Organotherapy Articles 11

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Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction
            (Beuth, 2008) Download
Systemic enzyme therapy was recently subjected to experimental investigations and to rigorous clinical studies in cancer patients. The designs of the relevant clinical cohort studies followed the guidelines of Good Epidemiological Practice and represent level IIB in evidence-based medicine (EBM). Scientifically sound experimental in vitro and in vivo investigations are far advanced and document promising immunological, anti-inflammatory, anti-infectious, and antitumor/antimetastatic activities of proteolytic enzyme mixtures (containing trypsin, chymotrypsin, and papain) or bromelain. EBM level II clinical studies, which are accepted by the European Union to show safety and efficacy of medical treatments, were performed to evaluate the benefit of complementary systemic enzyme therapy in cancer patients suffering from breast and colorectal cancers and plasmacytoma. These studies demonstrated that systemic enzyme therapy significantly decreased tumor-induced and therapy-induced side effects and complaints such as nausea, gastrointestinal complaints, fatigue, weight loss, and restlessness and obviously stabilized the quality of life. For plasmacytoma patients, complementary systemic enzyme therapy was shown to increase the response rates, the duration of remissions, and the overall survival times. These promising data resulted in an "orphan drug status" designation for a systemic enzyme product, which should motivate further studies on this complementary treatment.

Enzymes and cancer: a look toward the past as we move forward.
            (Block, 2008) Download
Several years ago, I was having lunch with a prominent German medical oncologist at a conference on cancer and CAM at the National Institutes of Health (NIH) in Washington, DC. I asked him what the most exciting thing in cancer CAM in Europe was at that time. “Enzymes,” he said. A bit surprised by his instantaneous response, I asked him what the second most exciting thing was. Again with no hesitation he blurted out, “More enzymes!”


 

Apoptotic effect of thymus extract plus Lactobacillus kefiri P-IF on human myeloid leukemia (HL60/AR) cancer cells.
            (Ghoneum et al., 2013) Download
We have recently reported the susceptibility of human Multidrug-Resistant (MDR) myeloid leukemia (HL60/AR) cells to the apoptotic effect of L. kefiri P-IF, a freeze-dried form of heat-killed Lactobacillus kefiri. In this study, we evaluated the synergizing apoptotic effects of L. kefiri P-IF in the presence of Thymax, a gross thymic extract, on HL60/AR cells. To identify any synergistic effect of these two agents, tumor cells were cultured for three days with 0.6-5.0 mg/ ml L. kefiri P-IF alone, 0.6-5.0 mg/ml Thymax alone, or a combination of both agents. The apoptotic response was assessed using a propidium iodide assay. The expression of Bcl-2, an anti-apoptotic protein, was determined by flow cytometry. Results showed that L. kefiri P-IF and Thymax induced apoptosis in HL60/AR cells in a dose dependent manner that was detected at 0.6 mg/mL and maximized at 5 mg/mL. However, treatment by L. kefiri P-IFplus Thymax synergistically induced higher levels of apoptosis in cancer cells that exceeds the effect of either agent alone. The synergistic apoptotic effect was associated with decreased expression of Bcl-2. This combination may represent a new class of adjuvant for the treatment of myeloid leukemia.

The history of the enzyme treatment of cancer.
            (Gonzalez, 2014) Download
Athough there exists some debate over who discovered pancreatic enzymes, it appears the French physician Lucien Corvisart first described trypsin in 1856. However, the German researcher Julius Kühne deserves credit for actually naming this protease in 1876 and for introducing the concept of digestive enzymes as catalysts secreted by the pancreas that allow for efficient breakdown of food in the gastrointestinal (GI) tract.

Proenzyme therapy of cancer.
            (Novak and Trnka, 2005) Download
Proteases and their inhibitors have long been investigated in numerous tumor systems, and at the tumor growing front, their balance has been universally found to be shifted towards higher proteolytic activities. However, out of many promising serine and metalloproteinase inhibitors, none are included in cancer treatment regimens at present. The current search for active antiproteolytic compounds is in contrast to the classical approach developed by John Beard, who suggested treating advanced cancer by fresh pancreatic extracts whose antitumor activity was based on their proteolytic potential. We followed John Beard's recommendations by using purified pancreatic proenzymes/enzymes, trypsinogen/trypsin (TG/TR), chymotrypsinogen/chymotrypsin (CG/CH) and amylase (AM). The mixture of these enzymatic activities produces potent antimetastatic and antitumor effects in cellular, animal and human systems. The treatment of cultured tumor cells with TR and CH at nanomolar [corrected] concentrations, comparable to those achieved in the blood of the patients, causes complete arrest of the directional movement of metastatic cells. Conversely, the same treatment of normal cells results in enhanced motility and an accelerated closure of the gap created in cell monolayers. Further, treatment of cells with serine proteases results in the formation of cellular 3-dimensional structures such as lamellae, cell streams and aggregates. In some cell types, the aggregates are compacted via cadherin-based cell-cell communication systems and form compact spheroids. In the highly metastatic cells with lower cadherin expression, the ability to form spheroids also diminishes. Tumor cells unable to form spheroids when treated with proteases are subject to elimination by apoptosis. In contrast, a large proportion of cells that form spheroids remain viable, although they are metabolically suppressed. Protease-treated tumor cells contain a disrupted actin cytoskeleton and exhibit a loss of front-to-back polarity. We hypothesize that the provision of zymogens, rather than the enzymes, was of crucial importance to the clinical effectiveness in the human trials conducted by Beard and his co-workers. The precursor nature of the active enzymes may offer protection against numerous serpins present in the tissues and blood. Experimental evidence supports the assertion that the conversion from proenzyme to enzyme occurs selectively on the surface of the tumor cells, but not on normal cells. We believe that this selectivity of activation is responsible for the antitumor/antimetastatic effect of proenzyme therapy and low toxicity to normal cells or tumor host. Elevated levels of endostatin and angiostatin appear in the blood of TG/CG/AM-treated tumor-bearing mice, but not in tumor mice treated with the vehicle alone or in proenzyme-treated tumor-free mice. These findings support the conclusion that proteolysis is the active mechanism of the proenzyme treatment. Future studies will focus on the molecular mechanisms of the proenzyme therapy including the identification of molecular target(s) on the tumor cells. In conclusion, we have discovered that proenzyme therapy, mandated first by John Beard nearly one hundred years ago, shows remarkable selective effects that result in growth inhibition of tumor cells with metastatic potential.


 

History and mechanisms of oral tolerance.
            (Rezende and Weiner, 2017) Download
Since its first description by Wells and Osbourne in 1911, oral tolerance has intrigued researchers due to its potential for therapeutic applications. Oral tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the oral route. Tolerance induction to commensal bacteria and dietary proteins represents the major immunological event taking place in the gut in physiological conditions. Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens: low doses of orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor clonal anergy/deletion. In this review, we highlight historical aspects and the mechanisms proposed for oral tolerance induction.

 


References

Beuth, J (2008), ‘Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction’, Integr Cancer Ther, 7 (4), 311-16. PubMed: 19116226
Block, KI (2008), ‘Enzymes and cancer: a look toward the past as we move forward.’, Integr Cancer Ther, 7 (4), 223-25. PubMed: 19116218
Ghoneum, M, M Henary, and Y Seto (2013), ‘Apoptotic effect of thymus extract plus Lactobacillus kefiri P-IF on human myeloid leukemia (HL60/AR) cancer cells.’, PubMed:
Gonzalez, NJ (2014), ‘The history of the enzyme treatment of cancer.’, Altern Ther Health Med, 20 Suppl 2 30-44. PubMed: 25362215
Novak, JF and F Trnka (2005), ‘Proenzyme therapy of cancer.’, Anticancer Res, 25 (2A), 1157-77. PubMed: 15868959
Rezende, RM and HL Weiner (2017), ‘History and mechanisms of oral tolerance.’, Semin Immunol, 30 3-11. PubMed: 28774470