Third Party Articles Describing Fermented Wheat Germ Extract Research

FWGE stands for Fermented Wheat Germ Extract and is the generic term for standardized extract manufactured by the fermentation of wheat germ by bakers’s yeast, also referred to as “MSC” in some studies and by the trade name Avemar®, registered trademark of Ariza Korlátolt Felelősségű Társaság, Hungary.

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1. Human (Clinical Trials) | 2. Review Articles | 3. In Vivo (Animal Studies) | 4. In vitro (Cell Line Studies)

A. Wright, KM, Is it Really From Heaven Above, Health Sciences Institute, December 2005
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B. Pelletier, M, Unplugging Cancer’s Power Supply, Anti-Aging Medical News, Summer, 2008
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C. Avemar – Frequently Asked Questions
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Avemar® Research Publications:
Listing of publications describing human clinical trials, in vitro and in vivo research with Avemar, fermented wheat germ extract, as of October 2008 – in publication date order by category.


1. Human (Clinical Trials)

a) Demidov LV, Manziuk LV, Kharkevitch GY, Pirogova NA, Artamonova EV, Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients: a randomized, pilot, phase II clinical study with a 7-year follow-up, Cancer Biother Radiopharm. 2008 Aug;23(4):477-82.
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OBJECTIVE: The fermented wheat germ extract (FWGE) nutraceutical (Avemar), manufactured under “good manufacturing practice” conditions and, fulfilling the self-affirmed “generally recognized as safe” status in the United States, has been approved as a “dietary food for special medical purposes for cancer patients” in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients. METHODS: In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE. RESULTS: At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p = 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p = 0.0298. CONCLUSIONS: The inclusion of Avemar into the adjuvant protocols of high-risk skin melanoma patients is highly recommended.

b) Sukkar SG, Cella F, Rovera GM, Nichelatti M, Ragni G, Chiavenna G, Giannoni A, Ronzani G, Ferrari C. A multicentric prospective open trial on the quality of life and oxidative stress in patients affected by advanced head and neck cancer treated with a new benzoquinone-rich product derived from fermented wheat germ (Avemar), Mediterr J Nutr Metab (2008).
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Abstract Background and aim: Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name Avemar) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of Avemar in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods: A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with Avemar in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the Avemar group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results: The levels of OS significantly decreased after 2 months in the group receiving Avemar (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in Avemar has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer.

c) Barabás J, Németh Z., Recommendation of the Hungarian Society for Face, Mandible and Oral Surgery in the indication of supportive therapy with Avemar, Orv Hetil. 2006 Sep 3;147(35):1709-11.
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The Hungarian Association of Oral and Maxillofacial Surgeons (Magyar Arc-, Állcsont- és Szájsebészeti Társaság) has reviewed the research results related to Avemar and issued its opinion as follows: For patients suffering from head- and neck tumors – primarily malignant tumorous diseases of the oral cavity, the progression of the disease can be slowed significantly, the five-year survival rate increased considerably, the quality of life improved, and the oxidative stress on the patients reduced by the long-term application of the supplementary formula Avemar. The Association considers the supportive treatment with the formula Avemar as an important part of the complex therapeutic protocols applied in stages II, III and IV of malignant tumorous diseases of the oral cavity.

d) Egészségügyi Tudományos Tanács Elnöksége, Recommendation of the Health Sciences Council’s Presidency regarding the legal prerequisites for the legal use of AVEMAR dietary supplement as a neoplastic agent, Orv Hetil. 2007 Jan 28;148(4):173.

e) Bálint G, Apáthy A, Gaál M, Telekes A, Resetár A, Blazsó G, Falkay G, Szende B,
Paksy A, Ehrenfeld M, Shoenfeld Y, Hidvégi M., Effect of Avemar–a fermented wheat germ extract–on rheumatoid arthritis. Preliminary data, Clin Exp Rheumatol. 2006 May-Jun;24(3):325-8.
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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.

f) Farkas E., Fermented wheat germ extract in the supportive therapy of colorectal cancer, Orv Hetil. 2005 Sep 11;146(37):1925-31.

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.

g) Sukkar, S.G, Edoardo, R., Oxidative Stress and Nutritional Prevention in Autoimmune Rheumatic Diseases, Autoimmunity Reviews, 3:199-206; 2004.
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Abstract Background and aim: Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name Avemar) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of Avemar in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with Avemar in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the Avemar group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results The levels of OS significantly decreased after 2 months in the group receiving Avemar (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in Avemar has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer.

h) Garami M, Schuler D, Babosa M, Borgulya G, Hauser P, Müller J, Paksy A, Szabó E, Hidvégi M, Fekete G., Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients, J Pediatr Hematol Oncol. 2004 Oct;26(10):631-5.
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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.

i) Jakab F, Shoenfeld Y, Balogh A, Nichelatti M, Hoffmann A, Kahán Z, Lapis K, Mayer A, Sápy P, Szentpétery F, Telekes A, Thurzó L, Vágvölgyi A, Hidvégi M., A medical nutriment has supportive value in the treatment of colorectal cancer, Br J Cancer. 2003 Aug 4;89 (3):465-9.
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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.

j) Jakab F, Mayer A, Hoffmann A, Hidvégi M., First clinical data of a natural immunomodulator in colorectal cancer, Hepatogastroenterology. 2000 Mar-Apr; 47(32):393-5.
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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.


2. Review articles

a) – Mueller T, Voigt W., Fermented wheat germ extract–nutritional supplement or anticancer drug?, Nutr J. 2011 Sep 5;10:89.
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Background: Fermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-a and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE.
Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies.

Conclusion: In conclusion, available data so far, justify the use of FWGE as a non-prescription medical nutriment for cancer patients. Further randomized, controlled and large scale clinical studies are mandatory, to further clarify the value of FWGE as a drug component of future chemotherapy regimens.

b) Heimbach JT, Sebestyen G, Semjen G, Kennepohl E., Safety studies regarding a standardized extract of fermented wheat germ, Int J Toxicol. 2007 May-Jun;26(3):253-9.
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“Avemar pulvis” is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 microg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary
supplement ingredient in the United States. Avemar pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a “medical nutriment for cancer patients.” Acute and subacute toxicity studies using rodents orally administered Avemar pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. The test substance showed no evidence of mutagenicity or genotoxicity in vitro or in vivo. Clinical studies using Avemar pulvis as a supplement to drug therapy in cancer patients at doses of 8.5 g/day not only showed no evidence of toxicity, but also showed a reduction in the side effects of chemotherapy. Overall, it was concluded that Avemar pulvis would not be expected to cause adverse effects under the conditions of its intended use as an ingredient in dietary supplements.

c) Johanning GL, Wang-Johanning F., Efficacy of a medical nutriment in the treatment of cancer, Altern Ther Health Med. 2007 Mar-Apr;13(2):56-63; quiz 64-5.
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Natural products are being used as supplements by cancer patients, with or without the knowledge of their cancer treatment team. It is important to know which of these products show efficacy against diseases such as cancer, and which are ineffective. It is also essential to define the mechanism(s) of action of natural products, especially as relevant to cancer prevention or treatment. The purpose of this article is to review the use of one such natural product, a fermented wheat germ extract (Avemar), in the treatment regimen of cancer patients. Avemar has shown efficacy in both animal cancer models and human clinical trials with cancer patients, but more well-controlled trials in humans are necessary to assess the full potential of Avemar in cancer treatment. Avemar exerts its anticancer effect via an array of mechanisms, likely because there are many undefined components in this product that modulate numerous biological systems in cancer patients.

d) Boros LG, Nichelatti M, Shoenfeld Y., Fermented wheat germ extract (Avemar) in the treatment of cancer and autoimmune diseases, Ann N Y Acad Sci. 2005 Jun;1051:529-42.
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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.

e) Nichelatti, M. & Hidvégi, M., Experimental and clinical results with Avemar (a dried extract from fermented wheat germ) in animal cancer models and in cancer patients,Nogyógyászati Onkológia, 7:180-185; 2002.
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In the late 1990’s, reports were published about a biotech process by which a fermented wheat germ extract could be produced. The product, called Avemar, available as a water soluble granulate for oral consumption, has gained much attention from cancer researchers of several countries, like Israel, Hungary, the United States, England and Russia. Studies show biological activity of Avemar that may be useful for the treatment of neoplastic diseases, effects which can be well used in the treatment of certain immune disturbances and improvement in patient quality of life which can be independent from the previous ones. ANIMAL EXPERIMENTS: Avemar treatment resulted in a statistically significant decreases in metastases compared with controls, 71% with 3LL-HH tumor (Lewis lung carcinoma), 50% decrease with HCR-25 human colon carcinoma and 85% with B16 melanoma. When used in combination with chemotherapy, Avemar did not reduce cytotoxic effect on primary tumors, but dramatically enhanced antimetastatic effect. CHEMOPREVENTIVE EFFECTS: In F-344 rats colon carcinogenesis was induced by injections of azoxymethane (AOM), 83% of AOM only animals developed colon tumors, an average of 2.3 tumors each. In animals given Avemar prior and after AOM injections, 44.8% developed colon tumors, and average of 1.3 tumors each, reducing tumor development by 70%. CLINICAL STUDIES: NEW METASTASES AND PROGRESSION-FREE SURVIVAL IN CANCER PATIENTS: An early open-label phase II clinical trial with Avemar was conducted in colorectal cancer patients, involving 30 consecutive subjects undergoing curative surgery. Patients were divided into control cohort and Avemar cohort groups. Patients of the control group received adjuvant chemotherapy alone (if necessary), whereas patients of the Avemar group received adjuvant chemotherapy (if necessary) plus 9 grams of Avemar once or twice daily, depending on their body weight. The median follow-up of all patients was 9 months, with range 6-11 months. No patients treated with Avemar showed new metastases, while in the control group 4 patients (22%) did. Another multicenter trial to evaluate disease progression-free and overall survival enrolled 170 consecutive colorectal cancer subjects. End-point analysis observed progression-related events (relapsed tumors, new metastatic lesions, deaths) were significantly more abundant in the control cohort, The log-rank test showed significant differences in favor of the Avemar patients, in both the cumulative probabilities of disease progression-free survival (primary endpoint) and overall survivals. Among all analyzed covariates (age, sex, UICC staging, Avemar treatment, radiotherapy and chemotherapy), the only strong predictors of survival in the Cox proportional hazards model were UICC stage and Avemar treatment. The treatment with Avemar was generally safe (no serious adverse events were recorded.) The results showed highly significant data in favor of Avemar treatment: that this wheat extract, in combination with surgery plus standard radio/chemoptherapy, can significantly inhibit overall tumor progression including the formation of new metastases, and could prolong the survival of colorectal cancer patients.

f) M. Boros, L.G., Cascante, M., Lee, W-N.P., Metabolic Profiling of Cell Growth and Death in Cancer: Applications in Drug Discovery, Drug Discovery Today, 7(6):18-26; 2002.
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Metabolic profiling using stable-isotope tracer technology enables the measurement of substrate redistribution within major metabolic pathways in living cells. This technique has been demonstrated that tranformed human cells exhibit profound metabolic shifts and that some and anti-cancer drugs produce their effects by forcing a reversion of these metabolic changes. By revealing tumor-specific metabolic shifts in tumor cells, metabolic profiling enables drug developers to identify the metabolic steps that control cell proliferation, thus aiding the identification of new anti-cancer targets and screening of lead compounds for anti-proliferative metabolic effects.


3. In vivo (Animal Studies)

a) Newell L, Tuscano J, o’Donnell R, Ma Y, Purified, Fermented, Extract of Triticum Aestivum Has Significant Independent Lymphomacidal Activity and Augments the Activity of Rituximab, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 2857
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Background: Non-Hodgkin’s lymphoma (NHL) affects over 400,000 people in the United States and its incidence increases with age. Treatment options include cytotoxic chemotherapy, which is often poorly tolerated by elderly patients, and monoclonal antibody (mAb) therapy. Nearly 70% of NHL patients eventually die of the disease. Development of effective alternate treatments with favorable toxicity profiles is necessary. Fermented wheat germ extract (FWGE) has shown anticancer potential in laboratory animals as well as in some small clinical studies; it is produced under GMP conditions in Europe and sold as AvemarTM. The mechanism of action of FWGE is unclear, but is thought to involve metabolic pathways involved in tumor cell death. We examined the effects of FWGE on NHL and found significant lymphomacidal activity using in vitro and in vivo assays. We then further purified and characterized the active components of FWGE in order to develop a more potent form and to understand the mechanism of action, physiologic, and immunologic properties.

Methods: FWGE was produced by fermenting purified wheat germ (Triticum aestivum) with Baker’s yeast. The FWGE was further purified by removing insoluble material, precipitating proteins, freeze drying, fractionating with Sepharose and Sephadex columns, and then dialyzing to remove small molecules. The resultant fermented wheat germ proteins (FWGP) were assessed for in vitro cytotoxicity and pro-apoptotic activity using a panel of NHL cell lines. In vivo lymphomacidal activity was assessed in nude mice bearing Raji lymphoma xenografts. Mice were treated with increasing daily doses of FWGE by gastric lavage and compared to untreated controls as well as the commercially available fermented wheat germ product, Avemar.

Results: In vitro killing assays with FWGE (regardless of the source) demonstrated lymphomacidal properties in three NHL cell lines (Jurkat, Raji, and Ramos). Pre-treatment of FWGE with heat or proteinase K reduced the lymphomacidal activity, suggesting that the active component was a protein. Nude mice bearing Raji lymphoma xenografts treated with FWGE confirmed the lymphomacidal properties of FGWE; there was no detectable toxicity as assessed by observation, mouse weight, or blood counts. The purified low molecular weight proteins (FWGP) also demonstrated lymphomacidal properties by cytotoxicity assays and murine NHL models, but at 1/1000th of the original dose. When FWGP was combined with rituximab, there was enhanced in vitro lymphomacidal activity, with over a 4000-fold reduction in the IC50. FWGP-induced NHL cell death was mediated by caspase-3-dependent apoptosis. FWGP augmented the host immune effector mechanisms, including ADCC and CDC, along with potent activation of NK-T cells (CD3/69/16), CD4+ T-cells and monocytes.

Conclusions: FWGE can be easily produced and has cytotoxic effects in in vitro assays and in vivo. The purified FWGP are quantifiable, and are 10–1000 times more potent than FWGE. The mechanism of FWGP activity is based on direct pro-apoptotic effects as well as augmentation of host immune mediators. FWGP has activity against various subtypes of NHL. Studies are ongoing to further characterize the immune effects and anti-cancer properties of FWGP, as is planning for a human clinical trial +/– rituximab in patients with NHL.

b) Iyer A, Brown L. Fermented Wheat Germ Extract (Avemar) in the Treatment of Cardiac Remodeling and Metabolic Symptoms in Rats, Evid Based Complement Alternat Med. 2009 Jul 21.
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Avemar, a product of industrial fermentation of wheat germ with a standardized content of benzoquinone and plant flavonoids, has been tested as an anti-cancer and immunomodulatory dietary supplement. Proposed mechanisms include anti-oxidant and anti-inflammatory actions. This study has determined whether these actions of Avemar may also be useful in the treatment of cardiovascular diseases. Two experimental rat models of cardiovascular remodeling were used in this project: the deoxycorticosterone acetate (DOCA)-salt-induced model of chronic hypertension (study I) and a high-carbohydrate/high-fat diet-induced model producing chronic symptoms of the metabolic syndrome and its associated cardiovascular complications (study II). Our results in these rat models of hypertension and diet-induced obesity show that treatment with Avemar improved cardiac function, decreased macrophage infiltration resulting in decreased collagen deposition in the ventricular myocardium, reversed an increased stiffness of the left ventricle in the diseased hearts and attenuated increased plasma malondialdehyde concentrations. In addition to the changes in the heart, Avemar reversed glucose intolerance, normalized systolic blood pressure and decreased visceral fat deposition in rats fed a high-fat/high-carbohydrate diet. In conclusion, the fermented wheat germ extract Avemar has a potential role in attenuating chronic hypertension, diabetes or metabolic syndrome-induced cardiovascular symptoms along with metabolic abnormalities such as glucose tolerance and obesity.

c) Tejeda, M., Gaal, D., Szucs, I.., Telkes, A., Avemar Inhibits the Growth of Mouse and Human Xenograft Mammary Carcinomas Comparable To Endocrine Treatments, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings, Part 1, Vol. 25, No. 18S, (June 20 Supplement), 2007: 21132.
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Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Combination of Avemar with any of the endocrine treatment enhanced the efficacy compared to endocrine monotherapy. Out of the four monotherapies the best result was achieved by Avemar (50% inhibition). The combination of Avemar with Examestane increased the tumor growth inhibition to 60.4% compared to control. The other treatments did not exceed the effect of Avemar monotherapy. In xenograft model Avemar produced 50% tumor growth inhibition compared to control and was more effective than the other treatments Examestane (26%), Anastrasol (25%) or Tamoxifen (42%). Combined treatment with Avemar always improved efficacy within the range of 3-10%. Avemar showed similar efficacy when T47/D (49%) and MDA-MB-231 (52%) xenografts were compared. Conclusions: The tumor growth inhibitory effect of Avemar on ER positive MXT mouse breast carcinoma as well as in T47/D xenograft models are comparable (equal or better) to standard endocrine treatments. Avemar certainly did not reduce the effect.

d) Telekes A, Resetar A, Balint G, Blazso G, Falkay G, Lapis K, Raso E, Szende B, Ehrenfeld M, Shoenfeld Y, Hidvegi M., Fermented wheat germ extract (avemar) inhibits adjuvant arthritis, Ann N Y Acad Sci. 2007 Sep;1110:348-61.
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Anti-inflammatory efficacy of the fermented wheat germ extract (FWGE, Avemar) in the rat adjuvant arthritis (AA) model was examined. To Wistar rats with AA, different doses of FWGE and anti-inflammatory drugs (indomethacin, dexamethasone) as monotherapies were administered and FWGE and either diclofenac or dexamethasone were also given in combination. Besides plethysmographies of the paws, histological investigations of synovial tissues were also performed along with detection of CD4+ and CD8+ T lymphocytes. Gene expressions of COX-1 and 2 were determined by real-time polymerase chain reaction (PCR). FWGE monotherapy significantly inhibited the development of the secondary (immune-mediated) response in AA, and dexamethasone and indomethacin exerted inhibitory effects in
a degree comparable to that of FWGE. Histological analysis of the affected joints confirmed the results. FWGE inhibited COX-1 and -2, while indomethacin enhanced COX-2 gene expressions. FWGE had an additive interaction with diclofenac. It is concluded that FWGE has significant anti-inflammatory efficacy confirmed by plethysmography, histology, and real-time PCR.

e) Marcsek Z, Kocsis Z, Jakab M, Szende B, Tompa A., The efficacy of tamoxifen in estrogen receptor-positive breast cancer cells is enhanced by a medical nutriment, Cancer Biother Radiopharm. 2004 Dec;19(6):746-53.
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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.

f) Stipkovits L, Lapis K, Hidvégi M, Kósa E, Glávits R, Resetár A., Testing the efficacy of fermented wheat germ extract against Mycoplasma gallisepticum infection of chickens,Poult Sci. 2004 Nov;83(11):1844-8.
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The effect of fermented wheat germ extract (FWGE, Immunovet-HBM) was studied in chickens challenged with Mycoplasma gallisepticum. Ninety M. gallisepticum- and M. synoviae-free 3-wk-old chickens were exposed to aerosol infection of M. gallisepticum. One group (30 birds) was treated with FWGE, a second group with tiamulin, and a third group was untreated. The fourth group was exposed to PBS aerosol as a negative control. On d 9, all chickens were slaughtered and examined for the presence of gross and histological lesions, the presence of the challenge strain in the organs and specific antibodies in the serum. Body weight gains and feed conversion rates were recorded. In the groups treated with FWGE and with tiamulin, the chickens remained clinically healthy: their BW gains were 441.7 g and 446.8 g, respectively. Feed conversion ratios were 1.72 and 1.71 for FWGE- and tiamulin-treated birds, respectively. Control birds had BW gain of 480.8 g, and feed conversion ratio of 1.78. The numbers of birds with gross lesions (15 and 11, respectively) and lesion scores (25 and 25, respectively) of the FWGE- and tiamulin-treated groups were significantly lower than in the infected untreated group (25 birds, lesion score of 190). No mycoplasma was reisolated from brain, liver, spleen, heart, or kidneys of the FWGE-treated birds, and the number of mycoplasma isolations from the respiratory tract samples was less frequent (10) than from the infected untreated group (64). In addition, 35 samples from other internal organs were also positive. Twenty percent of the birds treated with FWGE showed serological response with a 5.0% reaction score, whereas in the infected untreated group, 83.3% of birds were reactors, with a 62.5% reaction score.

g) Szende B, Marcsek Z, Kocsis Z, Tompa A., Effect of simultaneous administration of Avemar and cytostatic drugs on viability of cell cultures, growth of experimental tumors, and survival tumor-bearing mice, Cancer Biother Radiopharm. 2004 Jun;19(3):343-9.
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Avemar (Biromedicina Co., Budapest, Hungary), 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.

h) Ehrenfeld M, Blank M, Shoenfeld Y, Hidvegi M., AVEMAR (a new benzoquinone-containing natural product) administration interferes with the Th2 response in experimental SLE and promotes amelioration of the disease, Lupus. 2001;10(9):622-7.
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The potential of oral treatment with AVEMAR (AVEMAR), a new benzoquinone-containing fermentation product of wheat germ, on features of experimental systemic lupus erythematosus (SLE) in naive mice, induced by idiotypic manipulation, was studied. We assessed the effect of AVEMAR on the profile of autoantibody production and the response of Th1/Th2 related cytokines as well as the clinical picture of experimental SLE in the SLE-induced mice. When the product was given in the pre-immunization period, down-regulation of autoantibody production (anti-dsDNA, mouse 16/6 Id, and anti-histones) following treatment with AVEMAR was noted (eg anti-dsDNA decreased from 0.898+/-0.097 OD at 405 nm to 0.519+/-0.103 OD following treatment). This effect was sustained for at least 4 weeks after discontinuation of the therapy. Serological manifestations associated with a delay in Th2 response (IL-4 and IL-10) were recorded (eg IL-4 decreased from 91.7+/-8.11 to 59.55+/-7.78 ng/ml in splenocyte condition media). The mice showed normal ESR, WBC and less than 100 mg/dl of protein in the urine in comparison to > 300 mg/dl protein in the SLE non-treated mice. In conclusion, oral intake of AVEMAR can ameliorate the clinical manifestations of experimental SLE, via affecting the Th1/Th2 network inhibiting Th2 response.

i) Zalatnai A, Lapis K, Szende B, Rásó E, Telekes A, Resetár A , Hidvégi M., Wheat germ extract inhibits experimental colon carcinogenesis in F-344 rats, Carcinogenesis. 2001 Oct;22(10):1649-52.
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It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis has been induced by azoxymethane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three subcutaneous injections 1 week apart, 15 mg/kg body weight (b/w) each. In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 the basal diet and MSC were administered only. At the end of the experiment all the rats were killed by exsanguination, the abdominal large vessels were cut under a light ether anesthesia and a complete autopsy was performed. Percentage of animals developing colon tumors and number of tumors per animals: group 1 – 0 and 0; group 2- 83.0 and 2.3; group 3 – 44.8 (P < 0.001) and 1.3 (P < 0.004), group 4 – 0 and 0. All the tumors were of neoplastic nature also histologically. The numbers of the aberrant crypt foci (ACF) per area (cm(2)) in group 2 were 4.85 while in group 3 the ACF numbers were 2.03 only (P < 0.0001).

j) Hidvégi M, Rásó E, Tömösközi-Farkas R, Szende B, Paku S, Prónai L, Bocsi J, Lapis K., MSC, a new benzoquinone-containing natural product with antimetastatic effect, Cancer Biother Radiopharm. 1999 Aug;14(4):277-89.
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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.

k) Hidvégi M, Rásó E, Tömösközi Farkas R, Lapis K, Szende B., Effect of MSC on the immune response of mice, Immunopharmacology. 1999 Apr;41(3):183-6.
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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.

l) Szende B, Rásó E, Hidvégi M, Tömösköziné FR, Paku S, Prónai L, Bocsi J, Lapis K., A new benzoquinone-containing antimetastatic product, Orv Hetil. 1998 Nov 29;139(48):2893-7.

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.

m) Hidvégi M, Ráso E, Tömösközi-Farkas R, Paku S, Lapis K, Szende B., Effect of Avemar and Avemar + vitamin C on tumor growth and metastasis in experimental animals,Anticancer Res. 1998 Jul-Aug;18(4A):2353-8.
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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.


4. In vitro (Cell Line Studies)

a) Wang CW, Wang CK, Chang YJ, Choong CY, Lin CS, Tai CJ, Tai CJ, Preclinical evaluation on the tumor suppression efficiency and combination drug effects of fermented wheat germ extract in human ovarian carcinoma cells, Evid Based Complement Alternat Med. 2015;2015:570785.
Abstract
Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 μg/mL and 246.11 μg/mL after 48 h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate-ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES-2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients.
Link to full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359848/

b) Shibuya N, Inoue K, Tanaka G, Akimoto K, Kubota K, Augmented pentose phosphate pathway plays critical roles in colorectal carcinomas, Oncology. 2015;88(5):309-19.
Abstract
Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP(+) ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.

c) Tai CJ, Wang WC, Wang CK, Wu CH, Yang MD, Chang YJ, Jian JY, Tai CJ, Fermented wheat germ extract induced cell death and enhanced cytotoxicity of Cisplatin and 5-Fluorouracil on human hepatocellular carcinoma cells, Evid Based Complement Alternat Med. 2013;2013:121725.
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.
Link to full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881523/

d) Judson PL, Al Sawah E, Marchion DC, Xiong Y, Bicaku E, Zgheib NB, Chon HS, Stickles XB, Hakam A, Wenham RM, Apte SM, Gonzalez-Bosquet J, Chen DT, Lancaster JM., Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity, Int J Gynecol Cancer. 2012 Jul;22(6):960-7.
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OBJECTIVE: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists.

METHODS: In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level. RESULTS: We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate < 0.2) representing 27 biologic pathways (P < 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity.

CONCLUSIONS: Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE’s effect on human cancer cells.

RESEARCH HIGHLIGHTS: Fermented wheat germ extract has significant antiproliferative effects on OVCA cell lines and may enhance the effect of cisplatin-induced cell death.Genome-wide expression data reveal that FWGE sensitivity in ovarian cancer cells was associated with 2142 genes, representing 27 biologic pathways.

e) Z. Bago-Horvath, B. Forstner, M. Kalipciyan, A. Bedeir, M. Gruscj, O.Komina, J. Wesierska-Gadek, T. Szekeres, M. Hidvegi, R. Mader, Favourable anti-cancer activity of fermented wheat germ freeze-dried extract (avemar lyophilisate) in triple-negative breast cancer cells, May 01, 2011 European Society for Medical Oncology, Annals of Oncology 22 (Supplement 2): ii54–ii57, 2011
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Objective: The fermented wheat germ extract, which is the active ingredient of nutraceuticals widely used by cancer patients in Europe, Korea and the United States, possesses cytotoxic and anti-metastatic effects in various human malignancies. In estrogen responsive MCF-7 breast cancer cells, it has been shown to potentiate the induction of apoptosis by tamoxifen. However, its effects in triple-negative and Her2-overexpressing breast cancer cells and interactions with chemotherapy have not been investigated until now.

Methods: Cytotoxicity of Avemar lyophilisate alone and in combination with docetaxel was assessed by MTT and clonogenic assays in MCF-7 estrogen responsive, HCC-38 triple-negative and SKBR-3 Her2/neu overexpressing cells. Cell cycle phase distribution was determined by FACS. Apoptosisassociated activaton of caspase-3/7 was measured by Caspase-Glo Assay. Inhibition of tumor cell invasion was quantified using the ORIS Cell Invasion kit.

Results: Avemar lyophilisate exhibited highest cytotoxic activity against triple negative HCC-38 cells in MTT and clonogenic assays with IC50 values of 180 and 15 lg/ml, respectively, indicating likely clinical activity. In combination with docetaxel, additive and marginally synergistic effects were demonstrated in triple-negative HCC-38 and Her2/neu overexpressing SKBR-3 cells, whereas in the estrogen responsive MCF-7 cell line, cytotoxic activity of docetaxel was antagonized by Avemar lyophilisate. Perturbations in cell cycle phase distribution were differentially regulated by Avemar lyophilisate in estrogen receptor negative HCC-38, SKBR-3 and in estrogen receptor expressing MCF-7 cells, which was associated with altered activation of caspase-3/7. Invasive capacity of breast cancer cells was inhibited by Avemar lyophilisate in all three cancer cell lines investigated in a dose-independent manner.

Conclusions: Avemar lyophilisate exerts highest anti-cancer activity against triple negative HCC-38 human breast cancer cells. Due to its likely clinical activity against this human malignancy, further investigation of Avemar lyophilisate in triple-negative breast cancer is warranted.

f) Mueller T, Jordan K, Voigt W., Promising cytotoxic activity profile of fermented wheat germ extract (Avemar®) in human cancer cell linesJ Exp Clin Cancer Res. 2011 Apr 16;30:42. Click to view full text

Fermented wheat germ extract (FWGE) is currently used as nutrition supplement for cancer patients. Limited recent data suggest antiproliferative, antimetastatic and immunological effects which were at least in part exerted by two quinones, 2-methoxy benzoquinone and 2,6-dimethoxybenzquinone as ingredients of FWGE. These activity data prompted us to further evaluate the in vitro antiproliferative activity of FWGE alone or in combination with the commonly used cytotoxic drugs 5-FU, oxaliplatin or irinotecan in a broad spectrum of human tumor cell lines. We used the sulforhodamine B assay to determine dose response relationships and IC50-values were calculated using the Hill equation. Drug interaction of simultaneous and sequential drug exposure was estimated using the model of Drewinko and potential clinical activity was assessed by the model of relative antitumor activity (RAA). Apoptosis was detected by DNA gel electrophoresis.FWGE induced apoptosis and exerted significant antitumor activity in a broad spectrum of 32 human cancer cell lines. The highest activity was found in neuroblastoma cell lines with an average IC50 of 0.042 mg/ml. Furthermore, IC50-range was very narrow ranging from 0.3 mg/ml to 0.54 mg/ml in 8 colon cancer cell lines. At combination experiments in colon cancer cell lines when FWGE was simultaneously applied with either 5-FU, oxaliplatin or irinotecan we observed additive to synergistic drug interaction, particularly for 5-FU. At sequential drug exposure with 5-FU and FWGE the observed synergism was abolished.Taken together, FWGE exerts significant antitumor activity in our tumor model. Simultaneous drug exposure with FWGE and 5-FU, oxaliplatin or irinotecan yielded in additive to synergistic drug interaction. However, sequential drug exposure of 5-FU and FWGE in colon cancer cell lines appeared to be schedule-dependent (5-FU may precede FWGE).Further evaluation of FWGE as a candidate for clinical combination drug regimens appeared to be warranted.

g) Saiko P, Ozsvar-Kozma M, Graser G, Lackner A, Grusch M, Madlener S, Krupitza G, Jaeger W, Hidvegi M, Agarwal RP, Fritzer-Szekeres M, Szekeres T., Avemar, a nontoxic fermented wheat germ extract, attenuates the growth of sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells through induction of apoptosis, Oncology Reports, 2009 Mar;21(3):787-91.
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Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, Avemar inhibited the growth of sensitive H9 cells with IC50 values of 290 and 200 microg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC50 values of 180 and 145 microg/ml, respectively. Treatment with 300 microg/ml MSC for 48 h caused dose-dependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 microg/ml Avemar for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.

h) Telekes, A., Raso, E., Changes in The Kinase Expression Panel of K562 Human Leukemia After Avemar Treatment, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings, Part 1, Vol. 25, No. 18S (June 20 Supplement), 2007: 14143.
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Background: The positive effect of the wheat germ extract Avemar has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. Avemar given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of Avemar is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8×105 cell/ml), were treated with Avemar (500 µg/ml) and mRNS from 3-3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with Avemar for 48 hours. To determine the kinase expression pattern Kinase OpenArray™ plates were used, having over 500 kinase genes with controls in quadruplicates in each plate. Changes in expression was declared if the average value was over 1 (2-fold change in mRNA copy number) and the standard deviation was relatively small (2xSTDEV = AVERAGE). Results: We have found 16 kinases which expression has temporary or durative (maintained for 24 hour after washing) decreased (e.g.: CCL2, ABR, FLT1, EphB6, TGFa) and 30 which expression has increased (e.g.: CPT1B, IRE1, ITK, RON, LTK, EphB2, FASTK). Conclusions: Our result demonstrated that many of the kinases which expression was altered by Avemar treatment is known to participate in cell cycle, cell migration, apoptosis and signal transduction. Thus, our results might shed light on the main mechanism(s) of action of Avemar and raise the possibility to identify the active substance(es) of this natural extract.

i) Saiko P, Ozsvar-Kozma M, Madlener S, Bernhaus A, Lackner A, Grusch M, Horvath Z, Krupitza G, Jaeger W, Ammer K, Fritzer-Szekeres M, Szekeres T., Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human HL-60 promyelocytic leukemia cells, Cancer Lett. 2007 Jun 8;250(2):323-8. Epub 2006 Nov 29.
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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 72 h of incubation, Avemar inhibited the growth of HL-60 cells with IC50 values of 400, 190, and 160 microg/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.

j) Telekes A, Kiss-Tóth E, Nagy T, Qwarnstrom EE, Kúsz E, Polgár T, Resetár A, Dower SK, Duda E., Synergistic effect of Avemar on proinflammatory cytokine production and Ras-mediated cell activation, Ann N Y Acad Sci. 2005 Jun;1051:515-28.
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Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensitivity to Avemar, a fermented wheat germ extract. Avemar synergized with lipopolysaccharide and PMA in the induction of the transcription of cytokine genes and release of inflammatory cytokines. At higher concentrations the preparation had a significant negative effect on the proliferation and survival of activated myeloid cell types. Avemar treatment induced the synthesis of ICAM-1 and synergized with the ICAM-inducing effect of TNF, but had no effect on VCAM-1 expression on microvascular endothelial cells. The effect of Avemar on signaling pathways, which are involved in cell activation was studied on HeLa cells as a model system. Avemar treatment increased the activity of stress kinases in a concentration-dependent way, resulting in the activation of AP-1 transcription factor. NF-kappa B-sensitive reporters were also activated by Avemar; in contrast, no effect of the preparation was observed on PKA-sensitive signaling pathways.

k) . N. Lee, H. Park, K. E. Leem, Cytotoxic activities of fermented wheat germ extract (Avemar) on human gastric carcinoma cells by induction of apoptosis, Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 4254
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Background: The fermented wheat germ extract (code name:MSC, trade name: Avemar), is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. The objective of this study was to examine the in vitro cytotoxic activities of Avemar on 5 human gastric carcinoma cell lines and to test whether the mechanism involves induction of apoptosis. Methods: Cytotoxic activities of Avemar on 5 human gastric carcinoma cell lines (SNU-1, SNU-5, SNU-16, SNU-620, MKN-45) were examined using XTT cytotoxicity assay and apoptosis was measured by Sub-G1 fraction on flow histograms and annexin V- and propidium iodide-stained fraction on flow histogram. Results: Avemar dose-dependently suppressed the growth of all 5 examined gastric carcinoma cells by more than 90%, with ascending order of IC50 values: SNU-5 (0.37mg/mL), MKN-45 (0.49mg/mL), SNU-620 (0.52 mg/mL), SNU-1 (0.58 mg/mL) and SNU-16 (0.62mg/mL). Flow cytometry of Sub-G1 cells or annexin V- and propidium iodidestained cells indicated that the growth inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Conclusions: Avemar was found to dose-dependently inhibit the growth of gastric carcinoma cells possibly via an apoptosis-dependent pathway and has a potential to be an additive or synergistic effect with cytotoxic agents.

l) Illmer C, Madlener S, Horvath Z, Saiko P, Losert A, Herbacek I, Grusch M, Krupitza G, Fritzer-Szekeres M, Szekeres T., Immunologic and biochemical effects of the fermented wheat germ extract Avemar, Exp Biol Med (Maywood). 2005 Feb;230(2):144-9.
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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.

m) Comin-Anduix B, Boros LG, Marin S, Boren J, Callol-Massot C, Centelles JJ, Torres JL, Agell N, Bassilian S, Cascante M., Fermented wheat germ extract inhibits glycolysis/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells, J Biol Chem. 2002 Nov 29;277(48):46408-14. Epub 2002 Sep 25.
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The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC(50) concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G(1) peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodide- and annexin V-stained cells indicated that the growth-inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased (13)C incorporation and pentose cycle substrate flow into RNA ribose. This decrease in pentose cycle enzyme activities and carbon flow toward nucleic acid precursor synthesis provide the mechanistic understanding of the cell growth-controlling and apoptosis-inducing effects of fermented wheat germ. Avemar exhibits about a 50-fold higher IC(50) (10.02 mg/ml) for peripheral blood lymphocytes to induce a biological response, which provides the broad therapeutic window for this supplemental cancer treatment modality with no toxic effects.

n) Fajka-Boja R, Hidvégi M, Shoenfeld Y, Ion G, Demydenko D, Tömösközi-Farkas R, Vizler C, Telekes A, Resetar A, Monostori E., Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines, Int J Oncol. 2002 Mar;20(3):563-70.
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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.

o) Boros LG, Lee WN, Go VL., A metabolic hypothesis of cell growth and death in pancreatic cancer, Pancreas. 2002 Jan;24(1):26-33.
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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.

p) Boros LG, Lapis K, Szende B, Tömösközi-Farkas R, Balogh A, Boren J, Marin S, Cascante M, Hidvégi M., Wheat germ extract decreases glucose uptake and RNA ribose formation but increases fatty acid synthesis in MIA pancreatic adenocarcinoma cells, Pancreas. 2001 Aug;23(2):141-7.
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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.

q) Cosgrove DJ, Daniels DG, Greer EN, Hutchinson JB, Moran T, Whitehead FK, Isolation of methoxy- and 2:6-dimethoxy-p-benzoquinone from fermented wheat germ, Nature. 1952 Jun 7;169(4310):966-7.

r) Pethig R, Gascoyne PRC , Mclaughlin JA, Szent-Gyorgyi A, Enzyme-controlled scavenging of ascorbyl and 2,6-dimethoxysemiquinone free radicals in Ehrlich ascites tumor cells, Proc. Natl. Acad. Sci. USA, Cell Biology March 1985, Vol. 82, pp. 1439-1442.

s) Pethig R, Gascoyne PRC , Mclaughlin JA, Szent-Gyorgyi A, Interaction of the 2,6-dimethoxysemiquinone and ascorbyl free radicals with Ehrlich ascites cells: A probe of cell-surface charge, Proc. Natl. Acad. Sci. USA, Cell Biology April 1984, Vol. 81, pp. 2088-2091.

t) Pethig R, Gascoyne PRC , Mclaughlin JA, Szent-Gyorgyi A, Ascorbate-quinone interactions: Electrochemical, free radical, and cytotoxic properties, Proc. Nati Acad. Sci. USA, Biochemistry January 1983, Vol. 80, pp. 129-132.