Arginine deiminase produced by lactic acid bacteria as a potent anti-cancer drug.

Bacterial-based cancer immunotherapy has recently gained widespread attention due to its exceptional mechanism of rich pathogen-associated molecular patterns in anti-cancer immune responses. Contrary to conventional cancer therapies such as surgery, chemotherapy, radiation and phototherapy, bacteria-based cancer immunotherapy has the unique ability to suppress cancer by selectively accumulating and growing in tumours. In the view of this, several bacterial strains are being used for the treatment of cancer. Of which, lactic acid bacteria are a powerful, albeit still inadequately understood bacteria that possess a wide source of bioactive chemicals. Lactic acid bacteria metabolites, such as bacteriocins, short-chain fatty acids, exopolysaccharides show antitumour property. Amino acid pathways, which have lately been focussed as a new strategy to cancer therapy, are key element of the adaptability and dysregulation of metabolic pathways identified in proliferation of tumour cells. Arginine metabolism, in particular, has been shown to be critical for cancer therapy. As a result, better understanding of arginine metabolism in LAB and cancer cells could lead to new cancer therapeutic targets. This review will outline current advances in the interaction of arginine metabolism with cancer therapy and propose an arginine deiminase expression system to combat cancer more effectively.

Arginine metabolism and deprivation in cancer therapy.

Certain cancer cells with nutrient auxotrophy and have a much higher nutrient demand compared with normal human cells. Arginine as a versatile amino acid, has multiple biological functions in metabolic and signaling pathways. Depletion of this amino acid by arginine depletor is generally well tolerated and has become a targeted therapy for arginine auxotrophic cancers. However, the modulatory eff ;ect of arginine on cancer cells is very complicated and still controversial. Therefore, this article focuses on arginine metabolism and depletion therapy in cancer treatment to provide systemical review on this issue.

Development of Phage Lysins as Novel Therapeutics: A Historical Perspective.

Bacteriophage lysins and related bacteriolytic enzymes are now considered among the top antibiotic alternatives for solving the mounting resistance problem. Over the past 17 years, lysins have been widely developed against Gram-positive and recently Gram-negative pathogens, and successfully tested in a variety of animal models to demonstrate their efficacy. A lysin (CF-301) directed to methicillin resistant Staphylococcus aureus (MRSA) has effectively completed phase 1 human clinical trials, showing safety in this novel therapeutic class. To validate efficacy, CF-301 is currently the first lysin to enter phase 2 human trials to treat hospitalized patients with MRSA bacteremia or endocarditis. If successful, it could be the defining moment leading to the acceptance of lysins as an alternative to small molecule antibiotics. This article is a detailed account of events leading to the first therapeutic use and ultimate development of phage-encoded lysins as novel anti-infectives.

[Local immune and oxidative status in exacerbated chronic apical periodontitis]. / Mestnyi immunnyi i oksidantnyi status pri khronicheskom periodontite v stadii obostreniia.

The aim of the study was to define local immune and oxidative changes in patients with exacerbated chronic apical periodontitis. These changes were assessed in saliva of 67 patients with the mean age of 31±2.5 before and after treatment. The study revealed disturbances in cytokines and complement system balance and activation of lipids peroxidation. Combination of Gepon or Vobenzim with Essentiale forte H and Kaskatol proved to be the most effective for correction of this imbalance.

Molecular basis and current strategies of therapeutic arginine depletion for cancer.

Renewed interest in the use of therapeutic enzymes combined with an improved knowledge of cancer cell metabolism, has led to the translation of several arginine depletion strategies into early phase clinical trials. Arginine auxotrophic tumors are reliant on extracellular arginine, due to the downregulation of arginosuccinate synthetase or ornithine transcarbamylase-key enzymes for intracellular arginine recycling. Engineered arginine catabolic enzymes such as recombinant human arginase (rh-Arg1-PEG) and arginine deiminase (ADI-PEG) have demonstrated cytotoxicity against arginine auxotrophic tumors. In this review, we discuss the molecular events triggered by extracellular arginine depletion that contribute to tumor cell death.

In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts.

Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic.

[Lymphedema: clinic-therapeutic aspect].

Lymphedema may be presented in mild or less severe form. Nowadays, accurate diagnosis and effective therapy are available. Wearing surgical bandage, massage, exercise, and pumps form the core program for most patients with lymphedema. The application of pharmacological therapies has been notably absent from the management strategies for lymphatic vascular insufficiency states but lately some progress has been made by applying wobenzym in the treatment. Surgical approaches to improve lymphatic flow through vascular anastamosis have been, in large part, unsuccessful, but controlled liposuction affords lasting benefit in selected patients.

[Prophylaxis and prognosis of preeclampsia in patients with chronic pyelonephritis and chronic glomerulonephritis].

The investigations performed showed that pregnant women with chronic pyelonephritis (CP) and chronic glomerulonephritis (CG) have certain response to therapy done in accordance with level of kidney function activity. In the pregnant women with CP and CG and kidney functional reserve KFR > 10% and from 5 to 10% the treatment efficacy was higher and practically absent in pregnant women with KFR < 5%.

Enzymes, trophoblasts, and cancer: the afterlife of an idea (1924-2008).

In the early 20th century, advocacy of the enzyme therapy of cancer was primarily the work of one man, John Beard, DSc (1858-1924). He and his collaborators made a determined effort to establish this mode of therapy, especially in the years 1905 to 1911. Despite a brief flowering of international interest, Beard's efforts came to naught. During the 20th century, there was a succession of American researchers who continued to investigate this topic. This included Marshall William McDuffie, MD (1882-1945), Frank LeForest Morse, MD (1876-1953), Franklin Lloyd Shively, MD (1887-1971), and William Donald Kelley (1926-2005). In central Europe, India, and other parts of the globe, the use of pancreatic enzymes as an adjuvant treatment for cancer has become a fairly routine practice, at least among those doctors who utilize complementary and alternative medicine (CAM). It is also a well-established method for reducing inflammation and mitigating the adverse effects of cytotoxic treatment.

Where do the immunostimulatory effects of oral proteolytic enzymes ('systemic enzyme therapy') come from? Microbial proteolysis as a possible starting point.

Enteric-coated proteolytic enzyme preparations like Wobenzym and Phlogenzym are widely used for the so-called 'systemic enzyme therapy' both in humans and animals. Numerous publications reveal that oral proteolytic enzymes are able to stimulate directly the activity of immune competent cells as well as to increase efficiency of some of their products. But origins of the immunostimulatory effects of oral proteolytic enzymes are still unclear. The hypothesis described here suggests that it may be proteolysis of intestinal microorganisms that makes the immune competent cells to work in the immunostimulatory manner. The hypothesis was largely formed by several scientific observations: First, microbial lysis products (lipopolysaccharides, muropeptides and other peptidoglycan fragments, beta-glucans, etc.) are well known for their immunostimulatory action. Second, a normal human being hosts a mass of intestinal microorganisms equivalent to about 1 kg. The biomass (mainly due to naturally occurring autolysis) continuously supplies the host's organism with immunostimulatory microbial cell components. Third, the immunostimulatory effects resulting from the oral application of exogenously acting antimicrobial (lytic) enzyme preparations, such as lysozyme and lysosubtilin, are likely to be a result of the action of microbial lysis products. Fourth, cell walls of most microorganisms contain a considerable amount of proteins/peptides, a possible target for exogenous proteolytic enzymes. In fact, several authors have already shown that a number of proteases possess an ability to lyse the microbial cells in vitro. Fifth, the pretreatment of microbial cells (at least of some species) in vitro with proteolytic enzymes makes them more sensitive to the lytic action of lysozyme and, otherwise, pretreatment with lysozyme makes them more susceptible to proteolytic degradation. Sixth, exogenous proteases, when in the intestines, may participate in final steps of food-protein digestion. The resulting food-borne peptides have recently been shown to be potential activators of microbial autolysis. The main question that needs to be answered in order to verify the hypothesis is whether oral proteases are able (and to what extent) to lyse/mediate lysis of intestinal microorganisms in situ. Methods based on up-to-date molecular biology techniques to allow investigation of the influence of exogenous proteases on microbial lysis processes in vivo (in the intestines) need to be developed. Research testing of this hypothesis may have an important impact in development of novel preparations for the systemic enzyme therapy.

Unresponsive or non-compliant steatorrhea in cystic fibrosis?

In 105 pancreatic insufficient CF patients (steatorrhea and low fecal elastase-1 concentrations), the effectiveness of pancreatic enzyme therapy (PET) has been assessed (fecal fat losses and coefficient of fat reabsorption). Eight unresponsive subjects were checked for PET compliance with fecal chymotrypsin assay. Three patients were documented to be non-compliant. Unresponsive patients should undergo evaluation for PET compliance.

Cystic fibrosis: nutritional consequences and management.

Life expectancy for patients with Cystic Fibrosis (CF) has steadily improved during the last three decades, and death in childhood is now uncommon. Nutrition is a critical component of the management of CF, and nutritional status is directly associated with both pulmonary status and survival. Expert dietetic care is necessary, and attention must be given to ensuring an adequate energy intake in the face of demands which may be increased by inadequately controlled malabsorption, chronic broncho-pulmonary colonisation by bacteria and fungi, exacerbations of acute lung infection, impaired lung function, and the need for rehabilitation, repair and growth. Pancreatic enzyme replacement therapy (PERT) is needed by up to 90% of CF patients in Northern Europe, where the 'severe' mutation deltaF508 predominates, but a smaller proportion in Mediterranean countries and elsewhere, because pancreatic insufficiency is one of few features of CF which correlate with genotype. Complications of CF including liver disease and CF-related diabetes pose further challenges. In addition, deficiency of specific nutrients including fat soluble vitamins (particularly A, E and K) essential fatty acids and occasionally minerals occur for a variety of reasons. Osteopenia is common and poorly understood. Liver disease increases the likelihood of vitamin D deficiency. Glucose intolerance and diabetes affect at least 25% of CF adults, and the diabetes differs from both types 1 and 2 diabetes mellitus, but it inversely correlates with prognosis. Management consists of anticipating problems and addressing them vigorously as soon as they appear. Supplements of vitamins are routinely given. Energy supplements can be oral, enteral or, rarely, parenteral. All supplements, including PERT, are adjusted to individual needs.

Drug evaluation: ADI-PEG-20--a PEGylated arginine deiminase for arginine-auxotrophic cancers.

Pheonix is developing ADI-PEG-20, a PEGylated arginine deiminase for the potential treatment of hepatocellular carcinoma, for which the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products have granted the drug Orphan Drug status, and melanoma, for which the FDA has also awarded ADI-PEG-20 Orphan Drug status. ADI-PEG-20 is also being investigated for the potential treatment of influenza virus infection and hepatitis C virus infection.

[Proteolytic enzymes as an alternative in comparison with nonsteroidal anti-inflammatory drugs (NSAID) in the treatment of degenerative and inflammatory rheumatic disease: systematic review]. / Proteolytische Enzyme als therapeutische Alternative zu nichtsteroidalen Antirheumatika (NSAR) in der antiphlogistischen Therapie degenerativer und entzündlich-rheumatischer Erkrankungen. Systematischer Review.

BACKGROUND AND PURPOSE: The comparably high number of severe side effects due to treatment with nonsteroidal anti-inflammatory drugs (NSAID) calls for better tolerated substances. One possible alternative is seen in the systemic treatment with proteolytic enzyme preparations for oral administration. The aim of this study was to determine whether the results from controlled randomized trials on enzyme therapy prove equal anti-inflammatory effectiveness compared to NSAID in the treatment of degenerative or inflammatory rheumatic disease. METHODS: All drug preparations registered in Germany as having anti-inflammatory properties were listed. Among these preparations, a systematic search was carried out for randomized clinical therapeutic trials giving evidence for the anti-inflammatory effectiveness of enzyme preparations or their components. RESULTS: The anti-inflammatory effectiveness of three out of eight registered enzyme preparations was investigated in randomized trials. In total, seven trials were judged to be sufficiently documented and to allow valuation. All studies show severe methodical deficits, and the standard trial design (clinical trials during inpatient rehabilitation in combination with extensive accompanying treatment) does not allow clear-cut conclusions. CONCLUSION: According to the present state of knowledge, oral proteolytic enzyme treatment does not offer a justified alternative in comparison with NSAID in the anti-inflammatory treatment of rheumatic disease.

[Systemic enzymotherapy as a method of prophylaxis of postradiation complications in oncological patients]. / Systemna enzymoterapiia iak metod profilaktyky promenevykh uskladnen' u khvorykh na onkolohichni zakhvoriuvannia.

Set out in the paper are results of treatment of those patients with carcinoma of the lung, uterine cervix, hysterocarcinoma, breast cancer, malignant thymomas, malignant non-Hodgkin's lymphomas, and lymphogranulematosis having been administered combined, chemoradiation or radiation treatments against the background of a complex of accompanying therapy involving systemic enzymotherapy. Polyenzymic drugs were found to be capable of improving results of treatment of acute radiation reactions and preventing postradiation fibrous changes in the lungs, skin, fatty tissue, soft tissue, liver, kidneys. Thus, systemic enzymotherapy is capable of improving the quality of life and results of treatment of oncological patients.

[The adaptational properties and immunoregulatory action of a preparation of proteolytic enzymes in experimental stress]. / Adaptatsionnye svoistva i immunoreguliatornoe deistvie preparata proteoliticheskikh fermentov pri éksperimental'nom stresse.

The use of the experimental model of the development of acute secondary immunodeficiency, accompanied by the redistribution of immunoglobulins from plasma to blood cells, for evaluating the effect of immunomodulation is substantiated. The preparation of proteolytic enzymes Wobenzym [correction of "Vobenzyme"] has been shown to produce significant and dose-dependent decrease the sorption of immunoglobulins on mouse cells in the process of swimming.