Abstract
Plant extracts with a high content of proteolytic enzymes have been used for a long time in traditional medicine. Besides proteolytic enzymes from plants, ‘modern’ enzyme therapy additionally includes pancreatic enzymes. The therapeutic use of proteolytic enzymes is partly based on scientific studies and is partly empirical. The aim of the current review is to provide an overview of clinical trials of systemic enzyme therapy in oncology, and to discuss the evidence for their possible mechanisms of action.
Clinical studies of the use of proteolytic enzymes in oncology have mostly been carried out on an enzyme preparation consisting of a combination of papain, trypsin and chymotrypsin. This review of these studies showed that enzyme therapy can reduce the adverse effects caused by radiotherapy and chemotherapy. There is also evidence that, in some types of tumours, survival may be prolonged.
The beneficial effect of systemic enzyme therapy seems to be based on its anti-inflammatory potential. However, the precise mechanism of action of systemic enzyme therapy remains unsolved. The ratio of proteinases to antiproteinases, which is increasingly being used as a prognostic marker in oncology, appears to be influenced by the oral administration of proteolytic enzymes, probably via an induction of the synthesis of antiproteinases. Furthermore, there are numerous alterations of cytokine composition during therapy with orally administered enzymes, which might be an indication of the efficacy of enzyme therapy. Effects on adhesion molecules and on antioxidative metabolism are also reviewed.
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References
Vanhoof G, Cooreman W. Bromelain. In: Lauwers A, Scharpé S, editors. Pharmaceutical enzymes. New York: Marcel Dekker, 1997: 131–53
De Feo V. Medicinal and magical plants in the northern Peruvian Andes. Fitoterapia 1992; 53: 417–40
Rawlings ND, Barrett AJ. Evolutionary families of peptidases. Biochem J 1993; 290: 205–18
Rowan AD, Buttle DJ, Barrett AJ. The cysteine proteinases of the pineapple plant. Biochem J 1990; 266: 869–75
Harrach T, Eckert K, Schulze-Forster K, et al. Isolation and partial characterization of basic proteinases from stem bromelain. J Protein Chem 1995; 14: 41–52
Wrbka E, Kodras B. Unterstutzung der Chemotherapie inoperabler bronchopulmonaler Karzinome durch proteolytische Fermente. Wien Med Wochenschr 1978; 128: 153–8
Kim J-P, Wa WS, Kim SJ. Effect of rosette forming T-lymphocyte level in immunochemotherapy using Picibanil and Wobe-Mugos in gastric cancer patients. Leipner J [translation (data on file)]
Schedler M, Lind A, Schatzle W, et al. Adjuvant therapy with hydrolytic enzymes in oncology: a hopeful effort to avoid bleomycin induced pneumotoxicity [abstract]? J Cancer Res Clin Oncol 1980; 116: 697
Lahousen M. Modification of liver parameters by adjuvant administration of proteolytic enzymes following chemotherapy in patients with ovarian carcinoma [in German]. Wien Med Wochenschr 1995; 145: 663–8
Sakalova A, Dedik L, Gazova S, et al. Survival analysis of an adjuvant therapy with oral enzymes in multiple myeloma patients [abstract]. Br J Haematol 1998; 102: 353
Popiela T. Wobe-Mugos E® as additive therapy after surgical treatment of colon cancer patients in combination with chemotherapy. Gerestried, Germany: MUCOS Pharma GmbH & Co., 1999 (data on file)
Sebti SM, Mignano JE, Jani JP, et al. Bleomycin hydrolase: molecular cloning, sequencing, and biochemical studies reveal membership in the cysteine proteinase family. Biochemistry 1989; 28: 6544–8
Schwartz DR, Homanics GE, Hoyt DG, et al. The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance. Proc Natl Acad Sci U S A 1999; 96: 4680–5
Kesztele V, Hürbe E, Wischin W. Erfahrung mit proteolytischen Enzymen beim Bronchuskarzinom. Wien Med Wochenschr 1976; 25-27: 412–4
Beaufort F. Reduzierung von Strahlennebenwirkungen durch hydrolytische enzyme. Therapeutikon 1990; 4: 577–80
Vinzenz K, Stauder U. Die therapie der radiogenen mukositis mit enzymen. In: Vinzenz K, Waclawicek HW, editors. Chirurgische therapie von kopf-hals-karzinomen. Berlin: Springer-Verlag, 1992: 300–14
Gujral MS, Patnaik PM. Efficacy and safety of Wobe-Mugos E® in preventing side-effects of radiation therapy in patients with head and neck cancer — Gerestried, Germany: MUCOS Pharma GmbH & Co, 1998 (data on file)
Dale P. Efficacy and tolerance of Wobe-Mugos E® in reducing side-effects of radiation therapy in locally advanced cervical cancer — Gerestried, Germany: MUCOS Pharma GmbH & Co, 1998 (data on file)
Latha B, Ramakrishnan KM, Jayaraman V, et al. Action of trypsin: chymotrypsin (Chymoral forte DS) preparation on acute-phase proteins following burn injury in humans. Burns 1997; 23 Suppl. 1: 3–7
Latha B, Ramakrishnan M, Jayaraman V, et al. Serum enzymatic changes modulated using trypsin: chymotrypsin preparation during burn wounds in humans. Burns 1997; 23: 560–4
Wood GR, Ziska T, Morgenstern E, et al. Sequential effects of an oral enzyme combination with rutoside in different in vitro and in vivo models of inflammation. Int J Immunother 1997; 13: 139–46
Stauder G, Pollinger W, Fruth C. Systemic enzyme therapy: an overview of new clinical studies [German]. Allgemeinmedizin 1990; 19: 188–91
Gettins P, Patston PA, Olson ST. Serpins: structure, function and biology. Heidelberg: Springer-Verlag, 1996
Fisher JD, Weeks RL, Curry WM, et al. Effects of an oral enzyme preparation, Chymoral®, upon serum proteins associated with injury (acute phase reactants) in man. J Med 1974; 5: 258–73
Foekens JA, Look MP, Bolt-de Vries J, et al. Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients. Br J Cancer 1999; 79: 300–7
Kennedy AR. Chemopreventive agents: protease inhibitors. Pharmacol Ther 1998; 78: 167–209
Pemberton PA. The role of serpin superfamily members in cancer. Cancer J 1997; 10: 24–30
Joslin G, Wittwer A, Adams S, et al. Cross-competition for binding of α1-antitrypsin (α1 AT)-elastase complexes to the serpin-enzyme complex receptor by other serpin-enzyme complexes and by proteolytically modified α1 AT. J Biol Chem 1993; 268: 1886–93
Olson ST, Bock PE, Kvassman J, et al. Role of the catalytic serine in the interactions of serine proteinases with protein inhibitors of the serpin family. J Biol Chem 1995; 270: 30007–17
Lah TT, Kos J. Cyteine proteinases in cancer progression and their clinical relevance for prognosis. Biol Chem 1998; 379: 125–30
Verspaget HW. Proteases as prognostic markers in cancer. BMJ 1998; 316: 790–1
Lah TT, Kokalj-Kunovar M, Strukelj B, et al. Stefins and lysosomal cathepsins B, L and D in human breast carcinoma. Int J Cancer 1992; 50: 36–44
Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of bromelain with or without its proteolytic and anticoagulant activity. J Cancer Res Clin Oncol 1988; 114: 507–8
Batkin S, Taussig S, Szekerczes J. Modulation of pulmonary metastasis (Lewis lung carcinoma) by bromelain, an extract of the pineapple stem (Ananas comosus). Cancer Invest 1988; 6: 241–2
Taussig SJ, Szekerezes J, Batkin S. Inhibition of tumor growth in vitro by bromelain, an extract of the pineapple plant (Ananas comosus). Planta Medica 1985; 51: 538–9
Bellelli A, Mattioni M, Rusconi V, et al. Inhibition of tumor growth, invasion and metastasis in Papain-immunized mice. Invasion Metastasis 1990; 10: 142–69
Mazourov VI, Lila AM, Klimko NN, et al. The efficacy of systemic enzyme therapy in the treatment of rheumatoid arthritis. Int J Immunother 1997; 13: 85–92
Lackovic V, Rovensky J, Horvathová M, et al. Interferon production in whole blood cultures from volunteers and rheumatoid arthritis patients after medication with oral enzymes. Int J Immunother 1997; 13: 159–66
Baenkler H-W. Medizinische Immunologie: Grundlagen, Diagnostik, Klinik, Therapie, Prophylaxe, Sonderbereiche. Landsberg am Lech, Germany: Ecomed, 1995
Desser L, Rehberger A, Kokron E, et al. Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of polyenzyme preparations. Oncology 1993; 50: 403–7
Barrett AJ. α2-Macroglobulin. Methods Enzymol 1981; 80: 737–54
James K. Interactions between cytokines and α2-macroglobulin. Immunol Today 1990; 11: 163–6
Borth W. α2-Macroglobulin, a multifunctional binding protein with targeting characteristics. FASEB J 1992; 6: 3345–53
Borth W, Dunky A, Kleesiek K. α2-Macroglobulin-proteinase complexes as correlated with α1-proteinase inhibitor-elastase complexes in synovial fluids of rheumatoid arthritis patients. Arthritis Rheum 1986; 29: 319–25
Harrach T, Gebauer F, Eckert K, et al. Bromelain proteinases modulate the CD44 expression on human Molt 4/8 leukemia and SK-Mel 28 melanoma cells in vitro. Int J Oncol 1994; 5: 485–8
Gebauer F, Micheel B, Stauder G, et al. Proteolytic enzymes modulate the adhesion molecule CD44 on malignant cells in vitro. Int J Immunother 1997; 13: 111–9
Grabowska E, Eckert K, Fichtner I, et al. Bromelain proteases suppress growth, invasion and lung metastasis of B16F10 mouse melanoma cells. Int J Oncol 1997; 11: 243–8
Targoni OS, Tary-Lehmann M, Lehmann PV. Prevention of mutine EAE by oral hydrolytic enzyme treatment. J Autoimmun 1999; 12: 191–8
Sakalova A, Kunze R, Holomanova D, et al. Density of adhesive proteins after oral administration of proteolytic enzymes in multiple myeloma [in Slovak]. Vnitr Lek 1995; 41: 822–6
Strobel T, Swanson L, Cannistra CA. In vivo inhibition of CD44 limits intra-abdominal spread of a human ovarian cancer xenograft in nude mice: a novel role for CD44 in the process of peritoneal implantation. Cancer Res 1997; 57: 1228–32
Zawadzki V, Perschl A, Rosel M, et al. Blockade of metastasis formation by CD44-receptor globulin. Int J Cancer 1998; 75: 919–24
Zavadová E, Desser L, Mohr T. Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation. Cancer Biother 1995; 10: 147–52
Latha B, Ramakrishnan M, Jayaraman V, et al. The efficacy of trypsin: chymotrypsin preparation in the reduction of oxidative damage during burn injury. Burns 1998; 24: 532–8
Netti C, Bandi GL, Pecile A. Anti-inflammatory action of proteolytic enzymes of animal vegetable or bacterial origin administered orally compared with that of known anti-phlogistic compounds. Farmaco — Edizione Pratica 1972; 27: 453–66
Ito C, Yamaguchi K, Shibutani Y, et al. Anti-inflammatory actions of proteases, bromelain, trypsin and their mixed preparation. Folia Pharmacol Japan 1979; 75: 227–37
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Leipner, J., Saller, R. Systemic Enzyme Therapy in Oncology. Drugs 59, 769–780 (2000). https://doi.org/10.2165/00003495-200059040-00004
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DOI: https://doi.org/10.2165/00003495-200059040-00004