Semin Thromb Hemost 2007; 33(7): 712-721
DOI: 10.1055/s-2007-991540
© Thieme Medical Publishers

Inhibition of Platelet Function: Does It Offer a Chance of Better Cancer Progression Control?

Ewa Sierko1 , 2 , Marek Z. Wojtukiewicz1 , 2
  • 1Department of Oncology, Medical University, Bialystok, Poland
  • 2Comprehensive Cancer Center, Bialystok, Poland
Further Information

Publication History

Publication Date:
14 November 2007 (online)

ABSTRACT

Thrombocytosis is frequently (10 to 57%) observed in cancer patients. Although the mechanisms underlying thrombocytosis are not yet fully elucidated, tumor-derived factors with thrombopoietin-like activity, growth factors, platelet-derived microparticles, and factors released from bone marrow endothelial cells as well as growth factors secreted by megakaryocytes (acting via an autocrine loop) are claimed to influence this process. The course of cancer is strongly associated with hypercoagulable state, which results from direct influences of tumor cells themselves and various indirect mechanisms. Activated platelets provide procoagulant surface amplifying the coagulation process. It is well documented that proteins of the hemostatic system influence different steps of metastasis, angiogenesis, and proteolytic events. Much less is known about the role of platelets in tumor growth and their possible contribution to prevention of tumor cells from the host immune system. Multidirectional activities of platelets during tumor development and metastatic dissemination create a possibility of introducing antiplatelet agents in anticancer therapy. The spectrum of plausible therapies includes antibodies against glycoprotein IIb-IIIa, direct thrombin inhibitors, protease activated receptor-1 targeted therapy, as well as cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors. However, there is no sufficient information on a specific type of cancer where progression does depend on platelet function. Despite numerous experimental studies conducted, to date none of the new specific antiplatelet agents were tested in clinical trials in a cancer patient population.

REFERENCES

  • 1 Francis J L, Biggerstaff J, Amirkhosravi A. Hemostasis and malignancy.  Semin Thromb Hemost. 1998;  24 93-109
  • 2 Zacharski L R, Wojtukiewicz M Z, Costantini V, Ornstein D L, Memoli V A. Pathways of coagulation/fibrinolysis activation in malignancy.  Semin Thromb Hemost. 1992;  18 104-116
  • 3 Rickles F R, Levine M, Edwards R L. Hemostatic alterations in cancer patients.  Cancer Metastasis Rev. 1992;  11 237-248
  • 4 Sierko E, Wojtukiewicz M Z. Platelets and angiogenesis in malignancy.  Semin Thromb Hemost. 2004;  30 95-108
  • 5 Uppenkamp M, Makarove E, Petrasch S, Brittinger G. Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis.  Ann Hematol. 1998;  77 217-223
  • 6 Kato N, Yasukawa K, Onozuka T, Kimura K. Paraneoplastic syndromes of leukocytosis, thrombocytosis, and hypercalcemia associated with squamous cell carcinoma.  J Dermatol. 1999;  26 352-358
  • 7 Estrov Z, Talpaz M, Mavlight G et al.. Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis.  Am J Med. 1995;  98 551-558
  • 8 Gastl G, Plante M, Finstad C L et al.. High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer.  Br J Haematol. 1993;  83 433-441
  • 9 Suzuki A, Takahashi T, Nakamura K et al.. Thrombocytosis in patients with tumors producing colony-stimulating factor.  Blood. 1992;  80 2052-2059
  • 10 Raffi S, Shapiro F, Pettengeli R et al.. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors.  Blood. 1995;  86 3353-3363
  • 11 Baj-Krzyworzeka M, Majka M, Pratico D et al.. Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells.  Exp Hematol. 2002;  30 450-459
  • 12 Schwarz R E. Platelet counts and prognosis of pancreatic cancer.  Lancet. 1999;  353 2158-2159
  • 13 Slichter S J, Harker L A. Hemostasis in malignancy.  Ann N Y Acad Sci. 1974;  230 252-262
  • 14 Tang D G, Honn K V. Adhesion molecules and tumor metastasis: an update.  Invasion Metastasis. 1994-95;  14 109-122
  • 15 Honn K V, Tang G T, Chen Y Q. Platelets and cancer metastasis: more than an epiphenomenon.  Semin Thromb Hemost. 1992;  18 392-415
  • 16 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases.  Nat Med. 1995;  1 27-31
  • 17 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy.  Neoplasia. 2001;  3 371-384
  • 18 Wojtukiewicz M Z, Sierko E, Rak J. Contribution of the hemostatic system to angiogenesis in cancer.  Semin Thromb Hemost. 2004;  30 5-20
  • 19 Timár J, Tówári J, Rásó E, Mèszáros L. Platelet-mimicry of cancer cells: epiphenomenon with clinical significance.  Oncology. 2005;  69 185-201
  • 20 Heemskerk J WM, Bevers E M, Lindhout T. Platelet activation and blood coagulation.  Thromb Haemost. 2002;  88 186-193
  • 21 Andrews R K, Shen Y, Gardiner E E, Berndt M C. Platelet adhesion receptors and (patho)physiological thrombus formation.  Histol Histopathol. 2001;  16 969-980
  • 22 Chen H, Locke D, Liu Y, Kahn M L. The platelet receptor GPVI mediates both adhesion and signaling responses to collagen in a receptor density-dependent fashion.  J Biol Chem. 2002;  277 3011-3019
  • 23 Kamata T, Takada Y. Platelet integrin alphaIIbbeta3-ligand interactions: what we learn from the structure?.  Int J Hematol. 2001;  74 382-389
  • 24 Coughlin S R. Protease-activated receptors and platelet function.  Thromb Haemost. 1999;  82 353-356
  • 25 Di Virgilio F, Chiozzi P, Ferrari D et al.. Nucleotide receptors: an emerging family of regulatory molecules in blood cells.  Blood. 2001;  97 587-600
  • 26 Rendu F, Brohard-Bohn B. The platelet release reaction: granules' constituents, secretion and functions.  Platelets. 2001;  12 261-273
  • 27 Wehmeier A, Tschope D, Esser J et al.. Circulating activated platelets in myeloproliferative disorders.  Thromb Res. 1991;  61 271-278
  • 28 Blann A D, Gurney M, Wadley D, Bareford D, Stonelake P, Lip G Y. Increased soluble P-selectin in patients with hematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor.  Blood Coagul Fibrinolysis. 2001;  12 43-50
  • 29 Caine G J, Lip G Y, Stonelake P S, Ryan P, Blann A D. Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma.  Thromb Haemost. 2004;  92 185-190
  • 30 Karpatkin S, Nierodzik M L, Klepfish A. Role of platelets, thrombin in cancer.  Vessels. 1996;  2 17-23
  • 31 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient.  Semin Thromb Hemost. 1999;  25 173-182
  • 32 Yu J L, Rak J W. Shedding of tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the mein source of TF activity released from human cancer cells.  J Thromb Haemost. 2004;  2 2065-2067
  • 33 Nomura S, Fukuhara S. Platelet microparticles.  Methods Mol Biol. 2004;  272 269-277
  • 34 Kitagawa H, Yamamoto N, Yamamoto K et al.. Involvement of platelet membrane glycoprotein Ib and glycoprotein IIb/IIIa complex in thrombin-dependent and -independent platelet aggregations induced by tumor cells.  Cancer Res. 1989;  49 537-541
  • 35 Hejna M, Raderer M, Zielinsky C C. Inhibition of metastasis by anticoagulants.  J Natl Cancer Inst. 1999;  91 22-36
  • 36 Gasic G J, Gasic T B, Steward C C. Antimetastatic effects associated with platelet reduction.  Proc Natl Acad Sci USA. 1968;  61 46-52
  • 37 Nierodzik M L, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo.  Thromb Haemost. 1995;  74 282-290
  • 38 McCarty O J, Mouse S A, Bray P F, Konstantopoulos K. Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions.  Blood. 2000;  96 1789-1797
  • 39 Felding-Habermann B. Tumor cell-platelet interaction in metastatic disease.  Haemostasis. 2000;  31(Suppl 1) 55-58
  • 40 Chopra H, Timar J, Rong X et al.. Is there a role for the tumor cell integrin αIIbß3 in tumor-cell induced platelet aggregation.  Clin Exp Metastasis. 1992;  10 125-137
  • 41 Steinert B W, Tang D G, Grossi I M, Umbarger L A, Honn K V. Studies on the role of platelet eicosanoid metabolism and integrin αIIbß3in tumor-cell-induced platelet aggregation.  Int J Cancer. 1993;  54 92-101
  • 42 Lip G YH, Chin B SP, Blann A D. Cancer and the prothrombotic state.  Lancet Oncol. 2002;  3 27-34
  • 43 Nash G F, Turner L F, Schully M F, Kakkar A K. Platelets and cancer.  Lancet Oncol. 2002;  3 425-430
  • 44 Pasqualini M E, Mohn C E, Petiti J P, Manzo P, Eynard A R. COX and LOX eicosanoids modulate platelet activation and procoagulation induced by two murine cancer cells.  Prostaglandins Leukot Essent Fatty Acids. 2000;  63 377-383
  • 45 Boucharaba A, Serre C-M, Grès S et al.. Platelet-derived lysophosphatic acid supports the progression of osteolytic bone metastases in breast cancer.  J Clin Invest. 2004;  114 1714-1725
  • 46 Belloc C, Lu H, Soria C et al.. The effect of platelets on invasiveness and protease production of human mammary tumor cells.  Int J Cancer. 1995;  60 413-417
  • 47 Verheul H MW, Hoekman K, Lupu F et al.. Platelet and coagulation activation with vascular endothelial growth factor generation in soft tissue sarcomas.  Clin Cancer Res. 2000;  6 166-171
  • 48 Ischii L, Fukushima N, Ye X, Chun J. Lysophospholipid receptors: signaling and biology.  Annu Rev Biochem. 2004;  73 321-354
  • 49 Van Corven E J, Groenink A, Jalink K, Eicholtz T, Moolenaar W H. Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins.  Cell. 1989;  59 45-54
  • 50 Möhle R, Green D, Moore M A, Nachman R L, Rafii S. Constitutive production and thrombin-induced relaease of vascular endothelial growth factor by human megakaryocytes and platelets.  Proc Natl Acad Sci USA. 1997;  94 663-668
  • 51 Salgado R, Vermeulen P B, Benoy I et al.. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients.  Br J Cancer. 1999;  80 892-897
  • 52 Verheul H MW, Hoekman K, Luykx-de Bakker S et al.. Platelet transporter of vascular endothelial growth factor.  Clin Cancer Res. 1997;  3 2187-2190
  • 53 Wartiovaara U, Salven P, Mikkola Heta I. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation.  Thromb Haemost. 1998;  80 171-175
  • 54 Ohm J E, Carbone D P. VEGF as a mediator of tumor-associated immunodeficiency.  Immunol Res. 2001;  23 263-272
  • 55 Yang L, Carbone D P. Tumor-host immune interactions and dendritic cell dysfunction.  Adv Cancer Res. 2004;  92 13-27
  • 56 Nieswandt B, Hafner M, Echtenacher B, Männel D N. Lysis of tumor cells by natural killer cells in mice is impeded by platelets.  Cancer Res. 1999;  59 1295-1300
  • 57 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med. 1971;  285 1182-1186
  • 58 Verheul H M, Jorna A S, Hoekman K et al.. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets.  Blood. 2000;  96 4216-4221
  • 59 Pipili-Synetos E, Papadimitriou E, Maragoudakis M E. Evidence that platelets promote tube formation by endothelial cells on matrigel.  Br J Pharmacol. 1998;  125 1252-1257
  • 60 Kisucka J, Butterfield C E, Duda D G et al.. Platelets and platelet adhesion support angiogenesis while preventing excessive hemorrhage.  Proc Natl Acad Sci USA. 2006;  103 855-860
  • 61 Rhee J S, Black M, Schubert U et al.. The functional role of blood platelet components in angiogenesis.  Thromb Haemost. 2004;  92 394-402
  • 62 Brill A, Dashevsky O, Rivo J, Gozal Y, Varon D. Platelet-derived microparticles induce angiogenesis and stimmulate post-ischaemic revascularization.  Cardiovasc Res. 2005;  67 30-38
  • 63 McDowell G, Temple I, Li C et al.. Alteration in platelet function in patients with early breast cancer.  Anticancer Res. 2005;  25 3963-3966
  • 64 Werther K, Chjritensen I J, Nielsen H J. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets.  Scand J Clin Lab Invest. 2002;  62 343-350
  • 65 Kim S J, Choi I K, Park K H et al.. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: correlations with clinical parameters and survival.  Jpn J Clin Oncol. 2004;  34 184-190
  • 66 Ma L, Perini R, McKnight W, Klein A, Hollenberg M D, Wallace J L. Proteinase-activated receptors 1 and 4 counter-regulate endostatin and VEGF release from human platelets.  Proc Natl Acad Sci USA. 2005;  102 216-220
  • 67 Brock T A, Dvorak H F, Senger D R. Tumour secreted vascular permeability factor increases cytosolic Ca2 + and von Willebrand factor release in human cells.  Am J Pathol. 1991;  138 213-221
  • 68 Thurston G, Rudge J S, Ioffe E et al.. Angiopoietin-1 protects the adult vasculature against leakage.  Nat Med. 2000;  6 460-463
  • 69 Clauss M, Gerlach M, Gerlach H et al.. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.  J Exp Med. 1990;  172 1535-1545
  • 70 Friesel R, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling.  Thromb Haemost. 1999;  82 748-754
  • 71 Valter M M, Wietler O D, Pietsche T, Pietsch T. Differential control of VEGF synthesis and secretion in human glioma cells by IL-1 and EGF.  Int J Dev Neurosci. 1999;  17 565-577
  • 72 Guo P, Gu W, Xu L et al.. Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment.  Am J Pathol. 2003;  162 1083-1093
  • 73 Tomita N, Morishita R, Taniyama Y et al.. Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis ets-1.  Circulation. 2003;  107 1411-1417
  • 74 Lee O H, Bae S K, Bae M H et al.. Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models.  Br J Cancer. 2000;  82 385-391
  • 75 Dunn S E, Tores J V, Nihei N, Barrett J C. The insulin growth factor-1 elevates urokinase-type plasminogen activator-1 in human breast cancer cells: a new avenue for breast cancer therapy.  Mol Carcinog. 2000;  27 10-17
  • 76 Breier G, Blum S, Peli J et al.. Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis.  Int J Cancer. 2002;  97 142-148
  • 77 Davis S, Yancopoulos G D. Yin and yang in angiogenesis.  Curr Top Microbiol Immunol. 1999;  237 173-185
  • 78 McMahon G A, Petitclerc E, Stefansson S et al.. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis.  J Biol Chem. 2001;  276 33964-33968
  • 79 VanWijk M J, VanBavel E, Sturk A, Nieuwland R. Microparticles in cardiovascular diseases.  Cardiovasc Res. 2003;  59 277-287
  • 80 Teuscher E, Weidlich V. Adenosine nucleotides, adenosine and adenine as angiogenesis factors.  Biomed Biochim Acta. 1985;  44 493-495
  • 81 English D, Welch Z, Kovala A T et al.. Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis.  FASEB J. 2000;  14 2255-2265
  • 82 Freyssinet J M. Cellular microparticles: what are they bad or good for?.  J Thromb Haemost. 2003;  1 1655-1662
  • 83 Janowska-Wieczorek A, Wysoczynski M, Kijowski J et al.. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer.  Int J Cancer. 2005;  113 752-760
  • 84 Good D J, Polverini P J, Rastinejad F et al.. A tumor supprressor-dependent inhibitor of angiogenesis is immunologically and functionally indistiguishable from a fragment of thrombospondin.  Proc Natl Acad Sci USA. 1990;  87 6624-6628
  • 85 Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis.  Nature. 1982;  297 307-312
  • 86 Nakabayashi M, Morishita R, Nakagami H et al.. HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model.  Diabetologia. 2003;  46 115-123
  • 87 Pizurki L, Zhou Z, Glynos K, Roussos C, Papapetropoulos A. Angiopoietin-1 inhibits endothelial permeability, neutrophil adherence and IL-8 production.  Br J Pharmacol. 2003;  139 329-336
  • 88 Jurasz P, Santos-Martinez M J, Radomska A, Radomski M W. Generation of platelet angiostatin mediated by urokinase plasminogen activator: effects on angiogenesis.  J Thromb Haemost. 2006;  4 1095-1106
  • 89 Sawicki G, Salas E, Murat J et al.. Release of gelatinase A during platelet activation mediates aggregation.  Nature. 1997;  386 616-619
  • 90 Menashi S, He L, Soria C et al.. Modulation of endothelial cells fibrinolytic activity by platelets.  Thromb Haemost. 1991;  65 77-81
  • 91 Huang S, Van Arsdall M, Tedjarati S et al.. Contribution of stromal metalloproteinase 9 to angiogenesis and growth of human ovarian carcinoma in mice.  J Natl Cancer Inst. 2002;  94 1134-1142
  • 92 Kazes I, Elalamy I, Sraer J D et al.. Platelet release of trimolecular complex components MT1-TIMP2-MMP2: involvement in MMP2 activation and platelet aggregation.  Blood. 2000;  96 3064-3069
  • 93 Vlodavsky I, Eldor A, Haimovitz-Friedman A et al.. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation.  Invasion Metastasis. 1992;  12 112-127
  • 94 Coller B S, Peerschke E L, Scudder L E, Sullivan C A. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombastenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa.  J Clin Invest. 1983;  72 325-328
  • 95 Coller B S. Anti-GpIIb/IIIa drugs: current strategies and future directions.  Thromb Haemost. 2001;  86 427-443
  • 96 Trikha M, Zhou Z, Timar J et al.. Multiple roles for platelet GPIIb/IIa and platelet alpha v beta 3 integrins in tumor growth, angiogenesis, and metastasis.  Cancer Res. 2002;  62 2824-2833
  • 97 Amirkhosravi A, Amaya M, Siddiqui F et al.. Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor-cell-activated platelets and experimental metastasis.  Platelets. 1999;  10 285-292
  • 98 Trikha M, Zhou Z, Jordan J, Nakada M T. ReoPro and m7E3 F(ab')2 inhibit β3 integrin mediated tumor growh and angiogenesis.  [abstract] Proc Am Assoc Cancer Res. 2000;  42 824
  • 99 Engelberg H. Actions of heparins that may affect the malignant process.  Cancer. 1999;  85 257-272
  • 100 Amirkhosravi A, Mousa S A, Amaya M et al.. Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb-IIIa antagonist XV454.  Thromb Haemost. 2003;  90 549-554
  • 101 Sheu J R, Lin C H, Chung Jl, Teng C M, Huang T F. Triflavin, an Arg-Gly-Asp containing snake venom peptide, inhibits aggregation of human platelets induced by human hepatoma cell line.  Thromb Res. 1992;  66 679-691
  • 102 Chiang H S, Swaim M W, Huang T F. Characterization of platelet aggregation induced by human colon adenocarcinoma cells and its inhibition by snake venom peptides, trigramin and rhodostomin.  Br J Haematol. 1994;  87 325-331
  • 103 Chiang H S, Swaim M W, Huang T F. The Arg-Gly-Asp-containing peptide, rhodostomin, inhibits in vitro cell adhesion to extracellular matrices and platelet aggregation caused by saos-2 human osteosarcoma cells.  Br J Cancer. 1995;  71 265-270
  • 104 Chiang H S, Swaim M W, Huang T F. Characterization of platelet aggregation induced by human breast carcinoma and its inhibition by snake venom peptides, trigramin and rhodostomin.  Breast Cancer Res Treat. 1995;  33 225-235
  • 105 Lever R, Page C P. Novel drug development opportunities for heparin.  Nat Rev Drug Discov. 2002;  1 140-148
  • 106 da Silva M S, Horton J A, Wijelath J M et al.. Heparin modulates integrin-mediated cellular adhesion: specificity of interaction with alpha and beta integrin subunits.  Cell Adhes Commun. 2003;  10 59-67
  • 107 Borsig L, Wong R, Feramisco J et al.. Heparin and cancer revised: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis.  Proc Natl Acad Sci USA. 2001;  98 3352-3357
  • 108 Ludwig R J, Beohme B, Podda M et al.. Endothelial P-selectin as a target of heparinb action in experimental melanoma lung metastasis.  Cancer Res. 2004;  64 2743-2750
  • 109 Kakkar A K. Low molecular weight heparin and survival in cancer.  Haematological Rep. 2005;  1 27
  • 110 Butenas S, Cawthern K, Veer C et al.. Antiplatelet agents in tissue factor-induced blood coagulation.  Blood. 2001;  97 2314-2322
  • 111 Waltermann A, Wolzt M, Petersmann K et al.. Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo.  Arterioscler Thromb Vasc Biol. 1999;  19 1757-1760
  • 112 Gasic G J, Gasic T B, Stewart C C. Antimetastatic effect associated with platelet reduction.  Proc Natl Acad Sci USA. 1968;  61 46-52
  • 113 Sheu J R, Lin C H, Pung H C, Teng C M, Huang T F. Triflavin, an Arg-Gly-Asp-containing peptide, inhibits tumor cell-induced platelet aggregation.  Jpn J Cancer Res. 1993;  84 1062-1071
  • 114 Damiano B P, Derian C K, Maryanoff B E, Zhang H C, Gordon P A. RWJ-58259: a selective antagonists of protease activated receptor-1.  Cardiovasc Drug Rev. 2003;  21 313-326
  • 115 Shi X, Gangedharan B, Brass L F, Ruf W, Mueller B M. Protease-activated receptors (PAR-1 and PAR-2) contribute to tumor cell motility and metastasis.  Mol Cancer Res. 2004;  2 395-402
  • 116 Zania P, Kritikou S, Flordellis C S, Maragoudakis M E, Tsopanoglou N E. Blockage of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis.  J Pharmacol Exp Ther. 2006;  318 246-254
  • 117 Nash G F, Walsh D C, Kakkar A K. The role of the coagulation system in tumour angiogemesis.  Lancet Oncol. 2001;  2 608-613
  • 118 Nigam S, Zakrzewic A, Eskafi S, Roscher A. Clinical significance of prostacyclin and thromboxane in cancer of the female breast and genital tract.  Cancer Metastasis Rev. 1992;  11 411-420
  • 119 Nie D, Che M, Zacharek A et al.. Differential expression of thromboxane synthase in prostate carcinoma: role in tumor cell motility.  Am J Pathol. 2004;  164 429-439
  • 120 Honn K V, Tang D G, Butovich I A, Liu B, Timar J, Hagmann W. 12-lipooxygenases and 12(S)-HETE: role in cancer metastasis.  Cancer Metastasis Rev. 1994;  13 365-366
  • 121 Tang D G, Li L, Zhu Z et al.. BMD188, a novel hydroxamic acid compound, demonstrates potent an prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases.  Pathol Oncol Res. 1998;  4 179-190
  • 122 Gasic G J, Gasic T B, Galanti N, Johnson T, Murphy S. Platelet tumor interactions in mice. The role of platelets in spread of malignant diseases.  Int J Cancer. 1973;  11 704-718
  • 123 Wood Jr S, Hilgard P. Aspirin and tumor metastasis.  Lancet. 1972;  2 1416-1417
  • 124 Mamytbeková A, Rezábek K, Kacerovská H, Grimová J, Svobodová J. Antimetastatic effect of flurbiprofen and other platelet aggregation inhibitors.  Neoplasma. 1986;  33 417-421
  • 125 Mehta P, Lawson D, Ward M B, Lee-Ambrose L, Kimura A. Effect of tromboxane A2 inhibition on osteogenic sarcoma cell-induced platelet aggregation.  Cancer Res. 1986;  46 5061-5063
  • 126 Bando H, Yamashita T, Tsubura E. Effects of antiplatelet agents on pulmonary metastases.  Gann. 1984;  75 284-291
  • 127 Mussoni L, Poggi A, De Gaetano G, Donati M B. Effect of diltazole, an inhibitor of platelet aggregation, on a metastasizing tumor in mice.  Br J Cancer. 1978;  37 126-129
  • 128 Hilgard P, Heller H, Schmidt C G. The influence of platelet aggregation inhibitors on metastasis formation in mice (3LL).  Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 1976;  86 243-250
  • 129 Lichtner R B, Hutchinson G, Wedderburn N, Hellmann K. Antiplatelet pyrimido-pyrimidines and metastasis.  Cancer Treat Rev. 1985;  12 221-234
  • 130 Lichtner R B, Hutchinson G, Hellmann K. The pyrimido-pyrimidines derivatives RA233 and RX-RA85 affect cell cycle distribution of two murine tumour cell lines.  Eur J Cancer Clin Oncol. 1989;  25 945-951
  • 131 Stackpole C W, Fornabaio D M, Alterman A L. Failure of orally administered RA233 to influence B16 melanoma growth or metastasis.  Clin Exp Metastasis. 1987;  5 165-180
  • 132 Li X T, Hellmann K. Effect of DRA233 alone and combined with radiation on experimental tumour metastasis. Part 1.  Clin Exp Metastasis. 1983;  1 51-59
  • 133 Gastpar H. Modification of metastasis formation by inhibition of platelet aggregation. Experimental and clinical results.  Laryngol Rhinol Otol (Stuttg). 1983;  62 578-585
  • 134 Kohga S, Kinjo M, Tanaka K, Ogawa H, Ishihara M, Tanaka N. Effects of 5-(2-chlorobenzyl)-4,5,6,7,-tetrahydrothieno[3,2-C]pyridine hydrochloride (ticlopidine), a platelet aggregation inhibitor, on blood-borne metastasis.  Cancer Res. 1981;  41 4710-4714
  • 135 Fabra A, de Castellarnau C, Carretero F, Martinez E, Sancho M J, Rutllant M L. Effects of ticlopidine on metastasis production in mice bearing Lewis lung carcinoma.  Invasion Metastasis. 1987;  7 53-60

Ewa SierkoM.D. 

Department of Oncology, Medical University

12 Ogrodowa St., 15-027 Bialystok, Poland

Email: ewa.sierko@iq.pl

    >