title: The immunopharmacologic potential of Semaxanib and new generation directed therapeutic drugs: Receptor tyrosine kinase regulation with anti-tumorigenensis/angiogenesis properties.
abstract: Molecular signaling of messages emanating from cellular membranes through receptor tyrosine kinases (RTKs) is a major mechanism for intercellular communication and transduction during development and metabolism, as well as in disease-associated processes. The phosphorylation status and signaling activity of RTKs are determined by a dynamic equilibrium of the activity of both RTKs and protein tyrosine phosphatases (PTPs). RTKs are essentially a class of cell-surface receptors for growth factors and other extracellular ligands, the most conspicuous perhaps are members of the vascular endothelial growth factor (VEGF) gene family, which plays a fundamental role in the growth and differentiation of vascular, as well as lymphatic endothelial cells. In particular, VEGF is a major regulator of normal (physiologic) and abnormal (cancerous) angiogenesis, including that associated with tumors and cancer. Blockers/inhibitors and regulators of RTKs are indeed promising cancer interventions, their specific mechanisms are yet to be unraveled. In this cutting-edge synopsis, I elaborate on breakthroughs/advances and current concepts of RTK regulation, further shedding light on exploring the role of potential regulators, particularly the RTK inhibitor Semaxanib, and the mechanisms associated with tumorigenesis in an effort to understand a potentially alleviating pharmacologic therapeutic intervention. This survey also tackles the loopholes and shortcomings of the aforementioned inhibitory role of Semaxanib, especially its inefficacy and ultimate discontinuation of relevant clinical trials.
authors: Cellular and Molecular Signaling Research Group, Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon.
authors: John J
authors: JJ
authors: Haddad
keywords: Bevacizumab; Cell signaling; Development; Disease; Gene regulation; Immunopharmacology; Kinase; Phosphorylation; RTK; Semaxanib; Transcription factors
references: Neoplasia. 2008 May;10(5):489-500
references: 18472966
references: Br J Pharmacol. 1997 Sep;122(1):59-70
references: 9298529
references: J Cell Sci. 2001 Mar;114(Pt 5):853-65
references: 11181169
references: Blood. 2001 Mar 1;97(5):1413-21
references: 11222388
references: Cell Immunol. 1995 Dec;166(2):196-206
references: 7497521
references: Genome Biol. 2001;2(3):REVIEWS3005
references: 11276432
references: Jpn J Clin Oncol. 2006 Feb;36(2):100-3
references: 16449240
references: Cytokine Growth Factor Rev. 2005 Aug-Oct;16(4-5):441-67
references: 15982921
references: FASEB J. 1999 Jan;13(1):9-22
references: 9872925
references: Br J Cancer. 2005 Oct 17;93(8):876-83
references: 16222321
references: Endocr Relat Cancer. 2001 Sep;8(3):161-73
references: 11566607
references: JAMA. 2003 Oct 22;290(16):2149-58
references: 14570950
references: Oncogene. 1995 Jan 5;10(1):135-47
references: 7824266
references: Science. 1988 Jul 1;241(4861):42-52
references: 3291115
references: J Med Chem. 2000 Jul 13;43(14):2655-63
references: 10893303
references: Mol Biosyst. 2009 Oct;5(10):1112-21
references: 19756300
references: Life Sci. 1993;53(19):1465-72
references: 8412509
references: Cancer Res. 1996 Aug 1;56(15):3540-5
references: 8758924
references: Curr Opin Neurobiol. 2000 Feb;10(1):103-10
references: 10679429
references: Cancer Pract. 2000 May-Jun;8(3):148-50
references: 11898141
references: Curr Med Chem. 1999 Sep;6(9):775-805
references: 10495352
references: Oncologist. 2000;5 Suppl 1:16-9
references: 10804086
references: Cancer Metastasis Rev. 1996 Jun;15(2):237-40
references: 8842496
references: Curr Opin Investig Drugs. 2001 Feb;2(2):280-6
references: 11816845
references: Blood. 2008 Feb 15;111(4):1834-9
references: 18048643
references: Anticancer Agents Med Chem. 2007 Nov;7(6):594-611
references: 18045055
references: Gan To Kagaku Ryoho. 1997 Jan;24(2):178-86
references: 9030228
references: Bioorg Med Chem. 1998 Oct;6(10):1799-810
references: 9839010
references: Exp Hematol. 1992 May;20(4):500-4
references: 1314737
references: Anticancer Drug Des. 2000 Feb;15(1):29-41
references: 10888034
references: Clin Cancer Res. 2000 Dec;6(12):4848-58
references: 11156244
references: Annu Rev Physiol. 1991;53:217-39
references: 1710435
references: Int Immunopharmacol. 2004 Apr;4(4):475-93
references: 15099526
references: Curr Opin Drug Discov Devel. 1998 Sep;1(2):131-46
references: 19649813
references: Cancer Res. 1999 Jan 1;59(1):99-106
references: 9892193
references: Science. 2004 Aug 20;305(5687):1163-7
references: 15284455
references: J Clin Oncol. 2008 Feb 1;26(4):620-5
references: 18235121
references: Nature. 1994 Feb 10;367(6463):576-9
references: 8107827
references: J Med Chem. 2000 Jan 13;43(1):1-18
references: 10633033
references: Drug Discov Today. 2000 Aug;5(8):344-353
references: 10893547
references: J Biol Chem. 2006 Sep 15;281(37):27178-89
references: 16829530
references: Presse Med. 1998 Jul 4-11;27(24):1221-4
references: 9767782
references: FEBS J. 2010 Jan;277(2):309-15
references: 19922468
references: Baillieres Clin Haematol. 1993 Sep;6(3):711-30
references: 7517738
references: Drugs Aging. 2000 Oct;17(4):249-55
references: 11087003
references: Nat Med. 1995 Jan;1(1):27-31
references: 7584949
references: Oncologist. 2000;5 Suppl 1:28-31
references: 10804088
references: Indian J Biochem Biophys. 2004 Dec;41(6):273-80
references: 22900354
references: Eur J Biochem. 1996 Mar 1;236(2):352-9
references: 8612602
references: Mol Cell Neurosci. 1999 May;13(5):313-25
references: 10356294
references: J Med Chem. 1998 Jul 2;41(14):2588-603
references: 9651163
references: Cancer Metastasis Rev. 1990 Nov;9(3):203-26
references: 1705486
references: Immunol Cell Biol. 1995 Dec;73(6):584-9
references: 8713482
references: J Med Chem. 2000 Jun 15;43(12):2310-23
references: 10882357
references: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7533-7
references: 8356051
references: Nat Med. 1997 Feb;3(2):158-64
references: 9018233
references: Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5192-6
references: 1594631
references: Oncogene. 1995 Nov 16;11(10):2039-45
references: 7478523
references: Cancer Res. 2001 Feb 15;61(4):1477-85
references: 11245454
references: Nature. 1995 Jul 6;376(6535):62-6
references: 7596435
references: Am J Clin Oncol. 2006 Apr;29(2):109-15
references: 16601426
references: Expert Opin Investig Drugs. 1998 Apr;7(4):553-73
references: 15991993
references: Biochem Pharmacol. 2001 Feb 1;61(3):253-70
references: 11172729
references: Traffic. 2001 Jan;2(1):12-8
references: 11208164
references: Nature. 1995 Feb 16;373(6515):573-80
references: 7531822
references: Lancet. 1998 May 30;351(9116):1598-9
references: 9620709
references: Nat Nanotechnol. 2008 Jul;3(7):418-22
references: 18654566
references: Curr Opin Drug Discov Devel. 1999 Jul;2(4):274-85
references: 19649955
references: Oncologist. 2000;5 Suppl 1:3-10
references: 10804084
references: Curr Opin Oncol. 2000 Mar;12(2):174-80
references: 10750730
references: J Invest Dermatol. 1995 May;104(5):744-9
references: 7738351
references: N Engl J Med. 2001 Apr 5;344(14):1052-6
references: 11287975
references: Oncologist. 2000;5 Suppl 1:11-5
references: 10804085
references: APMIS. 1997 Jul;105(7):497-509
references: 9269296
references: Gene. 2001 Jun 27;271(2):171-82
references: 11418238
references: J Biol Chem. 1996 Mar 8;271(10):5638-46
references: 8621427
references: Ann Ital Med Int. 2000 Jan-Mar;15(1):7-19
references: 10842887
references: J Biol Chem. 1998 Nov 13;273(46):30336-43
references: 9804796
references: N Engl J Med. 2001 Apr 5;344(14):1031-7
references: 11287972
references: Eur J Cancer. 2000 Aug;36(13 Spec No):1713-24
references: 10959057
references: N Engl J Med. 1994 Dec 1;331(22):1480-7
references: 7526212
references: J Neurooncol. 2000 Oct-Nov;50(1-2):189-200
references: 11245279
references: J Med Chem. 1999 Dec 16;42(25):5120-30
references: 10602697
references: Oncogene. 2000 Nov 20;19(49):5548-57
references: 11114734
references: Pharmacol Ther. 1999 May-Jun;82(2-3):195-206
references: 10454197
references: Cancer Res. 2001 May 1;61(9):3660-8
references: 11325836
references: Drug Resist Updat. 2000 Apr;3(2):67-73
references: 11498368
references: Diabetes. 1997 Sep;46(9):1473-80
references: 9287049
references: Nature. 1995 Jul 6;376(6535):66-70
references: 7596436
references: J Cell Sci. 2000 Jul;113 ( Pt 13):2345-54
references: 10852814
references: Cell. 1998 Mar 20;92(6):735-45
references: 9529250