.e.a., Lenalidomide for the Treatment of Resistant Discoid Lupus Erythematosus. Arch Dermatol., 2009. 145(3): p. 303-306.
9. Parseval, L.A.M.e.a., Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest., 2008. 118(1): p. 248-258.
10. Sharma, R.A.e.a., Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: Phase I clinical trial of three dosing schedules in patients with solid malignancies. European Journal of Cancer, 2006. 42(14): p. 2318-2325.
11. Choueiri, T.K.e.a., Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer, 2006. 107(11): p. 2609-2616.
12. Sanchorawala, V.e.a., Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood, 2007. 109(2): p. 492-496.
13. Rajkumar, S.V.e.a., Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood, 2005. 106(13): p. 4050-4053.
14. Richardson, P.G.e.a., A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood, 2006 108(10): p. 3458-3464.
15. Khan, A.C.e.a., Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study. Journal of Clinical Oncology, 2006. 24(34): p. 5343-5349.
16. Raza, A.e.a., Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood, 2008 111(1): p. 86-93.
17. Dimopoulos, M.A.e.a., Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): results of a phase 3 study (MM-010). Blood, 2005. 106: p. 6-11.
18. Palumbo, A.e.a., Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA-Italian Multiple Myeloma Network. Journal of Clinical Oncology, 2007. 25(28): p. 4459-4465.

Cat.No.	Product Name	Information
S1029	Lenalidomide	Lenalidomide is a TNF-α secretion inhibitor with IC50 of 13 nM in PBMCs. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide promotes cleaved caspase-3 expression and inhibit VEGF expression and induces apoptosis.
S1193	Thalidomide	Thalidomide was introduced as a sedative drug, immunomodulatory agent and also is investigated for treating symptoms of many cancers. Thalidomide inhibits cereblon (CRBN), a part of the cullin-4 E3 ubiquitin ligase complex CUL4-RBX1-DDB1.