Anti-cancer properties of low-molecular-weight heparin: Preclinical evidence

Summary

Malignant conditions are frequently associated with a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Heparin and, its pharmacokinetically improved versions, low-molecular-weight heparins (LMWH) are effective in the prevention and treatment of thromboembolic events in cancer patients. There are several lines of preclinical evidence suggesting potential benefits of LMWH in hypercoagulation and thrombosis as well as in various processes involved in tumour growth and metastasis.Tinzaparin is a LMWH produced by controlled enzymatic depolymerisation of unfractionated heparin. The efficacy of tinzaparin has been documented in several clinical trials across various conditions and in special patient populations.The main objective of this review is to present the existing knowledge on the preclinical anti-cancer properties of tinzaparin and other LMWH.The evidence for tinzaparin, as well as other LMWH, regarding interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of extra-cellular matrix, angiogenesis, selectin-mediated binding of platelet and cancer cells, chemokine signalling, tumour progression, and metastasis are reviewed. Certain clinical trials suggest improved survival of cancer patients with deep venous thrombosis treated with LMWH versus unfractionated heparin and when added to the promising preclinical anti-cancer properties of LMWH this warrants further investigations in prospective, randomised, controlled clinical trials in cancer patients.The benefits of LMWH in cancer might at least in part, be independent from its anti-coagulant activities, but may still be partially dependent on its anti-coagulant activities.

Keywords

Heparin - low-molecular-weight heparin - thrombosis - cancer - metastasis - tissue factor - tissue factor pathway inhibitor - selectin - angiogenesis - cancer-associated thrombosis - deep venous thrombosis - prophylaxis - treatment

• References

• 1 Bergqvist D. et al. Venous thromboembolism and cancer. Curr Probl Surg 2007; 44: 157-216.
• 2 de Lorenzo F. et al. The role of anticoagulation in cancer patients: facts and figures. Anticancer Agents Med Chem 2006; 06: 579-587.
• 3 Prandoni P. et al. Cancer and venous thromboembolism. Lancet Oncol 2005; 06: 401-410.
• 4 Khorana AA. et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110: 2339-2346.
• 5 Lyman GH. et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490-5505.
• 6 National Cancer Comprehensive Network Clinical Practise Guidelines in Oncology. Venous Thromboembolic Disease.V.2.2008. http://www.nccn.org/profes sionals/physician_gls/PDF/vte.pdf.
• 7 Mandala M. et al. Venous thromboembolism and cancer: guidelines of the Italian Association of Medical Oncology (AIOM). Crit Rev Oncol Hematol 2006; 59: 194-204.
• 8 Geerts WH. et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 338S-400S.
• 9 Smorenburg SM. et al. The effects of vitamin K-antagonists on survival of patients with malignancy: a systematic analysis. Thromb Haemost 2001; 86: 1586-1587.
• 10 Niers TM. et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit Rev Oncol Hematol 2007; 61: 195-207.
• 11 Prandoni P. et al. Cancer, thrombosis and heparininduced thrombocytopenia. Thromb Res 2007; 120 (Suppl. 02) S137-S140.
• 12 Rickles FR, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001; 102: V215-V224.
• 13 Mousa SA. Anticoagulants in thrombosis and cancer: the missing link. Semin Thromb Hemost 2002; 28: 45-52.
• 14 Falanga A, Marchetti M. Heparin in tumor progression and metastatic dissemination. Semin Thromb Hemost 2007; 33: 688-694.
• 15 Zwicker JI. et al. Cancer-associated thrombosis. Crit Rev Oncol Hematol 2007; 62: 126-136.
• 16 Deitcher SR. Cancer and thrombosis: mechanisms and treatment. J ThrombThrombolysis 2003; 16: 21-31.
• 17 Falanga A. et al. Guidelines for clotting studies in cancer patients. For the Scientific and Standardization Committee of the Subcommittee on Haemostasis and Malignancy International Society of Thrombosis and Haemostasis. Thromb Haemost 1993; 70: 540-542.
• 18 Mousa SA. et al. Tissue factor pathway inhibitor in thrombosis and beyond. Methods Mol Med 2004; 93: 133-155.
• 19 Castelli R. et al. The heparins and cancer: review of clinical trials and biological properties. Vasc Med 2004; 09: 205-213.
• 20 Allavena P. et al. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 2008; 66: 1-9.
• 21 Schaffner F, Ruf W. Tissue factor and protease-activated receptor signaling in cancer. Semin Thromb Hemost 2008; 34: 147-153.
• 22 Semeraro N, Colucci M. Tissue factor in health and disease. Thromb Haemost 1997; 78: 759-764.
• 23 Falanga A. et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96: 4261-4266.
• 24 Noonan DM. et al. Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev 2008; 27: 31-40.
• 25 Tyrrell DJ. et al. Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv Pharmacol 1999; 46: 151-208.
• 26 Ludwig RJ. et al. Structural requirements of heparin and related molecules to exert a multitude of anti-inflammatory activities. Mini Rev Med Chem 2006; 06: 1009-1023.
• 27 Sierko E, Wojtukiewicz MZ. Inhibition of platelet function: does it offer a chance of better cancer progression control?. SeminThromb Hemost 2007; 33: 712-721.
• 28 Amirkhosravi A. et al. The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin Thromb Hemost 2007; 33: 643-652.
• 29 Sierko E. et al. The role of tissue factor pathway inhibitor-2 in cancer biology. Semin Thromb Hemost 2007; 33: 653-659.
• 30 O’Reilly MS. Antiangiogenic antithrombin. Semin Thromb Hemost 2007; 33: 660-666.
• 31 Suzuki K, Hayashi T. Protein C and its inhibitor in malignancy. Semin Thromb Hemost 2007; 33: 667-672.
• 32 Hanly AM, Winter DC. The role of thrombomodulin in malignancy. Semin Thromb Hemost 2007; 33: 673-679.
• 33 Wojtukiewicz MZ. et al. The role of hemostatic system inhibitors in malignancy. Semin Thromb Hemost 2007; 33: 621-642.
• 34 Smorenburg SM, Van Noorden CJ. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacol Rev 2001; 53: 93-105.
• 35 Petralia GA. et al. Mechanisms of disease: the impact of antithrombotic therapy in cancer patients. Nat Clin Pract Oncol 2005; 02: 356-363.
• 36 Versteeg HH. et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood 2008; 111: 190-199.
• 37 Norrby K. Low-molecular-weight heparins and angiogenesis. APMIS 2006; 114: 79-102.
• 38 Mousa SA. Heparin, low molecular weight heparin, and derivatives in thrombosis, angiogenesis, and inflammation: emerging links. Semin Thromb Hemost 2007; 33: 524-533.
• 39 Bobek V, Kovarik J. Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother 2004; 58: 213-219.
• 40 Altundag K. et al. Recent findings for anti-metastatic potential of heparin. Clin Appl Thromb Hemost 2006; 12: 376-377.
• 41 Veldkamp CT. et al. The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin. Protein Sci 2005; 14: 1071-1081.
• 42 Harvey JR. et al. Inhibition of CXCR4-mediated breast cancer metastasis: a potential role for heparinoids?. Clin Cancer Res 2007; 13: 1562-1570.
• 43 Vlodavsky I. et al. Heparanase, heparin and the coagulation system in cancer progression. Thromb Res 2007; 120 (Suppl. 02) S112-S120.
• 44 Borsig L. Antimetastatic activities of modified heparins: selectin inhibition by heparin attenuates metastasis. Semin Thromb Hemost 2007; 33: 540-546.
• 45 Hostettler N. et al. P-selectinand heparanase-dependent antimetastatic activity of non-anticoagulant heparins. FASEB J 2007; 21: 3562-3572.
• 46 Nasser NJ. et al. Heparanase neutralizes the anticoagulation properties of heparin and low-molecularweight heparin. J Thromb Haemost 2006; 04: 560-565.
• 47 Gray E. et al. Heparin and low-molecular-weight heparin. Thromb Haemost 2008; 99: 807-818.
• 48 Gould MK. et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800-809.
• 49 Siragusa S. et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a metaanalysis. Am J Med 1996; 100: 269-277.
• 50 Dolovich LR. et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160: 181-188.
• 51 Morris TA. et al. No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis. Chest 2007; 132: 1131-1139.
• 52 Akl E. et al. Anticoagulation for the intial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2008; 01: CD006649.
• 53 Kuderer NM. et al. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer 2007; 110: 1149-1161.
• 54 Tagalakis V. et al. The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treat Rev 2007; 33: 358-368.
• 55 Akl EA. et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev 2007; 03: CD006652.
• 56 Lee AY. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-2129.
• 57 Kakkar AK. et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004; 22: 1944-1948.
• 58 Klerk CP. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130-2135.
• 59 Altinbas M. et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004; 02: 1266-1271.
• 60 Hainer JW. et al. Extending the role of antithrombotic agents: an example based on the low-molecularweight heparin, tinzaparin. Semin Thromb Hemost 2004; 30 (Suppl. 01) 3-9.
• 61 Liezorovicz A. et al. Prevention of perioperative deep vein thrombosis in general surgery: a multicentre double blind study comparing two doses of Logiparin and standard heparin. H.B.P.M. Research Group. Br J Surg 1991; 78: 412-416.
• 62 Lassen MR. et al. Prevention of thromboembolism in 190 hip arthroplasties. Comparison of LMW heparin and placebo. Acta Orthop Scand 1991; 62: 33-38.
• 63 Hull RD. et al. Subcutaneous low-molecularweight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-982.
• 64 Simonneau G. et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997; 337: 663-669.
• 65 Planes A. et al. Prevention of deep vein thrombosis after hip replacement--comparison between two lowmolecular heparins, tinzaparin and enoxaparin. Thromb Haemost 1999; 81: 22-25.
• 66 Hull R. et al. A comparison of subcutaneous lowmolecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329: 1370-1376.
• 67 Lapidus L. et al. Home treatment of deep vein thrombosis. An out-patient treatment model with oncedaily injection of low-molecular-weight heparin (tinzaparin) in 555 patients. Pathophysiol Haemost Thromb 2002; 32: 59-66.
• 68 Daskalopoulos ME. et al. Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomized trial. Eur J Vasc Endovasc Surg 2005; 29: 638-650.
• 69 Wells PS. et al. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Arch Intern Med 2005; 165: 733-738.
• 70 Dager WE. et al. Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis. Ann Pharmacother 2005; 39: 1182-1187.
• 71 Hull RD. et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062-1072.
• 72 Davies CW. et al. Early discharge of patients with pulmonary embolism: a two-phase observational study. Eur Respir J 2007; 30: 708-714.
• 73 Romera A. et al. A randomised open-label trial comparing long-term sub-cutaneous low-molecularweight heparin compared with oral-anticoagulant therapy in the treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg 2009; 37: 349-356.
• 74 Puskas A. et al. Spontaneous recanalization in deep venous thrombosis: a prospective duplex ultrasound study. Int Angiol 2007; 26: 53-63.
• 75 Mahe I. et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost 2007; 97: 581-586.
• 76 Mahe I. et al. Elderly medical patients treated with prophylactic dosages of enoxaparin: influence of renal function on anti-Xa activity level. Drugs Aging 2007; 24: 63-71.
• 77 Pautas E. et al. Safety profile of tinzaparin administered once daily at a standard curative dose in two hundred very elderly patients. Drug Saf 2002; 25: 725-733.
• 78 Siguret V. et al. Elderly patients treated with tinzaparin (Innohep) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days. Thromb Haemost 2000; 84: 800-804.
• 79 Smith MP. et al. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 2004; 190: 495-501.
• 80 Mousa SA. The low molecular weight heparin, tinzaparin, in thrombosis and beyond. Cardiovasc Drug Rev 2002; 20: 199-216.
• 81 Mousa SA, Mohamed S. Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy. Oncol Rep 2004; 12: 683-688.
• 82 Mousa SA. et al. Pharmacodynamic properties of the low molecular weight heparin, tinzaparin: effect of molecular weight distribution on plasma tissue factor pathway inhibitor in healthy human subjects. J Clin Pharmacol 2003; 43: 727-734.
• 83 Negaard HF. et al. Hypercoagulability in patients with haematological neoplasia: no apparent initiation by tissue factor. Thromb Haemost 2008; 99: 1040-1048.
• 84 Cloonan ME. et al. Efficacy of anticoagulants and platelet inhibitors in cancer-induced thrombosis. Blood Coagul Fibrinolysis 2007; 18: 341-345.
• 85 Mousa SA. Comparative efficacy of different lowmolecular-weight heparins (LMWHs) and drug interactions with LMWH: implications for management of vascular disorders. Semin Thromb Hemost 2000; 26 (Suppl. 01) 39-46.
• 86 Mousa SA, Johansen KB. Antithrombotic efficacy of low molecular weight heparin in hypercoagulation states and cancer-associated thrombosis. J Thromb Haemost 2007; 502: P-M-527.
• 87 Amirkhosravi A. et al. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost 2003; 01: 1972-1976.
• 88 Mousa SA. et al. Anti-metastatic effect of a nonanticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin. Thromb Haemost 2006; 96: 816-821.
• 89 Smiley SL. et al. The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth. J. Clin.Oncol. 2006 24. 18S Abstract
• 90 Daneshmand M. et al. A pharmacodynamic study of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients. Clin Cancer Res 2003; 09: 2457-2464.
• 91 Staehler M. et al. Therapeutic approaches in metastatic renal cell carcinoma. BJU Int 2005; 95: 1153-1161.
• 92 Bereczky B. et al. Selective antimetastatic effect of heparins in preclinical human melanoma models is based on inhibition of migration and microvascular arrest. Clin Exp Metastasis 2005; 22: 69-76.
• 93 Takahashi H. et al. A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity. Br J Pharmacol 2005; 146: 333-343.
• 94 Balzarotti M. et al. In vitro study of low molecular weight heparin effect on cell growth and cell invasion in primary cell cultures of high-grade gliomas. Oncol Res 2006; 16: 245-250.
• 95 Kragh M. et al. Non-anti-coagulant heparin inhibits metastasis but not primary tumor growth. Oncol Rep 2005; 14: 99-104.
• 96 Pross M. et al. Effect of low molecular weight heparin on intra-abdominal metastasis in a laparoscopic experimental study. Int J Colorectal Dis 2004; 19: 143-146.
• 97 Pross M. et al. Low-molecular-weight heparin (reviparin) diminishes tumor cell adhesion and invasion in vitro, and decreases intraperitoneal growth of colonadeno-carcinoma cells in rats after laparoscopy. Thromb Res 2003; 110: 215-220.
• 98 Mousa SA, Johansen KB. Anti-cancer efficacy of low molecular weight heparin in thrombosis-associated tumor growth. J Thromb Haemost 2007; 05 (Suppl. 02) P-M-525.
• 99 Khorana AA. et al. Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arterioscler Thromb Vasc Biol 2003; 23: 2110-2115.
• 100 Marchetti M. et al. Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thromb Res 2008; 121: 637-645.
• 101 Mousa SA, Mohamed S. Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor. Thromb Haemost 2004; 92: 627-633.
• 102 Tessler S. et al. Heparin modulates the interaction of VEGF165 with soluble and cell associated flk-1 receptors. J Biol Chem 1994; 269: 12456-12461.
• 103 Collen A. et al. Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro. Cancer Res 2000; 60: 6196-6200.
• 104 Szende B. et al. Effect of Fraxiparine and heparin on experimental tumor metastasis in mice. Anticancer Res 2005; 25: 2869-2872.
• 105 Ludwig RJ. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
• 106 Stevenson JL. et al. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
• 107 Kragh M, Loechel F. Non-anti-coagulant heparins: a promising approach for prevention of tumor metastasis (review). Int J Oncol 2005; 27: 1159-1167.
• 108 Casu B. et al. Non-anticoagulant heparins and inhibition of cancer. Pathophysiol Haemost Thromb 2008; 36: 195-203.
• 109 Simonis D. et al. Affinity and kinetics of different heparins binding to P and L-selectin. Semin Thromb Hemost 2007; 33: 534-539.
• 110 Stevenson JL. et al. Heparin attenuates metastasis mainly due to inhibition of P and L-selectin, but nonanticoagulant heparins can have additional effects. Thromb Res 2007; 120 (Suppl. 02) S107-S111.
• 111 Fritzsche J. et al. Melanoma cell adhesion can be blocked by heparin in vitro: suggestion of VLA-4 as a novel target for antimetastatic approaches. Thromb Haemost 2008; 100: 1166-1175.
• 112 Ludwig RJ. et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-2750.
• 113 Maugeri N. et al. Parnaparin, a low-molecularweight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost 2007; 97: 965-973.
• 114 Westmuckett AD. et al. Bemiparin and fluid flow modulate the expression, activity and release of tissue factor pathway inhibitor in human endothelial cells in vitro. Thromb Haemost 2001; 86: 1547-1554.
• 115 Vignoli A. et al. Differential effect of the low-molecular-weight heparin, dalteparin, and unfractionated heparin on microvascular endothelial cell hemostatic properties. Haematologica 2006; 91: 207-214.
• 116 Mousa SA, Johansen K. Pharmacodynamic effects of low molecular weight heparin in obese subjects following subcutaneous administration of 75 IU/kg on plasma tissue factor pathway inhibitor and nitric oxide. Int Angiol 2005; 24: 40-42.
• 117 Mousa SA. Are low molecular weight heparins the same?. Methods Mol Med 2004; 93: 49-59.
• 118 Bara L. et al. Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor. Thromb Res 1993; 69: 443-452.
• 119 Brodin E. et al. Intravascular release and urinary excretion of tissue factor pathway inhibitor during heparin treatment. J Lab Clin Med 2004; 144: 246-253.
• 120 Kakkar VV. et al. A comparative double-blind, randomised trial of a new second generation LMWH (bemiparin) and UFH in the prevention of post-operative venous thromboembolism. The Bemiparin Assessment group. Thromb Haemost 2000; 83: 523-529.
• 121 Hoppensteadt DA. et al. TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin. Thromb Res 1995; 77: 175-185.
• 122 Fareed J. et al. Pharmacologic validation of the clinical effects of an optimized low-molecular-weight heparin-reviparin. Semin Thromb Hemost 1995; 21: 212-227.
• 123 Bendz B. et al. Partial depletion of tissue factor pathway inhibitor during subcutaneous administration of unfractionated heparin, but not with two low molecular weight heparins. Br J Haematol 1999; 107: 756-762.
• 124 Ellison J. et al. Thromboprophylaxis following caesarean section--a comparison of the antithrombotic properties of three low molecular weight heparins--dalteparin, enoxaparin and tinzaparin. Thromb Haemost 2001; 86: 1374-1378.
• 125 Mantovani A. et al. Cancer-related inflammation. Nature 2008; 454: 436-444.
• 126 Zhang ZH. et al. Silencing of heparanase by siRNA inhibits tumor metastasis and angiogenesis of human breast cancer in vitro and in vivo. Cancer Biol Ther 2007; 06: 587-595.
• 127 Li JP. Heparin, heparan sulfate and heparanase in cancer: remedy for metastasis?. Anticancer Agents Med Chem 2008; 08: 64-76.
• 128 Mousa SA. Effect of low molecular weight heparin and different heparin molecular weight fractions on the activity of the matrix-degrading enzyme aggrecanase: structure-function relationship. J Cell Biochem 2005; 95: 95-98.
• 129 Varki NM, Varki A. Heparin inhibition of selectinmediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. Semin Thromb Hemost 2002; 28: 53-66.
• 130 Jeske WP. et al. Differentiating low-molecularweight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins. Semin Thromb Hemost 2008; 34: 74-85.
• 131 Kucher N. et al. Efficacy and safety of fixed lowdose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial. Arch Intern Med 2005; 165: 341-345.
• 132 Hirsh J, Raschke R. Heparin and low-molecularweight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 188S-203S.
• 133 Hochster HS. Bevacizumab in combination with chemotherapy: first-line treatment of patients with metastatic colorectal cancer. Semin Oncol 2006; 33 5 Suppl 10 S8-14.
• 134 Sandler A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542-2550.
• 135 Escudier B. et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370: 2103-2111.
• 136 Riess H. et al. Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy). BMC Cancer 2008; 08: 361.