{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T22:21:15Z","timestamp":1788560475706,"version":"build-2803163510"},"reference-count":28,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2003,6,1]]},"abstract":"<jats:p> Purpose: An increased incidence of thromboembolic events was observed during treatment with cisplatin-gemcitabine plus SU5416 (CG+SU5416), a tyrosine kinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor-1 and -2. Nine thromboembolic events occurred in eight of 19 patients. We performed an analysis of parameters of the coagulation cascade and vessel wall activation. <\/jats:p><jats:p> Materials and Methods: Markers for thrombin generation and endothelial cell activation were measured in three patients treated with CG+SU5416, two of whom developed a thromboembolic event. The results were compared with measurements in six patients treated with CG alone, and in 17 patients treated with SU5416 alone. <\/jats:p><jats:p> Results: During cycles 1 and 2 of treatment with CG+SU5416, a significant cycle-dependent activation of both the coagulation cascade and endothelial cells occurred, whereas platelet counts decreased. Change in platelet number had a significant negative predictive effect on soluble (s)-E-selectin levels. Significant activation of the coagulation cascade only was observed in the patients treated with CG alone, whereas in patients treated with SU5416 alone, significant endothelial cell activation was observed. <\/jats:p><jats:p> Conclusion: We hypothesize that endothelial cells deprived of VEGF after exposure to SU5416 became activated and more susceptible to damage during treatment with CG+SU5416, which was aggravated by a transient decrease in platelets, which are, among other things, carriers of VEGF. These results suggests that VEGF, in addition to being a permeability, proliferation, and migration factor, also is a maintenance and protection factor for endothelial cells, and that platelets may have a role in maintaining vascular integrity. <\/jats:p>","DOI":"10.1200\/jco.2003.08.046","type":"journal-article","created":{"date-parts":[[2003,5,29]],"date-time":"2003-05-29T02:05:58Z","timestamp":1054173958000},"page":"2192-2198","source":"Crossref","is-referenced-by-count":103,"title":["Potential Role of Platelets in Endothelial Damage Observed During Treatment With Cisplatin, Gemcitabine, and the Angiogenesis Inhibitor SU5416"],"prefix":"10.1200","volume":"21","author":[{"given":"B.C.","family":"Kuenen","sequence":"first","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Levi","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.C.M.","family":"Meijers","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.W.M.","family":"van Hinsbergh","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Berkhof","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.K.","family":"Kakkar","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Hoekman","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.M.","family":"Pinedo","sequence":"additional","affiliation":[{"name":"From the Department of Medical Oncology, Department of Physiology, Institute for Cardiovascular Research, and Department of Clinical Epidemiology and Biostatistics, VU Medical Center; and Department of Vascular Medicine and Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam; Gaubius Laboratory TNO-PG, Leiden, the Netherlands; and Imperial College, Hammersmith Hospital, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1038\/35025220"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(98)00066-7"},{"key":"R3","unstructured":"Mendel DB, Laird AD, Smolich BD, et al: Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent. Anticancer Drug Des 15:29,2000\u201341,"},{"key":"R4","unstructured":"Itokawa T, Nokihara H, Nishioka Y, et al: Antiangiogenic effect by SU5416 is partly attributable to inhibition of flt-1 receptor signaling. Mol Cancer Ther 1:295,2002\u2013302,"},{"key":"R5","unstructured":"Mendel DB, Schreck RE, West DC, et al: The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin Cancer Res 6:4848,2000\u20134858,"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.20.6.1657"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000030186.66672.36"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1656024"},{"key":"R9","doi-asserted-by":"crossref","unstructured":"Cejka J: Performance characteristics of a commercial kit for assay of factor VIII-related antigen. Clin Chem 30:814,1984\u2013815,","DOI":"10.1093\/clinchem\/30.5.814"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.2307\/2529876"},{"key":"R12","unstructured":"Verheul HM, Hoekman K, Luykx-de Bakker S, et al: Platelet:Transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187,1997\u20132190,"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026552415576"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(00)00294-2"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1016\/0165-2478(92)90211-6"},{"key":"R16","unstructured":"Gan XH, Jewett A, Bonavida B: Activation of human peripheral-blood-derived monocytes by cis-diamminedichloroplatinum: Enhanced tumoricidal activity and secretion of tumor necrosis factor-alpha. Nat Immun 11:144,1992\u2013155,"},{"key":"R17","unstructured":"Verheul HM, Hoekman K, Lupu F, et al: Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas. Clin Cancer Res 6:166,2000\u2013171,"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1038\/221033a0"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)05095-8"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.13.4216"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(01)76085-7"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(01)76083-3"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008339425708"},{"key":"R24","unstructured":"Shepro D: The American Microcirculatory Society Landis Award lecture: Endothelial cells, inflammatory edema, and the microvascular barrier\u2014Comments by a \u201cfree radical.\u201d Microvasc Res 35:246,1988\u2013264,"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)02232-9"},{"key":"R26","unstructured":"Rosen PJ, Amado R, Hecht JR, et al: A phase I\/II study of SU5416 in combination with 5-FU\/leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 19:3a,2000,  (abstr 5D)"},{"key":"R27","unstructured":"Rothenberg M, Berlin J, Cropp G, et al: Phase I\/II study of SU5416 in combination with irinotecan\/5-FU\/LV (IFL) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 20:75a,2001,  (abstr 298)"},{"key":"R28","unstructured":"Overmoyer B, Robertson K, Persons M, et al: A phase I pharmacokinetic and pharmacodynamic study of SU5416 and doxorubicin (ADR) in inflammatory breast cancer (IBC). Proc Am Soc Clin Oncol 20:99a,2001,  (abstr 391)"},{"key":"R29","unstructured":"Rosen P, Kabbinavar F, Figlin R, et al: A phase I\/II trial and pharmacokinetic study of SU5416 in combination with paclitaxel\/carboplatin. Proc Am Soc Clin Oncol 20:98a,2001,  (abstr 389)"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2003.08.046","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T20:26:56Z","timestamp":1653510416000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2003.08.046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,6,1]]},"references-count":28,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2003,6,1]]}},"alternative-id":["10.1200\/JCO.2003.08.046"],"URL":"https:\/\/doi.org\/10.1200\/jco.2003.08.046","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,6,1]]}}}