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DOI: 10.1055/s-2005-837406
© Georg Thieme Verlag Stuttgart · New York
Antikoagulation als onkologisches Therapieprinzip
Antineoplastic and antimetastatic effects of pharmacological anticoagulation in cancer patientsPublication History
eingereicht: 27.7.2004
akzeptiert: 2.12.2004
Publication Date:
27 January 2005 (online)

Zusammenfassung
Die Assoziation von Tumorerkrankungen mit thromboembolischen Komplikationen ist seit mehr als hundert Jahren bekannt. Während die thrombophile Diathese von Tumorpatienten und die paraneoplastische Thrombogenese pathophysiologisch teilweise geklärt sind, ergeben neuere Untersuchungen Hinweise dafür, dass Mediatoren der plasmatischen Hämostase Tumorwachstum, Angiogenese und Metastasierung beeinflussen. Die Grundlage einer antithrombotischen Prophylaxe und Therapie bei Tumorpatienten leitet sich deshalb nicht nur aus der bekannten Thromboseneigung der Patienten ab, sondern auch aus der potenziell antineoplastischen bzw. antimetastatischen Wirkung einer pharmakologischen Gerinnungshemmung. Erfolgversprechende Ergebnisse klinischer Studien lassen darauf schließen, dass das Überleben ausgewählter Tumorpatienten durch prophylaktische bzw. therapeutische Antikoagulation verbessert werden kann.
Summary
The association of cancer with thromboembolic events has been established for more than hundred years. While the thrombophilic diathesis of tumor patients and the neoplastic thrombogenesis have been elucidated pathophysiologically, at least in part, there is growing experimental and clinical evidence that factors of plasmic hemostasis promote tumor growth, angiogenesis, and metastasis. Thus, the rationale for antithrombotic prophylaxis and therapy of tumor patients might not only be based on the prevention of thromboembolic complications but also on the potentially antineoplastic and antimetastatic effects of pharmacological anticoagulation. Encouraging results of clinical studies indicate that prophylactic and therapeutic anticoagulation might improve the survival of selected patients with cancer.
Literatur
- 1
Bani M R, Falanga A, Alessio M G. et al .
Blood coagulation changes in nude mice bearing Human colon carcinomas.
Int J Cancer.
1992;
50
75-79
Reference Ris Wihthout Link
- 2
Belting M, Dorrell M I, Sandgren S. et al .
Regulation of angiogenesis by tissue factor cytoplasmic domain signaling.
Nat Med.
2004;
10
502-509
Reference Ris Wihthout Link
- 3
Bertolesi G E, Lauria C, Eijan A M.
Growth inhibition in vitro of murine mammary adenocarcinoma cells by heparin and chemically
modified heparins.
Tumour Biol.
1994;
15
275-283
Reference Ris Wihthout Link
- 4
Bick R L.
Cancer-associated thrombosis.
N Engl J Med.
2003;
349
109-111
Reference Ris Wihthout Link
- 5
Borsig L, Wong R, Feramisco J. et al .
Heparin and cancer revisited: mechanistic connections involving platelets, P-Selectin,
carcinoma mucins, and tumor metastasis.
Proc Natl Acad Sci USA.
2001;
98
3352-3357
Reference Ris Wihthout Link
- 6
Castle V, Varani J, Fligiel S, Prochownik E V, Dixit V.
Antisense-mediated reduction in thrombospondin reverses the malignant phenotype of
a human squamous carcinoma.
J Clin Invest.
1991;
87
1883-1888
Reference Ris Wihthout Link
- 7
Chahinian A P, Propert K J, Ware J H. et al .
A randomized trial of anticoagulation with warfarin and of alternating chemotherapy
in extensive small-cell lung cancer by the Cancer and Leukemia Group B.
J Clin Oncol.
1989;
7
993-1002
Reference Ris Wihthout Link
- 8
Colucci M, Delaini F, de Bellis V. et al .
Warfarin inhibits both procoagulant activity and metastatic capacity of Lewis lung
carcinoma cells. Role of Vitamin K deficiency.
Biochem Pharmacol.
1983;
32
1689-1691
Reference Ris Wihthout Link
- 9
Drake S L, Klein D J, Mickelson D J. et al .
Cell surface phosphatidylinositol-anchored heparan sulfate proteoglycan initiates
mouse melanoma cell adhesion to a fibronectin-derived, heparin-binding synthetic peptide.
J Cell Biol.
1992;
117
1331-1341
Reference Ris Wihthout Link
- 10
Engelberg H.
Actions of heparin in the atherosclerotic process.
Pharmacol Rev.
1996;
48
327-352
Reference Ris Wihthout Link
- 11
Esumi N, Fan D, Fidler I J.
Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin,
a highly specific thrombin inhibitor.
Cancer Res.
1991;
51
4549-3456
Reference Ris Wihthout Link
- 12
Even-Ram S, Uziely B, Cohen P. et al .
Thrombin receptor overexpression in malignant and physiological invasion processes.
Nat Med.
1998;
4
909-914
Reference Ris Wihthout Link
- 13
Even-Ram S C, Maoz M, Pokroy E. et al .
Tumor cell invasion is promoted by activation of protease activated receptor-1 in
cooperation with the alphavbeta5 integrin.
J Biol Chem.
2001;
276
10 952-10 962
Reference Ris Wihthout Link
- 14
Giovannucci E.
The prevention of colorectal cancer by aspirin use.
Biomed Pharmacother.
1999;
53
303-308
Reference Ris Wihthout Link
- 15
Groener A.
The influence of anticlotting agents on transplantation and growth of tumor tissue.
J Lab Clin Med.
1930;
16
369-372
Reference Ris Wihthout Link
- 16
Hettiarachchi R J, Lok J, Prins M H, Buller H R, Prandoni P.
Undiagnosed malignancy in patients with deep vein thrombosis: incidence, risk indicators,
and diagnosis.
Cancer.
1998;
83
180-185
Reference Ris Wihthout Link
- 17
Hettiarachchi R J, Smorenburg S M, Ginsberg J. et al .
Do heparins do more than just treat thrombosis? The influence of heparins on cancer
spread.
Thromb Haemost.
1999;
82
947-952
Reference Ris Wihthout Link
- 18
Holmgren L, O’Reilly M S, Folkman J.
Dormancy of micrometastases: balanced proliferation and apoptosis in the presence
of angiogenesis suppression.
Nat Med.
1995;
1
149-153
Reference Ris Wihthout Link
- 19
Kakkar A K, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson R C.
Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor.
Lancet.
1995;
346
1004-1005
Reference Ris Wihthout Link
- 20
Kakkar A K, Levine M N, Kadziola Z. 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
Reference Ris Wihthout Link
- 21
Kohanna F H, Sweeney J, Hussey S, Zacharski L R, Salzman E W.
Effect of perioperative low-dose heparin administration on the course of colon cancer.
Surgery.
1983;
93
433-438
Reference Ris Wihthout Link
- 22
Lapierre F, Holme K, Lam L. et al .
Chemical modifications of heparin that diminish its anticoagulant but preserve its
heparanase-inhibitory, angiostatic, anti-tumor and anti-metastatic properties.
Glycobiology.
1996;
6
355-366
Reference Ris Wihthout Link
- 23
Lebeau B, Chastang C, Brechot J M. et al. „Petites Cellules” Group .
Subcutaneous heparin treatment increases survival in small cell lung cancer.
Cancer.
1994;
74
38-45
Reference Ris Wihthout Link
- 24
Lee A, Levine M N, Baker R I. et al .
Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous
thromboembolism in patients with cancer.
N Engl J Med.
2003;
349
146-153
Reference Ris Wihthout Link
- 25
Levine M, Hirsh J, Gent M. et al .
Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism
in stage IV breast cancer.
Lancet.
1994;
343
886-889
Reference Ris Wihthout Link
- 26
Lind S E, Caprini J A, Goldshteyn S. et al .
Correlates of thrombin generation in patients with advanced prostate cancer.
Thromb Haemost.
2003;
89
185-189
Reference Ris Wihthout Link
- 27
Maurer L H, Herndon J E, Hollis D R. et al .
Randomized trial of chemotherapy and radiation therapy with or without warfarin for
limited-stage small-cell lung cancer: a Cancer and Leukemia Group B Study.
J Clin Oncol.
1997;
15
3378-3387
Reference Ris Wihthout Link
- 28
Meyer G, Marjanovic Z, Valcke J. et al .
Comparison of low-molecular-weight heparin and warfarin for the secondary prevention
of venous thromboembolism in patients with cancer: a randomized controlled study.
Arch Intern Med.
2002;
162
1729-1735
Reference Ris Wihthout Link
- 29
Miller M D, Krangel M S.
Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory
cytokines.
Crit Rev Immunol.
1992;
12
17-46
Reference Ris Wihthout Link
- 30
Mizuno K, Inoue H, Hagiya M. et al .
Hairpin loop and second kringle domain are essential sites for heparin binding and
biological activity of hepatocyte growth factor.
J Biol Chem.
1994;
269
1131-1136
Reference Ris Wihthout Link
- 31
Mousa S A, Bozarth J, Barrett J S.
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
Reference Ris Wihthout Link
- 32
Petersen B O, Shuman S.
Histidine 265 is important for covalent catalysis by vaccinia topoisomerase and is
conserved in all eukaryotic type I enzymes.
J Biol Chem.
1997;
272
3891-3896
Reference Ris Wihthout Link
- 33
Pilch J, Habermann R, Felding-Habermann B.
Unique ability of integrin alpha(v)beta 3 to support tumor cell arrest under dynamic
flow conditions.
J Biol Chem.
2002;
277
21 930-21 938
Reference Ris Wihthout Link
- 34
Schulman S, Lindmarker P.
Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism.
Duration of anticoagulation trial.
N Engl J Med.
2000;
342
1953-1958
Reference Ris Wihthout Link
- 35
Smorenburg S M, Hettiarachchi R J, Vink R, Buller H R.
The effects of unfractionated heparin on survival in patients with malignancy - a
systematic review.
Thromb Haemost.
1999;
82
1600-1604
Reference Ris Wihthout Link
- 36
Sorensen B B, Rao L V, Tornehave D, Gammeltoft S, Petersen L C.
Antiapoptotic effect of coagulation factor VIIa.
Blood.
2003;
102
1708-1715
Reference Ris Wihthout Link
- 37
Sorensen H T, Mellemkjaer L, Olsen J H, Baron J A.
Prognosis of cancers associated with venous thromboembolism.
N Engl J Med.
2000;
343
1846-1850
Reference Ris Wihthout Link
- 38
Sy M S, Guo Y J, Stamenkovic I.
Inhibition of tumor growth in vivo with a soluble CD44-immunoglobulin fusion protein.
J Exp Med.
1992;
176
623-627
Reference Ris Wihthout Link
- 39
Taniguchi T, Kakkar A K, Tuddenham E G, Williamson R C, Lemoine N R.
Enhanced expression of urokinase receptor induced through the tissue factor-factor
VIIa pathway in human pancreatic cancer.
Cancer Res.
1998;
58
4461-4467
Reference Ris Wihthout Link
- 40
Trousseau A.
Phlegmasia alba dolens.
Clinique Medicale de L‘Hotel Dieu de Paris..
2nd edition
Paris: Bailliere,
1865;
Reference Ris Wihthout Link
- 41
Tyagi S C, Kumar S, Katwa L.
Differential regulation of extracellular matrix metalloproteinase and tissue inhibitor
by heparin and cholesterol in fibroblast cells.
J Mol Cell Cardiol.
1997;
29
391-404
Reference Ris Wihthout Link
- 42
van Meijer M, Smilde A, Tans G. et al .
The suicide substrate reaction between plasminogen activator inhibitor 1 and thrombin
is regulated by the cofactors vitronectin and heparin.
Blood.
1997;
90
1874-1882
Reference Ris Wihthout Link
- 43
Vlodavsky I, Friedmann Y, Elkin M. et al .
Mammalian heparanase: gene cloning, expression and function in tumor progression and
metastasis.
Nat Med.
1999;
5
793-802
Reference Ris Wihthout Link
- 44
von Tempelhoff G F, Harenberg J, Niemann F. et al .
Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin
on cancer survival following breast and pelvic cancer surgery: A prospective randomized
double-blind trial.
Int J Oncol.
2000;
16
815-824
Reference Ris Wihthout Link
- 45
Wojtukiewicz M Z, Sierko E, Zacharski L R. et al .
Tissue factor-dependent coagulation activation and impaired fibrinolysis in situ in
gastric cancer.
Semin Thromb Hemost.
2003;
29
291-300
Reference Ris Wihthout Link
- 46
Wrenshall L E, Cerra F B, Singh R K, Platt J L.
Heparan sulfate initiates signals in murine macrophages leading to divergent biologic
outcomes.
J Immunol.
1995;
154
871-880
Reference Ris Wihthout Link
- 47
Zacharski L R, Henderson W G, Rickles F R. et al .
Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head
and neck, and prostate. Final report of VA cooperative study #75.
Cancer.
1984;
53
2046-52
Reference Ris Wihthout Link
- 48
Zacharski L R, Memoli V A, Morain W D, Schlaeppi J M, Rousseau S M.
Cellular localization of enzymatically active thrombin in intact human tissues by
hirudin binding.
Thromb Haemost.
1995;
73
793-797
Reference Ris Wihthout Link
Priv.-Doz. Dr. M. Stockschläder
Institut für Hämostaseologie und Transfusionsmedizin, Heinrich-Heine-Universität Düsseldorf
Moorenstraße 5
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Email: stockschlaeder@med.uni-duesseldorf.de