Skip to main content
SpringerLink
Log in

Systemic Enzyme Therapy in Oncology

Effect and Mode of Action

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Vanhoof G, Cooreman W. Bromelain. In: Lauwers A, Scharpé S, editors. Pharmaceutical enzymes. New York: Marcel Dekker, 1997: 131–53

    Google Scholar 

  2. De Feo V. Medicinal and magical plants in the northern Peruvian Andes. Fitoterapia 1992; 53: 417–40

    Google Scholar 

  3. Rawlings ND, Barrett AJ. Evolutionary families of peptidases. Biochem J 1993; 290: 205–18

    PubMed  CAS  Google Scholar 

  4. Rowan AD, Buttle DJ, Barrett AJ. The cysteine proteinases of the pineapple plant. Biochem J 1990; 266: 869–75

    PubMed  CAS  Google Scholar 

  5. 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

    Article  PubMed  CAS  Google Scholar 

  6. Wrbka E, Kodras B. Unterstutzung der Chemotherapie inoperabler bronchopulmonaler Karzinome durch proteolytische Fermente. Wien Med Wochenschr 1978; 128: 153–8

    PubMed  CAS  Google Scholar 

  7. 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)]

  8. 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

    Google Scholar 

  9. 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

    PubMed  CAS  Google Scholar 

  10. 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

    Google Scholar 

  11. 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)

    Google Scholar 

  12. 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

    Article  PubMed  CAS  Google Scholar 

  13. 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

    Article  PubMed  CAS  Google Scholar 

  14. Kesztele V, Hürbe E, Wischin W. Erfahrung mit proteolytischen Enzymen beim Bronchuskarzinom. Wien Med Wochenschr 1976; 25-27: 412–4

    Google Scholar 

  15. Beaufort F. Reduzierung von Strahlennebenwirkungen durch hydrolytische enzyme. Therapeutikon 1990; 4: 577–80

    Google Scholar 

  16. 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

    Chapter  Google Scholar 

  17. 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)

  18. 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)

  19. 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

    Article  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. 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

    CAS  Google Scholar 

  22. Stauder G, Pollinger W, Fruth C. Systemic enzyme therapy: an overview of new clinical studies [German]. Allgemeinmedizin 1990; 19: 188–91

    Google Scholar 

  23. Gettins P, Patston PA, Olson ST. Serpins: structure, function and biology. Heidelberg: Springer-Verlag, 1996

    Google Scholar 

  24. 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

    PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. Kennedy AR. Chemopreventive agents: protease inhibitors. Pharmacol Ther 1998; 78: 167–209

    Article  PubMed  CAS  Google Scholar 

  27. Pemberton PA. The role of serpin superfamily members in cancer. Cancer J 1997; 10: 24–30

    CAS  Google Scholar 

  28. 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

    PubMed  CAS  Google Scholar 

  29. 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

    Article  PubMed  CAS  Google Scholar 

  30. Lah TT, Kos J. Cyteine proteinases in cancer progression and their clinical relevance for prognosis. Biol Chem 1998; 379: 125–30

    PubMed  CAS  Google Scholar 

  31. Verspaget HW. Proteases as prognostic markers in cancer. BMJ 1998; 316: 790–1

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  CAS  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

  36. 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

    PubMed  CAS  Google Scholar 

  37. 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

    CAS  Google Scholar 

  38. 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

    CAS  Google Scholar 

  39. Baenkler H-W. Medizinische Immunologie: Grundlagen, Diagnostik, Klinik, Therapie, Prophylaxe, Sonderbereiche. Landsberg am Lech, Germany: Ecomed, 1995

    Google Scholar 

  40. 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

    Article  PubMed  CAS  Google Scholar 

  41. Barrett AJ. α2-Macroglobulin. Methods Enzymol 1981; 80: 737–54

    Article  PubMed  CAS  Google Scholar 

  42. James K. Interactions between cytokines and α2-macroglobulin. Immunol Today 1990; 11: 163–6

    Article  PubMed  CAS  Google Scholar 

  43. Borth W. α2-Macroglobulin, a multifunctional binding protein with targeting characteristics. FASEB J 1992; 6: 3345–53

    PubMed  CAS  Google Scholar 

  44. 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

    Article  PubMed  CAS  Google Scholar 

  45. 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

    PubMed  CAS  Google Scholar 

  46. 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

    CAS  Google Scholar 

  47. 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

    PubMed  CAS  Google Scholar 

  48. Targoni OS, Tary-Lehmann M, Lehmann PV. Prevention of mutine EAE by oral hydrolytic enzyme treatment. J Autoimmun 1999; 12: 191–8

    Article  PubMed  CAS  Google Scholar 

  49. 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

    PubMed  CAS  Google Scholar 

  50. 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

    PubMed  CAS  Google Scholar 

  51. Zawadzki V, Perschl A, Rosel M, et al. Blockade of metastasis formation by CD44-receptor globulin. Int J Cancer 1998; 75: 919–24

    Article  PubMed  CAS  Google Scholar 

  52. 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

    Article  PubMed  Google Scholar 

  53. 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

    Article  PubMed  CAS  Google Scholar 

  54. 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

    PubMed  CAS  Google Scholar 

  55. 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

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Natural Medicine, Department of Internal Medicine, University Hospital Zurich, Zurich, CH-8091, Switzerland

    Jörg Leipner & Reinhard Saller

Authors
  1. Jörg Leipner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reinhard Saller
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leipner, J., Saller, R. Systemic Enzyme Therapy in Oncology. Drugs 59, 769–780 (2000). https://doi.org/10.2165/00003495-200059040-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200059040-00004

Keywords

Search

Navigation