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Immunomodulatory Drugs

The IMiDs are a group of unique, orally bioavailable agents that have been refined using the parent IMiD compound, thalidomide, as a structural template. Modification of the thalidomide structure through the addition of an amino group at the 4 position of the phthaloyl ring forms CC-4047 (Actimid), and the removal of a carbonyl on the ring forms lenalidomide. They were specifically designed to enhance immunomodulation and anticancer properties but with less side effects. Immunomodulatory drugs have been shown to be 50,000 times more potent than thalidomide at inhibiting tumor necrosis factor–α (TNF-α ) from preclinical studies.1,2 Studies reveal that thalidomide and IMiDs not only inhibit angiogenesis but also induce apoptosis and growth arrest in resistant myeloma cells. They also prevent the adhesion of myeloma cells to bone marrow stromal cells and thereby inhibit the enhanced secretion of migratory factors, such as interleukin (IL)–6, TNF-α , and vascular endothelial growth factor.3-7 Lenalidomide has proven to have more potent activity than thalidomide in the preclinical setting.1,8 Another thalidomide analogue, CC-4047 (Actimid), also demonstrates potent activity against TNF-α  and has recently entered clinical trials.9

References List

1. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4:314-322.
2. Muller GW, Chen R, Huang SY, et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett. 1999;9:1625-1630.
3. Anderson KC. Multiple Myeloma. Advances in disease biology: therapeutic implications. Semin Hematol. 2001;38:6-10.
4. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96:2943-2950.
5. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98:210-216.
6. Treon SP, Mitsiades C, Mitsiades N, et al. Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. J Immunother. 2001;24:263-271.
7. Lentzsch S, LeBlanc R, Podar K, et al. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia. 2003;17:41-44.
8. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer. 2002;2:927-937.
9. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22:3269-3276.

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