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DOI: 10.1055/s-2002-20560
Treatment of Malignancy by Activation of the Plasminogen System
Publikationsverlauf
Publikationsdatum:
05. März 2002 (online)
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ABSTRACT
The blood coagulation mechanism in general and the plasminogen system in particular contribute to malignant growth and dissemination in complex ways. This article reviews the extensive literature that has accumulated over the past half-century on effects of plasminogen activation on the natural history of experimental animal and human malignancy. Although the potent enzymes generated upon plasminogen activation may have a direct effect on tumor cells, it is more likely that their mechanism of action is related to disruption of the tumor cell-extracellular matrix interaction. These observations suggest novel approaches to the experimental therapy of cancer.
KEYWORD
Malignancy - fibrinolysis - plasminogen activation - extracellular matrix
REFERENCES
- 1 Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost. 1999; 82 259-270
- 2 Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-uPAR-PAI-1 system. Thromb Haemost . 1999; 82 298-304
- 3 Kwaan H C. Modulation of tumor matrix by components of the plasminogen-plasmin system. In: Adany R, ed. Tumor Matrix Biology Boca Raton, FL: CRC Press 1995: 215-234
- 4 Dunbar S D, Ornstein D L, Zacharski L R. Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin. Exp Opin Invest Drugs . 2000; 9 2085-2092
- 5 Cliffton E E, Grossi C E. Effect of human plasmin on the toxic effects and growth of blood-borne metastasis of the Brown-Pearce carcinoma and the V2 carcinoma of rabbit. Cancer . 1956; 9 1147-1152
- 6 Laki K, Yancey S T. Fibrinogen and the tumor problem. In: Laki K, ed. Fibrinogen New York: Marcel Dekker 1968: 359-367
- 7 Hoover Jr C H, Ketcham A S. Techniques for inhibiting tumor metastases. Cancer . 1975; 35 5-14
- 8 Klener P, Bubenik J, Donner L. Influence of heparin and defibrinase on transplantability of syngeneic tumors in mice. Neoplasma . 1978; 25 631-635
- 9 Grossi C E, Agostino D, Cliffton E E. The effect of human fibrinolysin on pulmonary metastases of Walker 256 carcinosarcoma. Cancer Res . 1960; 20 605-608
- 10 Fisher B, Fisher E R. Host factors influencing the development of metastases. Surg Clin North Am . 1962; 42 335-351
- 11 Agostino D, Cliffton E E. Anticoagulants and the development of pulmonary metastases. Arch Surg . 1961; 84 449-453
- 12 Cliffton E E, Agostino D. Factors affecting the development of metastatic cancer. Effect of alterations in clotting mechanism. Cancer . 1962; 15 276-283
- 13 Agostino D, Cliffton E E. Trauma as a cause of localization of blood-borne metastases: preventative effect of heparin and fibrinolysin. Ann Surg . 1965; 161 97-102
- 14 Hilgard P, Hiemeyer V. The cytotoxic effect of plasmin on Yoshida sarcoma cells. Rev Fr Etudes Clin Biol . 1969; 14 902-904
- 15 Agostino D, Cliffton E E. Decrease in pulmonary metastases: potentiation of nitrogen mustard effect by heparin and fibrinolysin. Ann Surg . 1963; 157 400-408
- 16 Fisher B, Fisher E R. Experimental studies of factors which influence hepatic metastases. VII. Effect of anticoagulants. Surgery . 1961; 50 240-247
- 17 Agostino D, Cliffton E E. Decrease of metastases of carcinosarcoma Walker 256 with irradiation and heparin or fibrinolytic agents. Radiology . 1962; 79 848-854
- 18 Cliffton E E, Agostino D. Irradiation and anticoagulant therapy to prevent pulmonary metastases of the V2 carcinoma in rabbits. Radiology . 1963; 80 236-243
- 19 Cliffton E E. Effect of fibrinolysis on spread of cancer. Fed Proc . 1966; 25 89-93
- 20 Kudrjashov B A, Kalishevskaya T M, Kolomina S M. Blood anticoagulating system and malignant tumours. Nature . 1969; 222 548-550
- 21 Wood Jr S, Holyoke D, Yardley J H. Mechanisms of metastasis production by blood-borne cancer cells. Can Cancer Conf . 1961; 4 167-223
- 22 Wood Jr S. Mechanisms of establishment of tumor metastases. In: Ioachim HL, ed. Pathobiology Annual New York: Appleton-Century-Crofts 1971: 281-308
- 23 Wood Jr S. Experimental studies of the intravascular dissemination of ascitic V2 carcinoma cells in the rabbit, with special reference to fibrinogen and fibrinolytic agents. Bull Schweiz Akad Med Wiss . 1964; 20 92-121
- 24 Taniguchi T. Basic and clinical studies on chemotherapy of cancer. J Jpn Cancer Soc . 1972; 7 290-309
- 25 Fisher B, Fisher E R. Anticoagulants and tumor cell lodgment. Cancer Res . 1967; 27 421-425
- 26 Grossi C E, Agostino D, Melamed M, Cliffton E E. The effect of human fibrinolysin on survival of carcinosarcoma 256 Walker cells in the blood. Cancer . 1961; 14 957-962
- 27 Thornes R D. Fibrinogen and the interstitial behavior of cancer. In: Ioachim HL, ed. Pathobiology Annual New York: Appleton-Century-Crofts 1971: 281-308
- 28 Thornes R D, Martin W T. The cytopathic effect of fibrinolytic agents and human placental fractions on HELA cells. Ir J Med Sci . 1961; 431 487-494
- 29 Tanaka K, Kohga S, Kinjo M, Kodama Y. Tumor metastasis and thrombosis, with special reference to thromboplastic and fibrinolytic activities of tumor cells. Monograph on Cancer Research. New York: GANN 1977: 97-119
- 30 Murthy M S, Summaria L J, Miller R J. Inhibition of tumor implantation at sites of trauma by plasminogen activators. Cancer . 1991; 68 1724-1730
- 31 Lisnell A, Mellgren J. Effect of heparin, protamine, dicoumarol, streptokinase and epsilon-amino-n-caproic acid on the growth of human cells in vitro. Acta Pathol . 1963; 57 145-153
- 32 Purushotham A D, Brown D C, McCulloch P, Choy A, George W D. Streptokinase inhibits pulmonary tumor seeding in an animal experimental model. J Surg Oncol . 1994; 57 3-7
- 33 Yamamoto M, Yamada T, Fukunaga K. Potentiation of cytotoxic drug effects. The significance of the combined therapy of cytotoxic drug and urokinase. Cancer Clin (Gan To Rinshou) . 1971; 17 750-759
- 34 Yamamoto M, Nashima A, Nagamatsu S. Potentiation of cytotoxic drug effects. The significance of the combined therapy with dextran sulfate. Recent Med (Saishin Igaku) . 1973; 28 996-1009
- 35 Taya T. Enhanced cell killing by thio-TEPA and urokinase. J Jpn Soc Urol (Nihon Hinnyouki Gakkai Zasshi) . 1979; 70 15-27
- 36 Nagai N. Coagulation and fibrinolysis system in tumor of the bladder. Effect of fibrinolytic and antifibrinolytic agents on N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced rat bladder tumor. J Jpn Soc Urol (Nihon Hinnyouki Gakkai Zasshi) . 1985; 76 31-40
- 37 Miyoshi T, Saito M, Arimizu N. Effect of radiation therapy combined with fibrinolytic agents on Ehrlich solid tumor in mice. J Jpn Soc Radiol . 1982; 42 895-898
- 38 Peterson H-I. Experimental studies on fibrinolysis in growth and spread of tumour. Acta Chir Scand . 1968; Suppl 394-394 Abst
- 39 Peterson H-I, Appelgren K L, Rudenstam C-M, Lewis D H. Studies on the circulation of experimental tumours. Eur J Cancer . 1969; 5 91-97
- 40 Peterson H-I, Appelgren K L, Rosengren B HO. Fibrinogen metabolism in experimental tumours. Eur J Cancer . 1969; 5 535-542
- 41 Rudenstam C M. Effect of fibrinolytic and antifibrinolytic therapy on the dissemination of experimental tumours. Bibl Anat . 1967; 9 418-424
- 42 Sugimura M, Tsubakimoto M, Kashibayashi Y, Kawakatsu K. Effect of human serum plus streptokinase on spontaneous pulmonary metastases of Vx2 carcinomas transplanted in the maxillary sinus of the rabbit. Int J Oral Surg . 1975; 4 112-120
- 43 Kodama Y, Tanaka K. Effect of urokinase on growth and metastases of rabbit V2 carcinoma. Gann . 1978; 69 9-18
- 44 DeWys W D, Kwaan H C, Bathina S. Effect of defibrination on tumor growth and response to chemotherapy. Cancer Res . 1976; 36 3584-3587
- 45 Chikahisa L, Matsuo K, Yamada Y. Modulation of tumor cell motility by plasmin. Invasion Metastasis . 1997; 17 323-333
- 46 Roszkowski W, Stachurska J, Gerdin B, Saldeen T, Kopec M. Peptides cleaved from fibrinogen by plasmin enhance the progression of L-1 sarcoma in BALB/c mice. Eur J Cancer Clin Oncol . 1981; 17 889-892
- 47 Hilgard P, Thornes R D. Anticoagulants in the treatment of cancer. Eur J Cancer . 1976; 12 755-762
- 48 Suzuki M, Abe I, Sato H. Combination of chemotherapy and proteolytic enzymes (an experimental approach). Recent Med (Saishin No Igaku) . 1973; 28 920-925
- 49 Zacharski L R, Rickles F R. Warfarin in the treatment of cancer. In: Poller L, Hirsh J, eds. Oral Anticoagulants London: Edward Arnold 1996: 228-238
- 50 Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med . 2000; 342 1953-1958
- 51 Zacharski L R, Ornstein D L. Heparin and cancer. Thromb Haemost . 1998; 80 10-23
- 52 Cliffton E E, Grossi C E. The rationale of anticoagulants in the treatment of cancer. J Med . 1974; 5 107-113
- 53 Zacharski L R. Anticoagulation in the treatment of cancer in man. In: Donati M, Davidson JF, Garattini S, eds. Malignancy and the Hemostatic System New York: Raven Press 1981: 113-128
- 54 Thornes R D. Anticoagulant therapy in patients with cancer. J Ir Med Assoc . 1969; 62 426-429
- 55 Larsen V, Mogensen B, Amris C J, Storm O. Fibrinolytic enzyme in the treatment of patients with cancer. Dan Med Bull . 1964; 2 137-140
- 56 Holt J AG. The extranuclear control of mitosis and cell function. A theory of cellular organization. Med Hypotheses . 1980; 6 145-192
- 57 Daido R, Koike A, Nomiyama S, Nakamura M, Watanabe T. The effect of selective administration of anticancer agents in massive doses combined with fibrinolytic enzyme (urokinase) in a case of hepatic cancer. Jpn J Cancer Clin (Gan No Rinsho) . 1972; 18 285-289
- 58 Martin Algarra S, Dy C, Anton Aparicio L. Tratamiento del carcinoma pulmonar de celulas pequeñas con urokinasa y quimioterapia intensiva. Resultados preliminares. Rev Med Univ Navarra . 1986; 30 41-48
- 59 Calvo F A, Harguindey S S, Anton Aparicio L. Urokinase combination chemotherapy for treatment of small cell carcinoma of the lung. Cancer Treat Symp . 1985; 2 105-108
- 60 Calvo F A, Hidalgo O F, Gonzalez F. Urokinase combination chemotherapy in small cell lung cancer. A phase II study. Cancer . 1992; 70 2624-2630
- 61 Salsali M, Cliffton E E. Superior vena cava obstruction with carcinoma of the lung. Surg Gynecol Obstet . 1965; 121 783-788
- 62 Salsali M, Cliffton E E. Superior vena caval obstruction in carcinoma of lung. NY State J Med . 1969; 69 2875-2880
- 63 Salsali M, Cliffton E E. Superior vena caval obstruction with lung cancer. Ann Thorac Surg . 1968; 6 437-442
- 64 Clery A P, Hogan B L, Holland P DJ. Early experience in a controlled clinical trial using streptokinase induced fibrinolysis during resections for colon and rectal carcinomas in an attempt to prevent hematogenous metastasis. J Ir Coll Phys Surg . 1972; 1 91-95
- 65 Thornes R D. Fibrinolytic therapy of leukaemia. J R Coll Surg Irel . 1970; 6 123-128
- 66 Thornes R D. Adjuvant therapy of cancer via the cellular immune mechanism or fibrin by induced fibrinolysis and oral anticoagulants. Cancer . 1975; 35 91-97
- 67 Thornes R D. Inhibition of antiplasmin, and effect of protease I in patients with leukaemia. Lancet . 1968; 2 1220-1223
- 68 Thornes R D, Deasy P F, Carroll R, Reen D J, MacDonell J D. The use of the proteolytic enzyme brinase to produce autocytotoxicity in patients with acute leukemia and its possible role in immunotherapy. Cancer Res . 1972; 32 280-284
- 69 Thornes R D. Unblocking or activation of the cellular immune mechanism by induced proteolysis in patients with cancer. Lancet . 1974; 2 382-384
- 70 Thornes R D, Smyth H, Browne O. The effects of proteolysis on the human immune mechanism in cancer. J Med . 1974; 5 92-97
- 71 Thornes R D, Smyth H, Brown O, Holland P DJ. B.C.G. plus protease I in malignant melanoma. (Letter to the Editor). Lancet . 1973; 2 1386
- 72 O'Brien E T, Thornes R D, O'Brien D, Hogan B. Inhibition of antiplasmin, and fibrinolytic effect of protease in patients with cancer. Lancet . 1968; 1 173-176
- 73 Hashimoto I, Kodama M, Hironaka T, Tanaka Y, Kubo Y. Basic studies on combined use of anticancer agents and urokinase. Med Postgrad . 1970; 8 358-362
- 74 Tsue M, Egami T, Murakami M. Clinical use of urokinase combined with mitomycin-C on intraperitoneal perfusion therapy. Jpn J Clin Exp Med (Rinsho To Kenkyu) . 1972; 49 2259-2260
- 75 Fukumoto K, Tadata M. Two clinical cases with stomach cancer significantly improved by combined use of 5-FU and urokinase. Med Postgrad . 1972; 10 35-36
- 76 Goto M. A clinical case with juvenile carcinomatous peritonitis improved by combined use of anticancer agent and urokinase. Med Postgrad . 1970; 8 325-327
- 77 Nakamura R. Clinical effect of combined therapy with mitomycin and urokinase on progressive uterine cancer. Med Postgrad . 1971; 9 115-118
- 78 Hisazumi H, Uchibayashi T, Naito K, Misaki T, Miyazaki K. The prophylactic use of thio-TEPA and urokinase in transitional cell carcinoma of the bladder: a preliminary report. J Urol . 1975; 114 394-398
- 79 Ogawa S, Okawa T, Kaneta K, Tsuya A, Utsunomiya J. Experiences gained in the treatment of locally advanced breast cancer with various combined treatment. A clinical trial aimed at improving the effectiveness of cancer chemotherapy. J Jpn Soc Radiol . 1976; 36 1069-1081
- 80 Yamamoto M, Saito T, Ouchi S. Clinical evaluation of the combination therapy of various anticancer agents and urokinase: comparison of tissue culture urokinase with urinary urokinase. Jpn J Cancer Chemother (Gan To Kagaku Ryouho) . 1982; 9 1461-1473
- 81 Saijo N. Chemotherapy against pulmonary metastasis from uterine cervical carcinoma. Jpn J Cancer Chemother (Gan To Kagaku Ryouhou) . 1982; 9 992-997
- 82 Haku S. Clinical use of urokinase on tumor of the bladder and ureteral stone. Jpn J Clin Exp Med (Rinsho To Kenkyu) . 1972; 49 2631-2632
- 83 Matsui R, Sakamoto H, Yamaguchi K, Masuda M, Noda N. Combined therapy with lysosome labiliser (urokinase MDS) and anticancer agent. Jpn J Clin Exp Med (Rinsho To Kenkyu) . 1972; 49 2290-2296
- 84 Niitani H, Suzuki A, Chikada C. Combined therapy with lysosome labilizer and anticancer agent. Recent Med (Saishin Igaku) . 1968; 23 21168-21172
- 85 Nagamatsu S, Nakajima M, Yamamura M. Experimental and clinical studies on combined use with protease as method to potentiate the effect of anticancer agents. A report in the 19th Japan Chemotherapy Society General Meeting, Tokyo, June 10-12, 1971, pp 17-19
- 86 Yamamoto M, Yamada T, Fukunaga S. Method to potentiate the effect of anti-tumor-drugs. Meanings of urokinase combination. Jpn J Cancer Clin (Gan No Rinsho) . 1971; 17 750-759
- 87 Yamamoto M. The role of induced fibrinolysis in cancer chemotherapy. Recent Med (Saishin Igaku) . 1971; 26 365-379
- 88 Tsuboi S, Kajiwara T, Kamata T. Combined therapy with urokinase on terminal cancer. Clin Rep . 1971; 5 478-485
- 89 Tanaka K. Cancer and fibrinolysis. Jpn J Cancer Chemother (Gan To Kagaku Ryouhou) . 1975; 2 545-557
- 90 Shimoyama M, Niitani H, Kimura K, Taniguchi T, Inagaki J. Lysosome and chemotherapy. Combined therapy of mitomycin C and the lysosome labilizer plasmin. Jpn J Clin Exp Med (Igaku No Ayumi) . 1968; 65 349-352
- 91 Niitani H. Anticancer therapy and its combination with lysosome labilizer. Recent Med (Saishin Igaku) . 1973; 28 912-919
- 92 Suda Y, Sekiine T. Biliary and pancreatic excretion of mitomycin C with special reference to the concomitant use of urokinase. Jpn J Cancer Chemother (Gan To Kagaku Ryouhou) . 1985; 12 2225-2226
- 93 Kato S, Matsuno S, Kakizaki K, Fukaya Y, Akaishi S. Effects of urokinase on the transfer of 1-hexylcarbamoyl-5-fluorouracil (HCFU) into blood, bile and pancreatic juice. Jpn J Cancer Chemother (Gan To Kagaku Ryouhou) . 1985; 12 2134-2138
- 94 Hanzawa T. Anticancer agents in the treatment of two cases of carcinomatous peritonitis and combined therapy with urokinase. Direct Correspondence 1970: 85-86
- 95 Dahl S. Treatment of cancer patients with infusions of plasmin. Oncologia . 1996; 20 35-38
- 96 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
- 97 Vasudevan J, Humphries J E, Gonias S L. Binding of anisoylated lys-plasminogen streptokinase activator complex to cells in culture. Thromb Haemost . 1993; 69 370-374
- 98 Hajjar K A, Acharya S S. Annexin II and regulation of cell surface fibrinolysis. Ann NY Acad Sci . 2000; 902 265-271
- 99 Meehan K R, Zacharski L R, Maurer L H. Studies of possible mechanisms for the effect of urokinase therapy in small cell carcinoma of the lung. Blood Coagul Fibrinolysis . 1995; 6 105-112
- 100 Hatton M WC, Ross B, Bardossy L. The procoagulant state of the VX-2 tumor in rabbit lung in vivo: relative accumulation of fibrinogen, prothrombin, plasminogen, antithrombin and heparin cofactor II within the tumor. Thromb Haemost . 1999; 82 1694-1702
- 101 Back N, Shields R R, DeWitt G, Branshaw R H, Ambrus C M. Uptake of fibrinogen and fibrinolytic enzymes by neoplastic tissue. J Natl Cancer Inst . 1966; 36 171-180
- 102 Amris C J, Larsen V, Mogensen B, Storm O. Turnover and distribution of 131I-labeled porcine plasmin in man and dog. Dan Med Bull . 1964; 2 146-152
- 103 Costantini V, Zacharski L R. Fibrin and cancer. Thromb Haemost . 1993; 69 406-414
- 104 Kwaan H C. The role of fibrinolysis in disease processes. Semin Thromb Hemost . 1984; 10 71-79
-
105 Adany R. Tumor Matrix Biology
New York: CRC Press 1995
- 106 Ashbaugh C D, Warren H B, Carey V J, Wessels M R. Molecular analysis of the role of the group A streptococcal cysteine protease, hyaluronic acid capsule, and M protein in a murine model of human invasive soft-tissue infection. J Clin Invest . 1998; 201 550-560
- 107 Peuhkurinen K J, Risteli L, Melkko J T. Thrombolytic therapy with streptokinase stimulates collagen breakdown. Circulation . 1970; 83 1969-1975
- 108 Salomon D S. Cell-cell and cell-extracellular matrix adhesion molecules communicate with growth factor receptors: an interactive signaling web. Cancer Invest . 2000; 18 591-593
- 109 Weiner H L, Zagzag D. Growth factor receptor tyrosine kinases: cell adhesion kinase family suggests a novel signaling mechanism in cancer. Cancer Invest . 2000; 18 544-554
- 110 Goldfinger L E, Jiang L, Hopkinson S B, Stack M S, Jones J C. Spatial regulation and activity modulation of plasmin by high-affinity binding to the G domain of the alpha3 subunit of laminin-5. J Biol Chem . 2000; 275 34887-34893
- 111 Felding-Habermann B, Ruggeri Z M, Cheresh D A. Distinct biological consequences of integrin alpha v beta 3-mediated melanoma cell adhesion to fibrinogen and its plasmic fragments. J Biol Chem . 1992; 267 5070-5077
- 112 Pintucci G, Bikfalvi A, Klein S, Rifkin D B. Angiogenesis and the fibrinolytic system. Semin Thromb Hemost . 1996; 22 517-524
-
113 Sawaya R. Fibrinolysis and the Central Nervous System
Philadelphia: Hanley & Belfus 1990
- 114 Glas-Greenwalt P, ed. Fibrinolysis in Disease. The Malignant Process, Interventions in Thrombogenic Mechanisms, and Novel Treatment Modalities. New York: CRC Press 1995
- 115 Collen D. Towards improved thrombolytic therapy. Lancet . 1993; 342 34-36
- 116 The European Myocardial Infarction Project Group. Prehospital thrombolytic therapy in patients with suspected acute myocardial infarction. Prehospital Thrombolysis for Myocardial Infarction-EMIP Group. N Engl J Med . 1993; 329 383-389
- 117 de Boer P J, Baars J W, Roem D. Activation of fibrinolysis and coagulation during interleukin 2 therapy. Thromb Haemost . 1991; 65 1053-1053 Abst
- 118 Negrier C, Bordet J C, Durbin S. Haemostasis modifications during interleukin 2 therapy in advanced renal cell cancer. Thromb Haemost . 1991; 65 1055-1055 Abst
- 119 Francis C W, Onundarson P T, Carstensen E L. Enhancement of fibrinolysis in vitro by ultrasound. J Clin Invest . 1992; 90 2063-2068
- 120 Okamoto S. Mode of action of non-enzymatic activators of fibrinolysis: with reference to an anti-tumor agent and to dextran sulfate. In: von Kaulla KN, Davidson JF, eds. Synthetic Fibrinolytic and Thrombolytic Agents Springfield, IL: Charles C Thomas 1975: 118-129
- 121 von Tempelhoff F G, Harenberg J, Niemann F. 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