LENALIDOMIDE AND INFALAMATION

by Selleckchem | Apr 12 2012

ROLE OF TUMOR NECROSIS FACTOR
Different types of molecules are there in the body for the purpose of communication between cells. Cytokines are one of such molecules that can induce a change such as growth, differentiation, movement or cell death. Tumor Necrosis factor abbreviated as TNF is one of such cytokines that plays a role in the development of inflammation at the site of disease or microbial attack. Its high levels are associated with the development of inflammation in many types of diseased conditions e.g., different types of cancers, autoimmune disorders (rheumatoid arthritis, ankylosing spondylitis and Crohn's disease etc.), and skin diseases e.g., refractory asthma and psoriasis. Due to its relatedness to many diseases, TNF-alpha is given importance in medical research as well as literature.

INHIBITION OF TUMOR NECROSIS FACTOR
Inhibition of TNF has been quite active area of research and different types of natural and artificial compounds have been studied. Naturally occurring TNF inhibitors include curcumin, green tea, and cannabis to xanthine derivatives. The compounds inducing hallucination have also been studied. Of all the inhibitors, Monoclonal antibodies have been found to be most effective. TNF-alpha has been studied widely for its role in cancer and its inhibition in order to look for the treatment against cancer [1].

PROPERTIES OF LENALIDOMIDE
Lenalidomide TNF-alpha inhibitor is one of such inhibitors that has been studied for the treatment and application in myeloma. The structure of the compound shows an analog of Thalidomide i.e., 4-amino-glutamyl. It is sold under the trade name of Lenalidomide Revlimid and one can buy Lenalidomide 500 mg in the price of $60. The cost may differ from one to the other drug supplier depending upon the preparation purity. Lenalidomide is poorly soluble in ethanol or water and soluble in DMSO upto the extent of 100 mg/ml solution. Scientists, researchers and doctors can order Lenalidomide for their own purposes.

MODE OF ACTION OF LENALIDOMIDE
Lenalidomide anti inflammatory action, with some differences, is similar to that of its analog Thalidomide [2]. A lot of research is going on to unravel the mechanism of action of this drug, according to one, studied during myeloma treatment, mevalonate pathway is inhibited [3] while according to another report p21WAF-1 pathway is induced and a cascade of epigenetic modifications is involved when it is given in combination with or as a co-treatment with Pomalidomide against lymphoma and multiple myeloma [4]. It has also been shown to inhibit the phosphorylation of Gab1 that in turn slows down the in vitro proliferation process of leukemic cells [5]. In another study Lenalidomide showed anti-angiogenic response in vivo. Reduction in metastasis and phosphorylation of Akt has also been seen to be reduced in an in vitro system of endothelial cells [6]. It can also act an immunomodulating agent as seen hematological malignancies [7].

CLINICAL USAGE OF LENALIDOMIDE
Lenalidomide has been used in clinical trials for different types of diseases but the most successful studies were shown for treating cancers e.g., Hodgkin's Lymphoma, non-Hodgkin's Lymphoma, various solid tumors like pancreatic cancers and Chronic Lymphocytic Leukemia (CLL). Discoid Lupus Erythematosus can also be included in these. Cancers of lymphoma and Leukemia can also be treated with this drug either in the form a single drug agent or in combination with other drugs [8]. Lenalidomide in combination with Pomalidomide has also been studied in erythropoiesis model in in vitro conditions using CD34+ human progenitor cells [9].
Lenalidomide has also been studied against solid tumors in clinical trial phase I [10] which encouraged its trial in up till phase II against renal cell carcinoma and showed a quite efficient inhibition [11]. Different combinations against different diseases are being studied where they have shown success against amyloidosis [12], myeloma [13-14], CLL [15] and the patients of myelodysplastic syndromes (MDSs) [16].
In clinical trial phase III for the patients of relapsed/refractory multiple myeloma (RRMM) Lenalidomide has shown a remarkable efficiency [17] and due to its low toxicity profile it is promised for the patients in elderly myeloma stage [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).
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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.