Mechanism of action of lenalidomide in hematological malignancies.
Immunomodulatory drugs lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that lacks the neurologic side effects of sedation and neuropathy and has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Lenalidomide has been shown to be an immunomodulator, affecting both cellular and humoral limbs of the immune system. It has also been shown to have anti-angiogenic properties. Newer studies demonstrate its effects on signal transduction that can partly explain its selective efficacy in subsets of MDS. Even though the exact molecular targets of lenalidomide are not well known, its activity across a spectrum of neoplastic conditions highlights the possibility of multiple target sites of action.
Kotla
Venumadhav
V
Department of Medicine, Albert Einstein College of Medicine, Bronx, USA. venumadhav_kotla@yahoo.com
Goel
Swati
S
Nischal
Sangeeta
S
Heuck
Christoph
C
Vivek
Kumar
K
Das
Bhaskar
B
Verma
Amit
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects / Q000502:physiology; D000077269:Lenalidomide; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide
N Engl J Med. 2006 Sep 7;355(10):973-5
16908487
Am J Hematol. 2005 Aug;79(4):319-28
16044444
Blood. 2008 Jun 1;111(11):5291-7
18334676
J Immunol. 1999 Jul 1;163(1):380-6
10384139
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12974-9
19470455
Blood. 2002 Jun 15;99(12):4525-30
12036884
N Engl J Med. 2005 Feb 10;352(6):549-57
15703420
Semin Oncol. 2001 Dec;28(6):602-6
11740817
Immunopharmacology. 1996 Mar;31(2-3):213-21
8861747
Blood. 2009 Apr 30;113(18):4137-43
19182205
Clin J Oncol Nurs. 2007 Aug;11(4):569-74
17723971
Int J Lepr Other Mycobact Dis. 1985 Jun;53(2):201-5
3874920
Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11406-11
17576924
Cancer. 2006 Dec 1;107(11):2609-16
17075879
Cancer Res. 2007 Jan 15;67(2):746-55
17234786
Blood. 2004 Mar 1;103(5):1787-90
14512311
Blood. 2008 Feb 1;111(3):1101-9
17989313
Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4082-5
7513432
J Exp Med. 1993 Jun 1;177(6):1675-80
8496685
Ann Oncol. 2006 Dec;17(12):1766-71
16980599
N Engl J Med. 2007 Nov 22;357(21):2133-42
18032763
Cell Immunol. 1995 May;162(2):248-55
7743552
Br J Cancer. 2002 Nov 4;87(10):1166-72
12402158
Am J Clin Oncol. 2008 Jun;31(3):244-9
18525302
Cell Cycle. 2008 May 1;7(9):1121-7
18418038
Leukemia. 2001 Dec;15(12):1950-61
11753617
Cancer Control. 2006 Dec;13 Suppl:2-3
17242660
Bioorg Med Chem Lett. 1999 Jun 7;9(11):1625-30
10386948
Gynecol Oncol. 2007 Apr;105(1):194-8
17257661
Leukemia. 2004 Jan;18(1):113-9
14586479
Microvasc Res. 2005 Jan;69(1-2):56-63
15797261
Am J Hematol. 2009 Sep;84(9):553-9
19565649
Int J Biochem Cell Biol. 2007;39(7-8):1489-99
17369076
Blood. 2006 Aug 15;108(4):1158-64
16609064
Blood. 2005 Dec 15;106(13):4050-3
16118317
Eur J Haematol. 1991 Oct;47(4):277-81
1954986
Expert Opin Biol Ther. 2007 Feb;7(2):233-42
17250461
J Thorac Oncol. 2007 May;2(5):445-9
17473661
Nat Rev Cancer. 2004 Apr;4(4):314-22
15057291
Br J Haematol. 2007 Nov;139(4):578-89
17916100
J Cell Biochem. 2007 Jul 1;101(4):950-68
17546631
Leukemia. 2008 Oct;22(10):1925-32
18596740
Br J Haematol. 2005 Jan;128(2):192-203
15638853
Blood. 2002 Nov 1;100(9):3063-7
12384400
Blood. 2001 Jul 1;98(1):210-6
11418482
Clin Cancer Res. 2008 Jul 15;14(14):4650-7
18628480
J Immunol. 2002 May 15;168(10):4914-9
11994441
N Engl J Med. 2006 Oct 5;355(14):1456-65
17021321
PLoS Med. 2008 Feb;5(2):e35
18271621
Leukemia. 2007 Apr;21(4):659-67
17301813
Clin Cancer Res. 2007 Dec 1;13(23):7101-6
18056189
Blood. 2008 Jan 1;111(1):86-93
17893227
Blood. 2007 Jan 15;109(2):465-70
17008538
Cancer Control. 2006 Dec;13 Suppl:4-11
17242661
Exp Hematol. 2007 Apr;35(4 Suppl 1):137-43
17379099
Invest New Drugs. 2007 Jun;25(3):211-6
17103043
Scand J Immunol. 1981;13(6):553-62
7031850
J Clin Oncol. 2006 Dec 1;24(34):5343-9
17088571
Eur J Cancer. 2006 Sep;42(14):2318-25
16899362
J Clin Invest. 2007 May;117(5):1137-46
17476343
AAPS J. 2005 Mar 22;7(1):E14-9
16146335
Nature. 2008 Jan 17;451(7176):335-9
18202658
Leuk Res. 2006 Jul;30(7):849-58
16494942
Lancet Oncol. 2006 Jun;7(6):480-8
16750498
J Clin Oncol. 2007 Oct 1;25(28):4459-65
17785703
J Clin Oncol. 2008 Oct 20;26(30):4952-7
18606983
J Clin Invest. 2008 Jul;118(7):2427-37
18551193
Blood. 2000 Nov 1;96(9):2943-50
11049970