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AVEMAR - anticancer activity of fermented wheat germ extract (selected articles)

Avemar's anti-cancer effects were first demonstrated in animal experimental models which focused on tumour types widely used for the testing of anti-cancer agents, notably cytostatics.
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Cancer Lett. 2007 Jun 8;250(2):323-8.
Saiko P, Ozsvar-Kozma M, Madlener S, Bernhaus A, Lackner A, Grusch M, Horvath Z,
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital

Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human
Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in human HL-60 promyelocytic leukemia cells. After 24, 48, and 72h of incubation, Avemar inhibited the growth of HL-60 cells with IC(50) values of 400, 190, and 160mug/ml, respectively. Incubation with MSC caused dose-dependent induction of apoptosis in up to 85% of tumor cells. In addition, Avemar attenuated the progression from G2-M to G0-G1 phase of the cell cycle and was also found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of de novo DNA synthesis. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.

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Clin Exp Rheumatol. 2006 May-Jun;24(3):325-8.
Balint G, Apathy A, Gaal M, Telekes A, Resetar A, Blazso G, Falkay G, Szende B, Paksy A, Ehrenfeld M, Shoenfeld Y, Hidvegi M.
Fourth Department of Rheumatology, National Institute of Rheumatology and Physiotherapy, Bp.

Effect of Avemar--a fermented wheat germ extract--on rheumatoid arthritis. Preliminary data.
OBJECTIVE: To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA). METHODS: Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used.RESULTS: At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed.CONCLUSION:Supplementation of standard therapies with a continuous administration of Avemar is beneficial for RA patients.
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Ann N Y Acad Sci. 2005 Jun;1051:529-42.
Boros LG, Nichelatti M, Shoenfeld Y.
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

Fermented wheat germ extract (Avemar) in the treatment of cancer and autoimmune diseases.
Avemar, the product of industrial fermentation of wheat germ, possesses unique cancer-fighting characteristics. Taken orally, Avemar can inhibit metastatic tumor dissemination and proliferation during and after chemotherapy, surgery, or radiation. Benefits of Avemar treatment have been shown in various human cancers, in cultures of in vitro grown cancer cells, in the prevention of chemical carcinogenesis, and also in some autoimmune conditions. This document reviews the clinical and experimental results obtained with this extract so far. Special references are made for its safety, including its coadministration with anticancer drugs, as well as for its immunomodulatory activity, its molecular targets, and its use in cancer clinical trials.
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Exp Biol Med (Maywood). 2005 Feb;230(2):144-9.
Illmer C, Madlener S, Horvath Z, Saiko P, Losert A, Herbacek I, Grusch M, Krupitza G, Fritzer-Szekeres M, Szekeres T.
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.

Immunologic and biochemical effects of the fermented wheat germ extract Avemar.
Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to have antitumor effects. Avemar has the potential to significantly improve the survival rate in patients suffering from malignant colon tumors. We studied its effects in the HT-29 human colon carcinoma cell line. Avemar had an inhibiting effect on colonies of HT-29 cells with an IC50 value of 118 microg/ml (7 days of incubation); this value could be decreased to 100 and 75 microg/ml in the presence of vitamin C. In the cell line examined, Avemar induced both necrosis and apoptosis, as demonstrated by Hoechst/propidium iodide staining. The incubation of cells with 3200 microg/ml Avemar for 24 hrs caused necrosis in 28% and the induction of apoptosis in 22% of the cells. Avemar inhibited the cell-cycle progression of HT-29 cells in the G1 phase of the cell cycle. In addition, Avemar inhibited the activity of the key enzyme of de novo DNA synthesis, ribonucleotide reductase. In addition, we determined the effects of Avemar on the activity of cyclooxygenase-1 and -2. Both enzymes were significantly inhibited by Avemar with IC50 values of 100 and 300 microg/ml, respectively. We outline new explanations for its antitumor activity, which might serve as the basis for further studies using Avemar.
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Orv Hetil. 2005 Sep 11;146(37):1925-31.
Farkas E.
Biromedicina Elso Magyar Rakkutatasi Reszvenytarsasag, Budapest.

Fermented wheat germ extract in the supportive therapy of colorectal cancer
The role of the product in the treatment of colorectal cancer is reviewed in the light of experimental and clinical results to date. The fermented wheat germ extract (code name: MSC, trade name: Avemar) registered as a dietary food for special medical purposes for cancer patients to complement the active oncotherapy, exerted a growth inhibitory effect in HCR-25 human colon carcinoma xenograft, and had a synergistic effect with 5-FU in mouse C-38 colorectal carcinoma. The product is capable of chemoprevention of colon carcinoma in F-344 rats. One of the most significant underlying mechanism is a highly cancer cell specific induction of caspase-3 mediated cleavage of PARP. In the frame of supportive therapy, fermented wheat germ extract proved to be efficient in the treatment of colorectal cancer in humans. 30 patients following radical operation were treated with standard postoperative therapy, 12 of them were given fermented wheat germ extract as additive treatment: following a 9 month long administration, no new distant metastases were detected, in contrast to 4 out 18 treated with standard therapy alone. Out of 34 patients following radical surgery and treated with chemotherapy, 17 who were given fermented wheat germ extract, achieved an improved survival rate. In the frame of a controlled multicenter open label cohort study, 170 colorectal cancer patients received anticancer therapies (chemo/radiotherapy) completed with fermented wheat germ extract in 66 of them. Results (fermented wheat germ extract vs. control): new recurrences: 3.0% vs. 17.3% (p < 0.01); new metastases: 7.6% vs. 23.1% (p < 0.01); deaths: 12.1% vs. 31.7% (p < 0.01), progression-related events in total: 16.7% vs. 42.3% (p < 0.001). Survival analysis showed significant improvements in the fermented wheat germ extract group, regarding progression-free (p = 0.0184) and overall survival probabilities (p = 0.0278). Strong predictors of survival determined by Cox's proportional hazards were UICC stage and fermented wheat germ extract treatment. Mild gastrointestinal side effects were observed in 9 cases. Supportive application of fermented wheat germ extract in colorectal cancer is highly recommended.
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Cancer Biother Radiopharm. 2004 Dec;19(6):746-53.
Marcsek Z, Kocsis Z, Jakab M, Szende B, Tompa A.
National Institute of Chemical Safety, "Jozsef Fodor" National Center for Public Health, Budapest, Hungary

The efficacy of tamoxifen in estrogen receptor-positive breast cancer cells is enhanced by a medical nutriment.
Avemar, a fermented wheat germ extract, has been applied in the supplementary therapy of human cancers. Because tamoxifen is commonly used in the therapy of ER+ breast cancer, in this study the combined effect of tamoxifen and Avemar treatment was investigated on MCF-7 breast cancer cells, in order to detect a possible agonistic or antagonistic action. Cytotoxicity was measured by MTT assay, the percentage of mitoses and apoptotic cells was determined morphologically, apoptosis and S-phase was measured by flow cytometry, and estrogen-receptor activity was determined by semiquantitative measurement of the estrogen-responsive pS2 gene mRNA production. Tamoxifen (1 nM) alone had no effect on the percentage of the apoptotic cell fraction and significantly reduced the percentage of the S-phase, compared to untreated cells. Avemar (625 microg/mL) significantly increased apoptosis after 48 hours of treatment. Tamoxifen together with Avemar significantly increased apoptosis already 24 hours after starting treatment but had only a slight (not significant) effect on mitosis and S-phase. Estrogen-receptor activity of MCF-7 cells was enhanced by Avemar, decreased by tamoxifen, and was further decreased by combined tamoxifen and Avemar treatment. As apoptosis increased when Avemar was added to tamoxifen treatment, the use of supplementary therapy with Avemar in the case of ER+ breast tumors may enhance the therapeutic effects of tamoxifen.
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J Pediatr Hematol Oncol. 2004 Oct;26(10):631-5.
Garami M, Schuler D, Babosa M, Borgulya G, Hauser P, Muller J, Paksy A, Szabo E, Hidvegi M, Fekete G.
Second Department of Pediatrics, School of Medicine, Semmelweis University, Budapest, Hungary

Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients.
PURPOSE: An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (Avemar) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. METHODS: Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. RESULTS: During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). CONCLUSIONS: The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.
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Cancer Biother Radiopharm. 2004 Jun;19(3):343-9.
Szende B, Marcsek Z, Kocsis Z, Tompa A.
National Institute of Chemical Safety, Jozsef Fodor National Center for Public Health, 1450 Budapest, Hungary.

Effect of simultaneous administration of Avemar and cytostatic drugs on viability of cell cultures, growth of experimental tumors, and survival tumor-bearing mice.
Avemar, a wheat germ preparation with immunomodulant and antimetastatic activity, was applied simultaneously with cytostatic drugs of different modes of action, in vitro and in vivo, in order to find out whether this simultaneous administration exerts an antagonistic or a synergistic effect on the viability of cell cultures, tumor growth, and survival of animals, inoculated with a transplantable mouse tumor (3LL-HH). In vitro, Avemar did not influence the effect on the viability of MCF-7, HepG2, or Vero cells, exerted by Dacarbazine, 5-fluorouracyl, or Adriblastina. In vivo, Avemar, combined with Endoxan, Navelbine, and doxorubicin, did not prevent the tumor growth inhibitory effect of the cytostatic drugs. The combination of Avemar with the cytostatic drugs did not increase the toxicity of the cytostatic compounds, and did not exert any toxic effect. Avemar may be administered together with cytostatic drugs, without the risk of increasing toxicity or decreasing antiproliferative activity.
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Br J Cancer. 2003 Aug 4;89(3):465-9.
Jakab F, Shoenfeld Y, Balogh A, Nichelatti M, Hoffmann A, Kahan Z, Lapis K, Mayer A, Sapy P, Szentpetery F, Telekes A, Thurzo L, Vagvolgyi A, Hidvegi M.
Department of Surgery and Vascular Surgery, Uzsoki Teaching Hospital of Budapest, Hungary.

A medical nutriment has supportive value in the treatment of colorectal cancer.
MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients' choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, P<0.01; new metastases: 7.6 vs 23.1%, P<0.01; deaths: 12.1 vs 31.7%, P<0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P=0.0184) and overall survivals (P=0.0278) probabilities. Survival predictors in Cox's proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival.
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Int J Oncol. 2002 Mar;20(3):563-70.
Fajka-Boja R, Hidvegi M, Shoenfeld Y, Ion G, Demydenko D, Tomoskozi-Farkas R, Vizler C, Telekes A, Resetar A, Monostori E.
Lymphocyte Signal Transduction Laboratory, Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary.

Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines.
The fermented wheat germ extract (code name: MSC, trade name: Avemar), with standardized benzoquinone content has been shown to inhibit tumor propagation and metastases formation in vivo. The aim of this study was to understand the molecular and cellular mechanisms of the anti-tumor effect of MSC. Therefore, we have designed in vitro model experiments using T and B tumor lymphocytic cell lines. Tyrosine phosphorylation of intracellular proteins and elevation of the intracellular Ca2+ concentration were examined using immunoblotting with anti-phosphotyrosine antibody and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM and FuraRed-AM, respectively. Apoptosis was measured with cytofluorimetry by staining the DNA with propidium iodide and detecting the cell population. The level of the cell surface MHC class I molecules was analysed with indirect immunofluorescence on cytofluorimeter using a monoclonal antibody to the non-polymorphic region of the human MHC class I. MSC stimulated tyrosine phosphorylation of intracellular proteins and the influx of extracellular Ca2+ resulted in elevation of intracellular Ca2+ concentration. Prominent apoptosis of 20-40% was detected upon 24 h of MSC treatment of the cell lines. As a result of the MSC treatment, the amount of the cell surface MHC class I proteins was downregulated by 70-85% compared to the non-stimulated control. MSC did not induce a similar degree of apoptosis in healthy peripheral blood mononuclear cells. Inhibition of the cellular tyrosine phosphatase activity or Ca2+ influx resulted in the opposite effect increasing or diminishing the Avemar induced apoptosis as well as the MHC class I downregulation, respectively. A benzoquinone component (2,6-dimethoxi-p-benzoquinone) in MSC induced similar apoptosis and downregulation of the MHC class I molecules in the tumor T and B cell lines to that of MSC. These results suggest that MSC acts on lymphoid tumor cells by reducing MHC class I expression and selectively promoting apoptosis of tumor cells on a tyrosine phosphorylation and Ca2+ influx dependent way. One of the components in MSC, 2,6-dimethoxi-p-benzoquinone was shown to be an important factor in MSC mediated cell response.
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Pancreas. 2002 Jan;24(1):26-33
Boros LG, Lee WN, Go VL
Harbor-University of California Los Angeles Research and Education Institute, UCLA School of Medicine, Torrance, California 90502, USA

A metabolic hypothesis of cell growth and death in pancreatic cancer.
INTRODUCTION: Tumor cells, just as other living cells, possess the potential for proliferation, differentiation, cell cycle arrest, and apoptosis. There is a specific metabolic phenotype associated with each of these conditions, characterized by the production of both energy and special substrates necessary for the cells to function in that particular state. Unlike that of normal living cells, the metabolic phenotype of tumor cells supports the proliferative state. AIM: To present the metabolic hypothesis that (1) cell transformation and tumor growth are associated with the activation of metabolic enzymes that increase glucose carbon utilization for nucleic acid synthesis, while enzymes of the lipid and amino acid synthesis pathways are activated in tumor growth inhibition, and (2) phosphorylation and allosteric and transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate and sustain cell transformation from one condition to another. CONCLUSION: Evidence is presented that demonstrates opposite changes in metabolic phenotypes induced by TGF-beta, a cell-transforming agent, and tumor growth-inhibiting phytochemicals such as genistein and Avemar, or novel synthetic anti-leukemic drugs such as STI571 (Gleevec). Intermediary metabolic enzymes that mediate the growth signaling pathways and promote malignant cell transformation may serve as high-efficacy nongenetic novel targets for cancer therapies.

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Pancreas 2001 Aug; 23(2): 141-147.
Boros LG, Lapis K, Szende B, Tomoskozi-Farkas R, Balogh A, Boren J, Marin S, Cascante M, Hidvegi M.
UCLA School of Medicine, Harbor-UCLA Research and Education Institute, Torrance, California 90502, USA.

Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells
The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.

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Update Medical Publishing S.A., Athens- Stuttgart Hepato-Gastroenterology 2000;47:393-395
F. Jakab, A. Mayer, A.Hoffmann, M. Hidvegi
First Clinical Data of a Natural Immunomodulator in Colorectal Cancer

Background/Aims: MSC (trade-name AVEMAR) is a per os applicable complex of multiple, biologically active molecules obtained from fermented wheat-germ extract. Preclinical studies suggest potent anti-metastatic activity and it has a favourable toxicity profile. It has been aimed in a pilot-scale, phase II clinical study to document whether or not MSC as a support to surgery or plus chemotherapy adds any therapeutic benefit compared to the same combination without MSC in colorectal cancer. Methodology: From 1998 to June 1999, 18 control patients and 12 consecutive colorectal cancer patients respectively, were enrolled into this study. All patients underwent curative surgery. The control group (18 patients) received no other therapy or adjuvant chemotherapy alone. The MSC group (12 patients) received MSC alone or plus adjuvant chemotherapy. Until now, the median follow-up has been 9 month. Results: Interim data of the study document that the MSC group no new metastases, neither hepatic no other, have occurred, so far. On the contrary, several new metastases have developed in the control group. Conclusion: Orally administered MSC is a potent candidates to be regarded as a supportive therapy to surgery or plus chemotherapy for colorectal canter patient.
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AVEMAR is a natural immunomodulator in colorectal cancer

Clinical data shows that Avemar has an antimetastatic effect
BACKGROUND: AVEMAR is a per os applicable complex of multiple, biologically active molecules obtained from fermented wheat-germ extract. Preclinical studies suggest potent anti-metastatic activity and it has a favorable toxicity profile. It has been aimed in a pilot-scale, phase II clinical study to document whether or not AVEMAR as a support to surgery or plus chemotherapy adds any therapeutic benefit compared to the same combination without MSC in colorectal cancer. METHODOLOGY: From 1998 to June 1999, 18 control patients and 12 consecutive colorectal cancer patients respectively, were enrolled into this study. All patients underwent curative surgery. The control group (18 patients) received no other therapy or adjuvant chemotherapy alone. The AVEMAR group (12 patients) received AVEMAR alone or plus adjuvant chemotherapy. Until now, the median follow-up has been 9 months. RESULTS: Interim data of the study document that in the AVEMAR group no new metastases, neither hepatic nor other, have occurred, so far. On the contrary, several new metastases have developed in the control group. CONCLUSIONS: Orally administered AVEMAR is a potent candidate to be regarded as a supportive therapy to surgery or plus chemotherapy for colorectal cancer patients.
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Immunopharmacology 1999 Apr;41(3):183-186
Hidvegi M, Raso E, Tomoskozi Farkas R, Lapis K, Szende B.
Birochem, Budapest, Hungary.

Effect of MSC on the immune response of mice
The supposed immunostimulatory actions of MSC, a new fermented wheat germ extract standardized to its benzoquinone composition (trade name: AVEMAR) were studied examining blastic transformation of peripheral blood lymphocytes of mice treated with MSC. It was found that MSC significantly increased the degree of blastic transformation caused by Concanavalin A. Using the B10LP to C57Bl skin graft system, MSC (0.03 and 3.0 g kg(-1) applied orally) acted in favour of restoring the immune function. On the other hand, 2,6-dimethoxy-p-benzoquinone (DMBQ), applied in equivalent doses (0.012 and 1.2 mg kg(-l)), did not shorten the rejection time of skin grafts. The immune restoring effect, as well as the blastic transformation enhancing potential of MSC may be exploited in various cases of decreased immune response.
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Hepatogastroenterology 2000 Mar-Apr;47(32):393-5
Jakab F, Mayer A, Hoffmann A, Hidvegi M.
Department of Surgery, Uzsoki Teaching Hospital, Budapest, Hungary.

First clinical data of a natural immunomodulator in colorectal cancer
BACKGROUND/AIMS: MSC (trade-name AVEMAR) is a per os applicable complex of multiple, biologically active molecules obtained from fermented wheat-germ extract. Preclinical studies suggest potent anti-metastatic activity and it has a favorable toxicity profile. It has been aimed in a pilot-scale, phase II clinical study to document whether or not MSC as a support to surgery or plus chemotherapy adds any therapeutic benefit compared to the same combination without MSC in colorectal cancer. METHODOLOGY: From 1998 to June 1999, 18 control patients and 12 consecutive colorectal cancer patients respectively, were enrolled into this study. All patients underwent curative surgery. The control group (18 patients) received no other therapy or adjuvant chemotherapy alone. The MSC group (12 patients) received MSC alone or plus adjuvant chemotherapy. Until now, the median follow-up has been 9 months. RESULTS: Interim data of the study document that in the MSC group no new metastases, neither hepatic nor other, have occurred, so far. On the contrary, several new metastases have developed in the control group. CONCLUSIONS: Orally administered MSC is a potent candidate to be regarded as a supportive therapy to surgery or plus chemotherapy for colorectal cancer patients.
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Cancer Biother Radiopharm 1999 Aug; 14(4):277-289.
Hidvegi M, Raso E, Tomoskozi-Farkas R, Szende B, Paku S, Pronai L, Bocsi J, Lapis K.
1st Institute of Pathology and Experimental Cancer Research, Semmelweis Medical University, Budapest.

MSC, a new benzoquinone-containing natural product with antimetastatic effect
An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) has been invented by Hungarian chemists under the trade name of AVEMAR. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes in mice. The same treatment shortens the survival time of skin grafts in a co-isogenic mouse skin transplantation model, pointing to the immune-reconstructive effect of MSC. A highly significant antimetastatic effect of MSC has been observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic effect of MSC--besides the immune-reconstitution--may also be due to its cell adhesion inhibitory, cell proliferation inhibitory, apoptosis enhancing, and antioxidant characteristics, also observed in our in vitro experiments. It is even more noteworthy that combined treatment with MSC and one of the following antineoplastic agents (5-FU and DTIC)--both in wide use in every day clinical practice--exhibited a significantly enhanced antimetastatic effect in appropriate metastasis models (established from C38 mouse colon carcinoma and B16 mouse melanoma respectively) as compared to the effect elicited by any component of these therapeutic compositions (MSC + 5-FU and MSC + DTIC) administered alone. The results show that the fermented wheat germ extract (MSC) has more than an additive effect and synergistically enhanced the metastasis inhibitory effect of both antineoplastic agents studied till now. It is also worthy of mention that the synchronous treatment with MSC profoundly decreased the toxic side effects of the applied antineoplastic agents (decreased weight loss etc). Based on the biological effects of MSC--shown to be non-toxic by subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immune-deficiency.
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Birochem Ltd., Budapest, Hungary.
Hidvegi M, Raso E, Tomoskozi-Farkas R, Paku S, Lapis K, Szende B.
Anticancer Res 1998 Jul-Aug;18(4A):2353-8

Effect of AVEMAR and AVEMAR + vitamin C on tumor growth and metastasis in experimental animals
Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (AVEMAR) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with AVEMAR and vitamin C--administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with AVEMAR alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with AVEMAR and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of AVEMAR. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with AVEMAR alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if AVEMAR was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with AVEMAR and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--AVEMAR proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of AVEMAR and AVEMAR plus vitamin C are also discussed.
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Anticancer research 18:2353-2358 (1998)
Mate Hidvegi, Erzsebet Raso, Rita Tomoskozi-Farkas, Sandor Raku, Karol Lapis, Bela Szende
Hungary and Department of Biochemistry and Food Technology, Budapest Technical Univeristy; First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine; Budapest, Hungary

Effect of Avemar and Avermar + Vitamin C on Tumor Growth and Metastasis in Experimental Animals
We have investigated the effect of Avemar on liver colony formation from 3LL-HH cells implanted into the spleen of immunocompetent C57B1/6 mice and from human colon carcinoma xenograft (HCR 25) implanted into the spleen of immunosuppressed CBA/CA mice. In the 3LL-HH spleen-liver model Avemar + Vitamin C significantly reduced the number of metastases in the group treated continuously after inoculation of 3 x 10 cells. A slight decrease in the metastasis number was also observed in the couprs inoculated with lower number of tumor cells or treated with Avemar+ Vitamin C prior to tumor inoculation. Increasingly, where the inhibition of metastasis formation was the highest the primary tumor weight increased . To test the effect of Avemar on the growth and metastatization of human cancer, human colon carcinoma tutor line (HRC25) established in our laboratory was used. Growith of the primary splenic tumor was markedly inhibited, that was paralleled by significant reduction of number of liver metastases. Compared to the grontrol group the treatment also cause deduction of the side of liver colonies. Removal of the primary tumor resulted in lower number of metastases in the control group. That was further reduced by treating the mice with Avemar. Using the B16 melanoma tumor line (muscle-ling model), in the first experiment the mice were treated after tumor inoculation in the presence of primary tumor (Table III). Marked inhibition of metastasis formation in the lung was observed in the group treated with Avemar alone. The inhibition was 85% in the Avemar treated group, whereas vitamin C alone had no effect. Avemar + vitamin C treatment also caused a slight reduction in the primacy tumor weight. Interestingly, no inhibition of metastasis formation was observed at an other model where the primary tumor was removed 10 days after tumor inoculation. Wilms’ tumor is one of the most frequent childhood tumors. It’s transplantable rat analog, developed by some of us, is able to produce lung metastases when transplanted under the renal capsule. Avemar +vitamin C showed a strong inhibitory effect on the primary tumor C showed a strong inhibitory effect n the primary tumor growth as well as on the formation of lung metasteses. Primary tumor weight and the number of metastases decreased even more significantly when Avemar + vitamin C was administered in a diluted form. Interestingly, Avemar alone was ineffective in this model, whereas vitamin C reduced both primary tumor weight and the number of metastases.
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8th European Congress on Biotechnology
Rita Tomoskozi-Farkas, Mate Hidvegi
Budapest, Hungary, 17-21 August 1997

OPTIMIZATION OF CEREAL GERM FERMENTATION
One of the most important problems of cancer therapy is preventing metastasis. In the last few years researchers have been devoting more attention to immunostimulants and drugs of natural origin. Albert Szent-Gyorgyi worked on compound - 2,6-dimethoxy-p-benzoquinone (2,6-DMBQ) and 2-methoxy-benzoquinone (2MBQ) - which have anticancer and bacteriostatic effect as well. The aim of our work is to produce a drug of natural origin rich in 2-MBQ and 2,6-DMBQ which may suitable for in vivo experiments. By the reason of our previous studies we tried to increase the concentration of 2-MBQ and 2,6-DMBQ in wheat germ by yeast fermentation. To reach the optimal parameters of fermentation we used factorial design method. The simultaneous effect of reaction parameters and component concentrations on the 2,6-DMBQ formation was investigated.For the determination of the optimal 2,6-DMBQ formation the fermentation time was varied between 5 and 24 hours. The temperature range used was 25- 35 oC. The substrate - yeast ratio, the dried material - water ratio were varied between 1.5-3.5 and 5-10. We examined the effect of defatting of wheat germ, the intensity of mixing and light.
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Patologiai es Kiserleti Rakkutato Intezet, Semmelweis Orvostudomanyi Egyetem, Budapest.
Szende B, Raso E, Hidvegi M, Tomoskozine FR, Paku S, Pronai L, Bocsi J, Lapis K. I.
Orv Hetil. 1998 Nov 29;139 (48):2893-7.

A new benzoquinone-containing antimetastatic product
An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) was invented by Hungarian chemists under the trade--name of AVEMAR. The following biological effects of this product were observed. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes of mice. The same treatment shortens the survival time of skin grafts in co-isogenic mouse skin transplantation model, which points to immune-reconstructive effect of MSC. Highly significant anti-metastatic effect of MSC was observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic activity of MSC--besides the immune reconstitution--may also due to the cell-adhesion inhibitory, cell proliferation inhibitory, apoptosis-enhancing and antioxidant effects, which were also observed in our in vitro experiments. Based on the biological effects of MSC--which is non-toxic, according to subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immunedeprivation.

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seabuckthorn, seabuckthorn oil, sea-buckthorn, seabuckthorn oil