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• W2039346968 abstract "The origins of modern immunotherapy for cancer can be traced to reports from the late nineteenth and early twentieth centuries describing tumor regression associated with systemic bacterial infections. Such occurrences were apparently part of nineteenth century medical lore [1Bickels J. Kollender Y. Merinsky O. Meller I. Coley's toxin: historical perspective.Israel Med Assoc J. 2002; 4: 471-2PubMed Google Scholar, 2Gresser IA. Chekhov MD and Coley's toxin.N Engl J Med. 1987; 317: 457Crossref PubMed Scopus (17) Google Scholar] and provided a basis for the work of Dr William B. Coley, a surgeon at The Memorial Hospital for Cancer and Allied Diseases in New York City. From 1891 until his death in 1936, Coley studied the effects of inoculation with live bacterial cultures on human malignancy. His work was the subject of numerous published reports, which were summarized in detail in 1953 [3Nauts H.C. Fowler G.A.A. Bogato FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man.Acta Med Scand. 1953; 145: 5-103Google Scholar], and by the middle of the twentieth century an international literature, approximating 500 papers, existed on this subject. The clinical effects reported originally for this treatment, taken at face value, were no less than astounding! Complete, prolonged regression of advanced malignancy was described in many cases. Based on the combined reported experience, an estimated 80% 5-year survival was claimed in disease for which no treatment was otherwise available [3Nauts H.C. Fowler G.A.A. Bogato FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man.Acta Med Scand. 1953; 145: 5-103Google Scholar]. Coley's hypothesis was that an immune reaction against a ‘toxin’ present in the infectious material cross-reacted with and destroyed the tumor cells. In 1953, Coley's daughter, Helen Coley Nauts, established The Cancer Research Institute (http://www.cancerresearch.org/index.html) in her father's memory that continues to support research on the immunotherapy of malignancy. The appeal of an immunological explanation for Coley's observations was undoubtedly linked to progress in the budding field of clinical immunology [4Murray EGD. A synopsis of the history of medical bacteriology.in: Dubos, RJ Bacterial and Mycotic Infections of Man. 3rd edn. Lippincott, 1958: 1-13Google Scholar, 5Burnet M. The history of immunological ideas. Chapter 1.Cellular Immunology Bacterial and Mycotic Infections of Man. Cambridge University Press, 1969: 3-20Google Scholar]. Over a century earlier, Jenner had demonstrated that acquiring cowpox prevented smallpox and described skin test reactivity, which was understood later as a manifestation of delayed hypersensitivity. In the mid-nineteenth century, Pasteur pioneered vaccine development, which was followed later in the century by the rapid discovery of many pathogenic bacteria, and their corresponding toxins and antitoxins. Koch described the tuberculin reaction in 1891. Coley seemed to have ridden the incoming wave of immunological ideas in concluding that patients with severe streptococcal infection experienced arousal of an otherwise inexplicably dormant but potentially effective natural tumor defense mechanism. Unfortunately, subsequent tests of the immunotherapeutic hypothesis have produced less impressive results than Coley's [6Rosenberg SA. Principles of cancer management: biologic therapy.in: DeVita, Jr, VT Hellman, S Rosenberg, SA Cancer. Principles and Practice of Oncology. 6th edn. Lippincott Williams & Wilkins, 2001: 307-33Google Scholar]. While the belief persists that a provoked host immune response is potentially capable of spilling over to attack malignant cells, Coley's original approach has been long abandoned and neither Coley nor his ‘toxin’ is referenced in current comprehensive oncology texts [7DeVita Jr, V.T. Hellman S. Rosenberg S.A. Cancer. Principles and Practice of Oncology. 6th edn. Lippincott Williams & Wilkins, 2001Google Scholar, 8Kufe D.W. Pollock R.E. Weichselbaum R.R. Bast Jr, R.C. Gansler T.S. Holland J.F. Frei III, E. Cancer Medicine. BC Becker Inc., 2003Google Scholar]. The discrepancy between Coley's original observations and the results of subsequent immunotherapy trials may not have been the result of a problem with Coley's observations but with the hypothesis put forth to explain them. A re-examination of Coley's original observations in the light of current knowledge suggests that tumor regression may have been attributable to administration of a plasminogen activator rather than an immunogen. Systemic streptococcal disease (particularly erysipelas) was the most common naturally occurring infection associated with tumor regression, although other, e.g. staphylococcal, infections were implicated as well [3Nauts H.C. Fowler G.A.A. Bogato FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man.Acta Med Scand. 1953; 145: 5-103Google Scholar]. Disease regression was described for a variety of tumor types but the most dramatic examples of responsive tumor types were soft-tissue sarcomas, breast cancer and malignant melanoma [3Nauts H.C. Fowler G.A.A. Bogato FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man.Acta Med Scand. 1953; 145: 5-103Google Scholar]. Coley's initial, and most successful, attempts to deliberately reproduce the effects of infection on free-living cancer patients involved infusions of fresh, whole cultures of streptococci. As with natural streptococcal infections, regression of advanced disease was observed in many cases. At this point, the trail became more a maze than a fast track to cancer cure. Difficulties existed with the quality of the reports themselves; they resembled (literarily) nineteenth century standards of clinical quantification more closely than twentieth century standards. Christensen [9Christensen EA. Infection and malignant tumours.Acta Pathol Microbiol Scand. 1959; 46: 285-95Crossref PubMed Scopus (19) Google Scholar, 10Christensen E.A. Kjems E. Infection and malignant tumours.Acta Pathol Microbiol Scand. 1959; 46: 296-304Crossref PubMed Scopus (5) Google Scholar] commented that had these observations not been made by eminent clinicians of that time and had histological confirmation of the diagnosis not been available, no credibility would have been ascribed to the spectacular results reported. Another difficulty was that the contemporary basic science needed to define active element(s) in the crude culture broth and to monitor activity during the fractionation and purification steps was inadequate to guide rational product development and clinical trial design. Attempts to improve safety and efficacy of the ‘toxin’, including heat treatment, resulted in diminished clinical efficacy. Variable clinical effects could not be correlated with corresponding clinical laboratory test results. With general improvements in aseptic techniques and the advent of antibiotics, the possibility of observing the effects of severe natural infections on cancer outcome all but disappeared. There was an understandable aversion to placing patients at risk from inoculation with live streptococci and attention was directed increasingly to newer radiation therapy and, eventually, chemotherapy approaches to cancer treatment. The above problems notwithstanding, tumor regression associated with naturally occurring infections may indeed have been an ‘experiment of nature’ but not of the immunological type envisioned by Coley. We suggest that tumor responses in Coley's studies might have been the result of a plasminogen activator, particularly streptokinase (SK), which is capable of compromising tumor viability. In fact, SK in the bacterial culture broth was acknowledged later as possibly accounting for the ‘toxin’ effect [3Nauts H.C. Fowler G.A.A. Bogato FH. A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man.Acta Med Scand. 1953; 145: 5-103Google Scholar]. Perhaps activity was lost with purification, heat treatment and elimination of live bacteria while attempting to improve the ‘immunogen’ resulting in reduced antitumor activity. SK produced by virulent streptococci combines stoichiometrically with host plasminogen, triggering a conformational change and self-cleavage resulting in the formation of enzymically active plasmin [11Collen D. The plasminogen (fibrinolytic) system.Thromb Haemost. 1999; 82: 298-304Google Scholar]. Plasmin is a potent enzyme with relatively broad substrate specificity capable of initiating other protease cascades and of degrading a variety of plasma and extracellular matrix proteins. This accounts for the fact that SK is a streptococcal spreading factor that facilitates the dissection of organisms through tissue planes [12Huang T.-.T. Malke H. Ferretti JJ. Heterogeneity of the streptokinase gene in Group A streptococci.Infect Immun. 1989; 57: 502-6Crossref PubMed Google Scholar]. Lottenberg et al.[13Lottenberg R. DesJardin L.E. Wang H. Boyle MDP. Streptokinase-producing streptococci grown in human plasma acquire unregulated cell-associated plasmin activity.J Infect Dis. 1992; 166: 436-40Crossref PubMed Scopus (57) Google Scholar] demonstrated that plasminogen and SK-activated plasmin bind with high affinity to the surface of streptococci where plasmin is protected from physiological inhibition. Such unregulated protease activity enables strains of streptococci to traverse tissue barriers [13Lottenberg R. DesJardin L.E. Wang H. Boyle MDP. Streptokinase-producing streptococci grown in human plasma acquire unregulated cell-associated plasmin activity.J Infect Dis. 1992; 166: 436-40Crossref PubMed Scopus (57) Google Scholar, 14Wang H. Lottenberg R. Boyle MD. Analysis of the interaction of group A streptococci with fibrinogen, streptokinase and plasminogen.Microb Pathog. 1995; 18: 153-66Crossref PubMed Scopus (51) Google Scholar] and to induce systemic coagulation changes that may accompany severe erysipelas [15Sverdrup B. Blomback M. Borglund E. Hammer H. Blood coagulation and fibrinolytic systems in patients with erysipelas and necrotizing fasciitis.Scand J Infect Dis. 1981; 13: 29-36Crossref Scopus (10) Google Scholar, 16Hammer H. Blomback M. Sverdrup B. Borglund E. An improved quantitative method for the study of fibrinolysis in the skin as exemplified in patients with leukocytoclastic vasculitis and erysipelas.Acta Derm Venereol. 1980; 60: 287-93Google Scholar]. Focal streptococcal infections can become systemic, resulting in a coagulopathy that is capable of inducing tissue hemorrhage [17Ooe K. Nakada H. Udagawa H. Shimizu Y. Severe pulmonary hemorrhage in patients with serious Group A streptococcal infections: report of two cases.Clin Infect Dis. 1999; 28: 1317-19Crossref PubMed Scopus (13) Google Scholar]. Such reactions could account for the fact that severe erysipelas was the naturally occurring infection most often associated with tumor regression, possibly through SK production. The amount of SK produced by various strains of streptococci varies greatly [12Huang T.-.T. Malke H. Ferretti JJ. Heterogeneity of the streptokinase gene in Group A streptococci.Infect Immun. 1989; 57: 502-6Crossref PubMed Google Scholar] and SK has considerable variability in plasminogen activation on this basis [18McCoy H.E. Broder C.C. Lottenberg R. Streptokinases produced by pathogenic group C streptococci demonstrate species-specific plasminogen activation.J Infect Dis. 1991; 164: 515-21Crossref PubMed Scopus (68) Google Scholar]. These factors might explain the variability of results in different patients with natural infections, in patients treated with cultures of various strains of streptococci, and in different animal models. It is noteworthy that streptococcal cultures were effective against the Brown–Pearce carcinoma in the rabbit [9Christensen EA. Infection and malignant tumours.Acta Pathol Microbiol Scand. 1959; 46: 285-95Crossref PubMed Scopus (19) Google Scholar, 10Christensen E.A. Kjems E. Infection and malignant tumours.Acta Pathol Microbiol Scand. 1959; 46: 296-304Crossref PubMed Scopus (5) Google Scholar], one of the experimental tumor models shown in 1956 by Cliffton and Grossi to be inhibited by SK-activated plasmin [19Cliffton E.E. Grossi CE. Effect of human plasmin on the toxic effects and growth of blood-borne metastasis of the Brown–Pearce carcinoma and the V2 carcinoma of rabbits.Cancer. 1956; 9: 1147-52Crossref PubMed Scopus (25) Google Scholar]. Studies with bacterial cultures also demonstrated that a host factor (presumably plasminogen) was needed for the antitumor effect [9Christensen EA. Infection and malignant tumours.Acta Pathol Microbiol Scand. 1959; 46: 285-95Crossref PubMed Scopus (19) Google Scholar, 10Christensen E.A. Kjems E. Infection and malignant tumours.Acta Pathol Microbiol Scand. 1959; 46: 296-304Crossref PubMed Scopus (5) Google Scholar]. The affinity of streptococci for binding to fibrinogen and fibrin [14Wang H. Lottenberg R. Boyle MD. Analysis of the interaction of group A streptococci with fibrinogen, streptokinase and plasminogen.Microb Pathog. 1995; 18: 153-66Crossref PubMed Scopus (51) Google Scholar, 20Sherry S. Historical developments in fibrinolysis.in: Sawaya R Fibrinolysis and the Central Nervous System. Hanley & Belfus, Inc., 1990: 3-13Google Scholar, 21Seifert K.N. McArthur W.P. Bleiweis A.S. Brady LJ. Characterization of group B streptococcal glyceraldehyde-3-phosphate dehydrogenase. surface localization, enzymatic activity, and protein–protein interactions.Can J Microbiol. 2003; 49: 350-6Crossref PubMed Scopus (86) Google Scholar, 22Courtney H.S. Dale J.B. Hasty DL. Mapping the fibrinogen-binding domain of serum opacity factor of group a streptococci.Curr Microbiol. 2002; 44: 236-40Crossref PubMed Scopus (25) Google Scholar, 23D'Costa S.S. Boyle MD. Interaction of group A streptococci with human plasmin(ogen) under physiological conditions.Methods. 2000; 21: 165-77Crossref PubMed Scopus (29) Google Scholar, 24Rocha C.L. Fischetti VA. Identification and characterization of a new protein from Streptococcus pyogenes having homology with fibronectin and fibrinogen binding proteins.Adv Exp Med Biol. 1997; 418: 737-9Crossref Scopus (5) Google Scholar] could account for ‘homing’ of bacterial enzymatic activity to tumors laden with these proteins [25Costantini V. Zacharski L.R. Memoli V.A. Kisiel W. Kudryk B.J. Hunt J. Rousseau S.M. Stump DC. Fibrinogen deposition without thrombin generation in primary human breast cancer tissue.Cancer Res. 1991; 51: 349-53PubMed Google Scholar, 26Costantini V. Zacharski LR. Fibrin and cancer.Thromb Haemost. 1993; 69: 406-14Crossref PubMed Scopus (93) Google Scholar]. Thus, it is tempting to postulate that systemic streptococcal infections, whether naturally occurring or induced, might result in effects on tumor masses that can be reproduced by the administration of SK, other plasminogen activators, or plasmin. The fact that SK administration for the treatment of acute myocardial infarction elevates levels of the proteolytic degradation products of collagen [27Peuhkurinen K.J. Risteli L. Melkko J.T. Linnaluoto M. Jounela A. Risteli J. Thrombolytic therapy with streptokinase stimulates collagen breakdown.Circulation. 1991; 83: 1969-75Crossref PubMed Scopus (69) Google Scholar] further suggest that SK may mimic the effects of Coley's toxin on malignancy. Immunology did not acquire a biochemical or cellular identity [4Murray EGD. A synopsis of the history of medical bacteriology.in: Dubos, RJ Bacterial and Mycotic Infections of Man. 3rd edn. Lippincott, 1958: 1-13Google Scholar, 5Burnet M. The history of immunological ideas. Chapter 1.Cellular Immunology Bacterial and Mycotic Infections of Man. Cambridge University Press, 1969: 3-20Google Scholar], and bacterial and other activators of plasminogen were not characterized [20Sherry S. Historical developments in fibrinolysis.in: Sawaya R Fibrinolysis and the Central Nervous System. Hanley & Belfus, Inc., 1990: 3-13Google Scholar] until well after Coley's death. The ability of culture filtrates of hemolytic streptococci to lyze fibrin clots was not recognized until 1933 [28Tillett W.S. Garner RL. The fibrinolytic activity of hemolytic streptococci.J Exp Med. 1933; 68: 485-502https://doi.org/10.1084/jem.58.4.485Crossref Scopus (318) Google Scholar] and was evidently not linked by Coley to the possible mechanism of his ‘toxin’. The description at about the same time of the apparent efficacy of Coley's toxin [29Gray HJ. Thromboangiitis: significant findings and theory of etiology (non-specific protein therapy with Coley's erysipelas and prodigiosus toxins).Med Bull Vet Admin. 1935; 11: 16-23Google Scholar] and, later, SK [30Hussein E.A. El Dorri A. Intra-arterial streptokinase as adjuvant therapy for complicated Buerger's disease: early trials.Int Surg. 1993; 78: 54-8PubMed Google Scholar] for the treatment of Buerger's disease suggests a mechanism that is common to both vascular and neoplastic disease and that does not clearly have an immune basis. Advances in the past half-century have added further credence to the concept that activation of plasminogen may account for Coley's observations. The substantial older literature on the effects of plasminogen activators and plasmin on both experimental animal and human malignancies has been reviewed recently [31Zacharski L.R. Ornstein D.L. Gabazza E.C. D'Alessandro-Gabazza C.N. Brugarolas A. Schneider J. Treatment of malignancy by activation of the plasminogen system.Semin Thrombos Hemostas. 2002; 28: 5-17https://doi.org/10.1055/s-2002-20560Crossref PubMed Scopus (0) Google Scholar]. Profound and long-lasting effects following a single infusion of plasmin in some models bear striking resemblance to Coley's clinical observations. Proposed mechanisms of the effect of plasminogen activation on cancer include a direct toxic effect on the tumor cells, disruption of the tumor extracellular matrix, alteration of tumor growth factor activity and inhibition of metastasis. An up-dated view of the mechanisms by which the plasminogen activator/plasmin system regulates tumor growth must take into consideration the extensive literature on the divergent effects of the two naturally occurring plasminogen activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), on malignancy. Apart from the fact that both activate plasminogen, these two activators share little in common. uPA and its corresponding receptor participate in tissue remodeling that is part of the normal response to injury and both are up-regulated on tumor cells and in the stroma of many tumor types [32Andreasen P.A. Kjoller L. Christensen L. Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review.Int J Cancer. 1997; 72: 1-22Crossref PubMed Scopus (1445) Google Scholar, 33Zacharski L.R. Wojtukiewicz M.Z. Costantini V. Ornstein D.L. Memoli VA. Pathways of coagulation/fibrinolysis activation in malignancy.Semin Thromb Hemost. 1992; 18: 104-16Crossref PubMed Scopus (190) Google Scholar, 34Zacharski L.R. Loynes J.R. Ornstein D.L. Rigas JR. The plasminogen system and cancer.Biomed Prog. 2002; 15: 17-22Google Scholar, 35Dunbar S.D. Ornstein D.L. Zacharski LR. Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin.Exp Opin Invest Drugs. 2000; 9: 2085-92Crossref PubMed Scopus (39) Google Scholar, 36De Witte J.H. Sweep C.G. Klijn J.G. Grebenschikov N. Peters H.A. Look M.P. Van Tiemoven T.H. Heuvel J.J. Bolt-De Vries J. Benraad T.J. Foekens JA. Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer.Br J Cancer. 1999; 80: 286-94Crossref PubMed Scopus (44) Google Scholar, 37De Witte J.H. Sweep C.G. Klijn J.G. Grebenschikov N. Peters H.A. Look M.P. Van Tiemoven T.H. Heuvel J.J. Van Putten W.L. Benraad T.J. Foekens JA. Prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in cytosols and pellet extracts derived from 892 breast cancer patients.Br J Cancer. 1999; 79: 1190-8Crossref PubMed Scopus (38) Google Scholar, 38Chappuis P.O. Dieterich B. Sciretta V. Lohse C. Bonnefoi H. Remadi S. Sappino AP. Functional evaluation of plasmin formation in primary breast cancer.J Clin Oncol. 2001; 19: 2731-8Crossref PubMed Scopus (31) Google Scholar, 39Mignatti P. Rifkin DB. Plasminogen activators and angiogenesis.Curr Top Microbiol Immunol. 1996; 213: 33-50Crossref PubMed Scopus (33) Google Scholar, 40Mignatti P. Rifkin DB. Plasminogen activators and matrix metalloproteinases in angiogenesis.Enzyme Protein. 1996; 49: 117-37Crossref PubMed Scopus (291) Google Scholar, 41Kong H.L. Crystal RG. Gene therapy strategies for tumor antiangiogenesis.J Natl Cancer Inst. 1998; 90: 273-86Crossref PubMed Scopus (168) Google Scholar, 42Hanahan D. Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell. 1996; 86: 353-64Abstract Full Text Full Text PDF PubMed Scopus (6056) Google Scholar]. Increased uPA expression appears to promote tumor growth and metastases, and portends more rapid growth in animal models and poor clinical outcome. Correspondingly, inhibition of uPA improves cancer outcome [35Dunbar S.D. Ornstein D.L. Zacharski LR. Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin.Exp Opin Invest Drugs. 2000; 9: 2085-92Crossref PubMed Scopus (39) Google Scholar]. By contrast, up-regulation of tPA expression is associated with a more favorable outcome. The biological and clinical significance of this difference in expression of uPA and tPA is well-illustrated in breast cancer. Patients whose tumors over-express uPA have a much worse prognosis (disease-free survival and overall survival) compared to patients whose tumors over-expressed tPA [32Andreasen P.A. Kjoller L. Christensen L. Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review.Int J Cancer. 1997; 72: 1-22Crossref PubMed Scopus (1445) Google Scholar, 36De Witte J.H. Sweep C.G. Klijn J.G. Grebenschikov N. Peters H.A. Look M.P. Van Tiemoven T.H. Heuvel J.J. Bolt-De Vries J. Benraad T.J. Foekens JA. Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer.Br J Cancer. 1999; 80: 286-94Crossref PubMed Scopus (44) Google Scholar, 37De Witte J.H. Sweep C.G. Klijn J.G. Grebenschikov N. Peters H.A. Look M.P. Van Tiemoven T.H. Heuvel J.J. Van Putten W.L. Benraad T.J. Foekens JA. Prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in cytosols and pellet extracts derived from 892 breast cancer patients.Br J Cancer. 1999; 79: 1190-8Crossref PubMed Scopus (38) Google Scholar, 38Chappuis P.O. Dieterich B. Sciretta V. Lohse C. Bonnefoi H. Remadi S. Sappino AP. Functional evaluation of plasmin formation in primary breast cancer.J Clin Oncol. 2001; 19: 2731-8Crossref PubMed Scopus (31) Google Scholar]. It is instructive to consider differences between these two plasminogen activators from the point of view of their effects on angiogenesis. While uPA has been implicated in a pathway supporting angiogenesis [39Mignatti P. Rifkin DB. Plasminogen activators and angiogenesis.Curr Top Microbiol Immunol. 1996; 213: 33-50Crossref PubMed Scopus (33) Google Scholar, 40Mignatti P. Rifkin DB. Plasminogen activators and matrix metalloproteinases in angiogenesis.Enzyme Protein. 1996; 49: 117-37Crossref PubMed Scopus (291) Google Scholar], the opposite seems to be the case for tPA. tPA might act as an angiogenesis inhibitor by several mechanisms. For example, by initiating cascades of proteolysis, protein fragments with antiangiogenic activity may be released or ‘uncovered’ from parent proteins that are either devoid of antiangiogenic activity or even proangiogenic [41Kong H.L. Crystal RG. Gene therapy strategies for tumor antiangiogenesis.J Natl Cancer Inst. 1998; 90: 273-86Crossref PubMed Scopus (168) Google Scholar, 42Hanahan D. Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell. 1996; 86: 353-64Abstract Full Text Full Text PDF PubMed Scopus (6056) Google Scholar, 43O'Reilly M.S. Boehm T. Shing Y. Fukai N. Vasios G. Lane W.S. Flynn E. Birkhead J.R. Olsen B.R. Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.Cell. 1997; 88: 277-85Abstract Full Text Full Text PDF PubMed Scopus (4234) Google Scholar]. Another possibility is that tPA-generated plasmin may lead to cleavage of fibrinogen and fibrin, which are known to support angiogenesis [44Browder T. Folkman J. Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.J Biol Chem. 2000; 275: 1521-4Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 45Weitz J.I. Cruickshank M.K. Thong B. Leslie B. Levine M.N. Ginsberg J. Eckhardt T. Human tissue-type plasminogen activator releases fibrinopeptides A and B from fibrinogen.J Clin Invest. 1988; 82: 1700-7Crossref PubMed Scopus (43) Google Scholar]. A third possibility is that plasmin generated by tPA may, in the presence of a sulfhydryl donor, be converted into the potent antiangiogenic peptide, angiostatin, which consists of the first four kringle domains of plasminogen [46Soff GA. Angiostatin and angiostatin-related proteins.Cancer Metastasis Rev. 2000; 19: 97-107Crossref PubMed Scopus (104) Google Scholar, 47Gately S. Twardowski P. Stack M.S. Cundiff D.L. Grella D. Castellino F.J. Enghild J. Kwaan H.C. Lee F. Kramer R.A. Volpert O. Bouck N. Soff GA. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin.Proc Natl Acad Sci USA. 1997; 94: 10868-72Crossref PubMed Scopus (277) Google Scholar, 48O'Reilly M.S. Holmgren L. Shing Y. Chen C. Rosenthal R.A. Moses M. Lane W.S. Cao Y. Sage E.H. Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.Cell. 1994; 79: 315-28Abstract Full Text PDF PubMed Scopus (3160) Google Scholar]. Merchan et al. using assay systems measuring endothelial cell tube formation and endothelial cell proliferation in vitro, showed that angiogenesis was stimulated by native plasma but inhibited by plasma treated with both tPA and the sulfhydryl donor, Captopril [49Merchan J.R. Chan B. Kale S. Schnipper L.E. Sukhatme VP. In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril.J Natl Cancer Inst. 2003; 95: 388-99Crossref PubMed Scopus (54) Google Scholar]. Treatment with tPA or Captopril alone was minimally effective. Interestingly, antiangiogenic activity remained after removal of angiostatin by affinity chromatography or immunoprecipitation. Moreover, Matrigel plugs implanted in animals treated with this cocktail showed diminished angiogenesis. Treatment of three patients with recombinant tPA and Captopril resulted in an increase in plasma antiangiogenic activity that was not ascribable to angiostatin in the patient with maximal induction of antiangiogenic activity [49Merchan J.R. Chan B. Kale S. Schnipper L.E. Sukhatme VP. In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril.J Natl Cancer Inst. 2003; 95: 388-99Crossref PubMed Scopus (54) Google Scholar]. Gately et al. [47Gately S. Twardowski P. Stack M.S. Cundiff D.L. Grella D. Castellino F.J. Enghild J. Kwaan H.C. Lee F. Kramer R.A. Volpert O. Bouck N. Soff GA. The mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin.Proc Natl Acad Sci USA. 1997; 94: 10868-72Crossref PubMed Scopus (277) Google Scholar] demonstrated angiostatin generation from plasminogen activated by tPA, SK and tumor cell-derived uPA. This suggests that SK may resemble tPA [49Merchan J.R. Chan B. Kale S. Schnipper L.E. Sukhatme VP. In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril.J Natl Cancer Inst. 2003; 95: 388-99Crossref PubMed Scopus (54) Google Scholar] in terms of its ability to generate antiangiogenic activity. Unfortunately, recent reports of successful treatment of malignant pleural effusions with SK made no mention of the possible effects on the underlying tumor [50Maskell N.A. Gleeson FV. Images in clinical medicine. Effect of intrapleural streptokinase on a loculated malignant pleural effusion.N Engl J Med. 2003; 1348: e4.Crossref Google Scholar, 51Jerjes-Sanchez C. Ramirez-Rivera A. Elizalde J.J. Delgado R. Cicero R. Ibarra-Perez C. Arroliga A.C. Padua A. Portales A. Villareal A. Perez-Romo A. Intrapleural fibrinolysis with streptokinase as an adjunctive treatment in hemothorax and empyema: a multicenter trial.Chest. 1996; 109: 1514-19Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 52Davies C.W. Traill Z.C. Gleeson F.V. Davies RJ. Intrapleural streptokinase in the management of malignant multiloculated pleural effusions.Chest. 1999; 115: 729-33Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Documented effects of plasminogen activator therapy in patients with malignancy provide a basis for cautious implementation of formal phase I clinical trials [31Zacharski L.R. Ornstein D.L. Gabazza E.C. D'Alessandro-Gabazza C.N. Brugarolas A. Schneider J. Treatment of malignancy by activation of the plasminogen system.Semin Thrombos Hemostas. 2002; 28: 5-17https://doi.org/10.1055/s-2002-20560Crossref PubMed Scopus (0) Google Scholar]. Several commercially standardized formulations of tPA and SK having defined doses, schedules and toxicity profiles are currently on the market and available for testing. Pharmacological effects can be monitored by appropriate laboratory testing and tumor responses can be measured objectively. Careful selection of tumor types that are most likely to respond and of the plasminogen activator most likely to be effective should provide a starting point. Current best treatment options for some candidate tumor types, such as advanced soft tissue sarcomas, breast cancer and melanoma, have not improved patient outcome substantially since Coley's day [7DeVita Jr, V.T. Hellman S. Rosenberg S.A. Cancer. Principles and Practice of Oncology. 6th edn. Lippincott Williams & Wilkins, 2001Google Scholar, 8Kufe D.W. Pollock R.E. Weichselbaum R.R. Bast Jr, R.C. Gansler T.S. Holland J.F. Frei III, E. Cancer Medicine. BC Becker Inc., 2003Google Scholar] and innovative approaches as described here are appealing. In a broader context, plasminogen activator therapy is only one aspect of a larger body of evidence linking blood coagulation reactions and drugs that alter these reactions to regulation of tumor growth [53Zacharski LR. Malignancy as a solid phase coagulopathy. Implications for the etiology, pathogenesis and treatment of cancer.Semin Thrombos Hemostas. 2003; 29: 239-46https://doi.org/10.1055/s-2003-40962Crossref PubMed Scopus (25) Google Scholar]. The prospect that coagulation-reactive drugs in general, and plasminogen activators in particular, may alter malignant progression signals the prospect of new and more effective forms of experimental cancer treatment. Coley may indeed have been right, but for the wrong reason." @default.
• W2039346968 created "2016-06-24" @default.
• W2039346968 creator A5011742759 @default.
• W2039346968 creator A5022619172 @default.
• W2039346968 date "2005-03-01" @default.
• W2039346968 modified "2023-09-30" @default.
• W2039346968 title "Coley's toxin revisited: immunotherapy or plasminogen activator therapy of cancer?" @default.
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