The integrin antagonist, cilengitide, is a weak inhibitor of αIIbβ3 mediated platelet activation and inhibits platelet adhesion under flow

References

• Taugourdeau-Raymond S, Rouby F, Default A, Jean-Pastor MJ. Bevacizumab-induced serious side-effects: A review of the French pharmacovigilance database. Eur J Clin Pharmacol 2012;68:1103–1107
   PubMed Web of Science ®Google Scholar
• Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: A meta-analysis. JAMA 2008;300:2277–2285
   PubMed Web of Science ®Google Scholar
• Ferroni P, Formica V, Roselli M, Guadagni F. Thromboembolic events in patients treated with anti-angiogenic drugs. Curr Vasc Pharmacol 2010;8:102–113
   PubMed Web of Science ®Google Scholar
• Elice F, Rodeghiero F, Falanga A, Rickles FR. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol 2009;22:115–128
   PubMed Web of Science ®Google Scholar
• Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010;8:221–227
   PubMed Web of Science ®Google Scholar
• Buerkle MA, Pahernik SA, Sutter A, Jonczyk A, Messmer K, Dellian M. Inhibition of the alpha-nu integrins with a cyclic RGD peptide impairs angiogenesis, growth and metastasis of solid tumours in vivo. Br J Cancer 2002;86:788–795
   PubMed Web of Science ®Google Scholar
• MacDonald TJ, Stewart CF, Kocak M, Goldman S, Ellenbogen RG, Phillips P, Lafond D, Poussaint TY, Kieran MW, Boyett JM, et al. Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012. J Clin Oncol 2008;26:919–924
   PubMed Web of Science ®Google Scholar
• Yamada S, Bu XY, Khankaldyyan V, Gonzales-Gomez I, McComb JG, Laug WE. Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice. Neurosurgery 2006;59:1304–1312; discussion 1312
   PubMed Web of Science ®Google Scholar
• Stupp R, Hegi ME, Gorlia T, Erridge S, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam D-H, Weyerbrock A, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study. J Clin Oncol 2013;13:(suppl; abstr LBA2009)
   Google Scholar
• Dechantsreiter MA, Planker E, Matha B, Lohof E, Holzemann G, Jonczyk A, Goodman SL, Kessler H. N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 1999;42:3033–3040
   PubMed Web of Science ®Google Scholar
• Meyer Dos Santos S, Klinkhardt U, Schneppenheim R, Harder S. Using ImageJ for the quantitative analysis of flow-based adhesion assays in real-time under physiologic flow conditions. Platelets 2010;21:60–66
   PubMed Web of Science ®Google Scholar
• Meyer dos Santos S, Klinkhardt U, Scholich K, Nelson K, Monsefi N, Deckmyn H, Kuczka K, Zorn A, Harder S. The CX3C chemokine fractalkine mediates platelet adhesion via the von Willebrand receptor glycoprotein Ib. Blood 2011;117:4999–5008
   Google Scholar
• Vassallo RR Jr, Kieber-Emmons T, Cichowski K, Brass LF. Structure-function relationships in the activation of platelet thrombin receptors by receptor-derived peptides. J Biol Chem 1992;267:6081–6085
   PubMed Web of Science ®Google Scholar
• Hu DD, Hoyer JR, Smith JW. Ca2+ suppresses cell adhesion to osteopontin by attenuating binding affinity for integrin alpha v beta 3. J Biol Chem 1995;270:9917–9925
   PubMed Web of Science ®Google Scholar
• Valgimigli M, Campo G, Tebaldi M, Carletti R, Arcozzi C, Ferrari R, Percoco G. Abciximab: A reappraisal of its use in coronary care. Biol Targets Ther 2008;2:29–39
   PubMedGoogle Scholar
• Armstrong PC, Peter K. GPIIb/IIIa inhibitors: From bench to bedside and back to bench again. Thromb Haemost 2012;107:808–814
   PubMed Web of Science ®Google Scholar
• Fuentes QE, Fuentes QF, Andres V, Pello OM, de Mora JF, Palomo GI. Role of platelets as mediators that link inflammation and thrombosis in atherosclerosis. Platelets 2013;24:255–262
   PubMed Web of Science ®Google Scholar
• Tsao PW, Forsythe MS, Mousa SA. Dissociation between the anti-aggregatory & anti-secretory effects of platelet integrin alpha IIb beta 3 (GPIIb/IIIa) antagonists, c7E3 and DMP728. Thromb Res 1997;88:137–146
   PubMedGoogle Scholar
• Schneider DJ, Taatjes DJ, Sobel BE. Paradoxical inhibition of fibrinogen binding and potentiation of alpha-granule release by specific types of inhibitors of glycoprotein IIb-IIIa. Cardiovasc Res 2000;45:437–446
   PubMed Web of Science ®Google Scholar
• Peter K, Schwarz M, Ylanne J, Kohler B, Moser M, Nordt T, Salbach P, Kubler W, Bode C. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors. Blood 1998;92:3240–3249
   PubMed Web of Science ®Google Scholar
• Klinkhardt U, Graff J, Harder S. Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model. Clin Pharmacol Ther 2002;71:176–185
   PubMed Web of Science ®Google Scholar
• Alghisi GC, Ponsonnet L, Ruegg C. The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells. PLoS One 2009;4:e4449
   PubMed Web of Science ®Google Scholar
• Roest M, Reininger A, Zwaginga JJ, King MR, Heemskerk JW. Flow chamber-based assays to measure thrombus formation in vitro: Requirements for standardization. J Thromb Haemost: JTH 2011;9:2322–2324
   PubMed Web of Science ®Google Scholar
• Heemskerk JW, Sakariassen KS, Zwaginga JJ, Brass LF, Jackson SP, Farndale RW. Collagen surfaces to measure thrombus formation under flow: Possibilities for standardization. J Thromb Haemost 2011;9:856–858
   PubMed Web of Science ®Google Scholar
• Jirouskova M, Jaiswal JK, Coller BS. Ligand density dramatically affects integrin alpha IIb beta 3-mediated platelet signaling and spreading. Blood 2007;109:5260–5269
   Google Scholar
• Nurden AT. Is there a redundancy of beta3 and other platelet receptors in the brain and central nervous system? Platelets 2013;24:170–172
   PubMed Web of Science ®Google Scholar
• Coller BS. Binding of abciximab to alpha V beta 3 and activated alpha M beta 2 receptors: With a review of platelet-leukocyte interactions. Thromb Haemost 1999;82:326–336
   PubMed Web of Science ®Google Scholar
• Coller BS, Cheresh DA, Asch E, Seligsohn U. Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel. Blood 1991;77:75–83
   PubMed Web of Science ®Google Scholar
• Tam SH, Sassoli PM, Jordan RE, Nakada MT. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and alpha(v)beta3 integrins. Circulation 1998;98:1085–1091
   PubMed Web of Science ®Google Scholar
• Mas-Moruno C, Beck JG, Doedens L, Frank AO, Marinelli L, Cosconati S, Novellino E, Kessler H. Increasing alphavbeta3 selectivity of the anti-angiogenic drug cilengitide by N-methylation. Angew Chem Int Ed Engl 2011;50:9496–9500
   Google Scholar
• Bonnefoy A, Liu Q, Legrand C, Frojmovic MM. Efficiency of platelet adhesion to fibrinogen depends on both cell activation and flow. Biophys J 2000;78:2834–2843
   PubMed Web of Science ®Google Scholar
• Cook BC. Reactivity of human platelets with immobilized fibrinogen is dictated by the chemical character of the surface. Thromb Res 2001;104:39–48
   Google Scholar
• Peterson JE, Zurakowski D, Italiano JE Jr, Michel LV, Fox L, Klement GL, Folkman J. Normal ranges of angiogenesis regulatory proteins in human platelets. Am J Hematol 2010;85:487–493
   PubMed Web of Science ®Google Scholar
• Varner JA, Nakada MT, Jordan RE, Coller BS. Inhibition of angiogenesis and tumor growth by murine 7E3, the parent antibody of c7E3 Fab (abciximab; ReoPro). Angiogenesis 1999;3:53–60
   PubMedGoogle Scholar
• Trikha M, Zhou Z, Timar J, Raso E, Kennel M, Emmell E, Nakada MT. Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res 2002;62:2824–2833
   PubMed Web of Science ®Google Scholar
• Hodivala-Dilke KM, Reynolds AR, Reynolds LE. Integrins in angiogenesis: Multitalented molecules in a balancing act. Cell Tissue Res 2003;314:131–144
   PubMed Web of Science ®Google Scholar
• Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, Da Violante G, Gourlaouen M, Salih M, Jones MC, et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med 2009;15:392–400
   PubMed Web of Science ®Google Scholar
• Narita Y. Drug review: Safety and efficacy of bevacizumab for glioblastoma and other brain tumors. Jpn J Clin Oncol 2013;43:587–595
   PubMed Web of Science ®Google Scholar
• Costagliola C, Agnifili L, Arcidiacono B, Duse S, Fasanella V, Mastropasqua R, Verolino M, Semeraro F. Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration. Expert Opin Biol Ther 2012;12:1299–1313
   PubMed Web of Science ®Google Scholar
• Nabors LB, Mikkelsen T, Hegi ME, Ye X, Batchelor T, Lesser G, Peereboom D, Rosenfeld MR, Olsen J, Brem S, et al. A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer 2012;118:5601–5607
   PubMed Web of Science ®Google Scholar