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.

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.

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.

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.

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 (8x105 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.

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.

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 (8x105 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.