|
AVEMAR
- anticancer activity of fermented wheat germ extract (selected
articles)
Avemar's
anti-cancer effects were first demonstrated in animal experimental models
which focused on tumour types widely used for the testing of anti-cancer
agents, notably cytostatics.
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Cancer
Lett. 2007 Jun 8;250(2):323-8.
Saiko P, Ozsvar-Kozma M, Madlener S, Bernhaus A, Lackner A, Grusch M,
Horvath Z,
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical
University of Vienna, General Hospital
Avemar,
a nontoxic fermented wheat germ extract, induces apoptosis and inhibits
ribonucleotide reductase in human
Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to
significantly improve the survival rate in patients suffering from various
malignancies. We investigated its effects in human HL-60 promyelocytic
leukemia cells. After 24, 48, and 72h of incubation, Avemar inhibited
the growth of HL-60 cells with IC(50) values of 400, 190, and 160mug/ml,
respectively. Incubation with MSC caused dose-dependent induction of apoptosis
in up to 85% of tumor cells. In addition, Avemar attenuated the progression
from G2-M to G0-G1 phase of the cell cycle and was also found to significantly
reduce the in situ activity of ribonucleotide reductase, the key enzyme
of de novo DNA synthesis. We conclude that Avemar exerts a number of beneficial
effects which could support conventional chemotherapy of human malignancies.
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Clin Exp Rheumatol. 2006 May-Jun;24(3):325-8.
Balint G, Apathy A, Gaal M, Telekes A, Resetar A, Blazso G, Falkay G,
Szende B, Paksy A, Ehrenfeld M, Shoenfeld Y, Hidvegi M.
Fourth Department of Rheumatology, National Institute of Rheumatology
and Physiotherapy, Bp.
Effect of
Avemar--a fermented wheat germ extract--on rheumatoid arthritis. Preliminary
data.
OBJECTIVE: To investigate the effect of the fermented wheat germ extract
(Avemar)in patients with severe rheumatoid arthritis (RA). METHODS: Fifteen
female RA (Steinbrocker II-III) patients, who had unsuccessfully tried
two different DMARD treatments, were enrolled in an open-label, 1-year
long, pilot clinical study. DMARD and steroid therapies were recorded
and continued. All patients received Avemar as additional therapy. For
measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire
(HAQ) and the assessment of morning stiffness were applied. Patients were
evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon
test was used.RESULTS: At both 6 and 12 months, Ritchie index, HAQ and
morning stiffness showed significant improvements compared with the baseline
values. Dosages of steroids could be reduced in about half of the patients.
No side effects of Avemar were observed.CONCLUSION:Supplementation of
standard therapies with a continuous administration of Avemar is beneficial
for RA patients.
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Ann N Y
Acad Sci. 2005 Jun;1051:529-42.
Boros LG, Nichelatti M, Shoenfeld Y.
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center,
Torrance, CA 90502, USA.
Fermented
wheat germ extract (Avemar) in the treatment of cancer and autoimmune
diseases.
Avemar, the product of industrial fermentation of wheat germ, possesses
unique cancer-fighting characteristics. Taken orally, Avemar can inhibit
metastatic tumor dissemination and proliferation during and after chemotherapy,
surgery, or radiation. Benefits of Avemar treatment have been shown in
various human cancers, in cultures of in vitro grown cancer cells, in
the prevention of chemical carcinogenesis, and also in some autoimmune
conditions. This document reviews the clinical and experimental results
obtained with this extract so far. Special references are made for its
safety, including its coadministration with anticancer drugs, as well
as for its immunomodulatory activity, its molecular targets, and its use
in cancer clinical trials.
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Exp Biol
Med (Maywood). 2005 Feb;230(2):144-9.
Illmer C, Madlener S, Horvath Z, Saiko P, Losert A, Herbacek I, Grusch
M, Krupitza G, Fritzer-Szekeres M, Szekeres T.
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical
University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20,
A-1090 Vienna, Austria.
Immunologic
and biochemical effects of the fermented wheat germ extract Avemar.
Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to
have antitumor effects. Avemar has the potential to significantly improve
the survival rate in patients suffering from malignant colon tumors. We
studied its effects in the HT-29 human colon carcinoma cell line. Avemar
had an inhibiting effect on colonies of HT-29 cells with an IC50 value
of 118 microg/ml (7 days of incubation); this value could be decreased
to 100 and 75 microg/ml in the presence of vitamin C. In the cell line
examined, Avemar induced both necrosis and apoptosis, as demonstrated
by Hoechst/propidium iodide staining. The incubation of cells with 3200
microg/ml Avemar for 24 hrs caused necrosis in 28% and the induction of
apoptosis in 22% of the cells. Avemar inhibited the cell-cycle progression
of HT-29 cells in the G1 phase of the cell cycle. In addition, Avemar
inhibited the activity of the key enzyme of de novo DNA synthesis, ribonucleotide
reductase. In addition, we determined the effects of Avemar on the activity
of cyclooxygenase-1 and -2. Both enzymes were significantly inhibited
by Avemar with IC50 values of 100 and 300 microg/ml, respectively. We
outline new explanations for its antitumor activity, which might serve
as the basis for further studies using Avemar.
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Orv Hetil.
2005 Sep 11;146(37):1925-31.
Farkas E.
Biromedicina Elso Magyar Rakkutatasi Reszvenytarsasag, Budapest.
Fermented
wheat germ extract in the supportive therapy of colorectal cancer
The role of the product in the treatment of colorectal cancer is reviewed
in the light of experimental and clinical results to date. The fermented
wheat germ extract (code name: MSC, trade name: Avemar) registered as
a dietary food for special medical purposes for cancer patients to complement
the active oncotherapy, exerted a growth inhibitory effect in HCR-25 human
colon carcinoma xenograft, and had a synergistic effect with 5-FU in mouse
C-38 colorectal carcinoma. The product is capable of chemoprevention of
colon carcinoma in F-344 rats. One of the most significant underlying
mechanism is a highly cancer cell specific induction of caspase-3 mediated
cleavage of PARP. In the frame of supportive therapy, fermented wheat
germ extract proved to be efficient in the treatment of colorectal cancer
in humans. 30 patients following radical operation were treated with standard
postoperative therapy, 12 of them were given fermented wheat germ extract
as additive treatment: following a 9 month long administration, no new
distant metastases were detected, in contrast to 4 out 18 treated with
standard therapy alone. Out of 34 patients following radical surgery and
treated with chemotherapy, 17 who were given fermented wheat germ extract,
achieved an improved survival rate. In the frame of a controlled multicenter
open label cohort study, 170 colorectal cancer patients received anticancer
therapies (chemo/radiotherapy) completed with fermented wheat germ extract
in 66 of them. Results (fermented wheat germ extract vs. control): new
recurrences: 3.0% vs. 17.3% (p < 0.01); new metastases: 7.6% vs. 23.1%
(p < 0.01); deaths: 12.1% vs. 31.7% (p < 0.01), progression-related
events in total: 16.7% vs. 42.3% (p < 0.001). Survival analysis showed
significant improvements in the fermented wheat germ extract group, regarding
progression-free (p = 0.0184) and overall survival probabilities (p =
0.0278). Strong predictors of survival determined by Cox's proportional
hazards were UICC stage and fermented wheat germ extract treatment. Mild
gastrointestinal side effects were observed in 9 cases. Supportive application
of fermented wheat germ extract in colorectal cancer is highly recommended.
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Cancer Biother
Radiopharm. 2004 Dec;19(6):746-53.
Marcsek Z, Kocsis Z, Jakab M, Szende B, Tompa A.
National Institute of Chemical Safety, "Jozsef Fodor" National
Center for Public Health, Budapest, Hungary
The efficacy
of tamoxifen in estrogen receptor-positive breast cancer cells is enhanced
by a medical nutriment.
Avemar, a fermented wheat germ extract, has been applied in the supplementary
therapy of human cancers. Because tamoxifen is commonly used in the therapy
of ER+ breast cancer, in this study the combined effect of tamoxifen and
Avemar treatment was investigated on MCF-7 breast cancer cells, in order
to detect a possible agonistic or antagonistic action. Cytotoxicity was
measured by MTT assay, the percentage of mitoses and apoptotic cells was
determined morphologically, apoptosis and S-phase was measured by flow
cytometry, and estrogen-receptor activity was determined by semiquantitative
measurement of the estrogen-responsive pS2 gene mRNA production. Tamoxifen
(1 nM) alone had no effect on the percentage of the apoptotic cell fraction
and significantly reduced the percentage of the S-phase, compared to untreated
cells. Avemar (625 microg/mL) significantly increased apoptosis after
48 hours of treatment. Tamoxifen together with Avemar significantly increased
apoptosis already 24 hours after starting treatment but had only a slight
(not significant) effect on mitosis and S-phase. Estrogen-receptor activity
of MCF-7 cells was enhanced by Avemar, decreased by tamoxifen, and was
further decreased by combined tamoxifen and Avemar treatment. As apoptosis
increased when Avemar was added to tamoxifen treatment, the use of supplementary
therapy with Avemar in the case of ER+ breast tumors may enhance the therapeutic
effects of tamoxifen.
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J Pediatr
Hematol Oncol. 2004 Oct;26(10):631-5.
Garami M, Schuler D, Babosa M, Borgulya G, Hauser P, Muller J, Paksy A,
Szabo E, Hidvegi M, Fekete G.
Second Department of Pediatrics, School of Medicine, Semmelweis University,
Budapest, Hungary
Fermented
wheat germ extract reduces chemotherapy-induced febrile neutropenia in
pediatric cancer patients.
PURPOSE: An open-label, matched-pair (by diagnosis, stage of disease,
age, and gender) pilot clinical trial was conducted to test whether the
combined administration of the medical nutriment MSC (Avemar) with cytotoxic
drugs and the continued administration of MSC on its own help to reduce
the incidence of treatment-related febrile neutropenia in children with
solid cancers compared with the same treatments without MSC. METHODS:
Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled
in this study. At baseline, the staging of the tumors was the same in
each pair (mostly pTNM = T2N0M0), with the exception of two cases in which
patients in the MSC group had worse prognoses (metastasis at baseline).
There were no significant differences in the average age of the patients,
the length of treatment time (MSC) or follow-up, the number of patients
with central venous catheters, the number of chemotherapy cycles, the
frequency of preventive counterneutropenic interventions, or the type
and dosage of antibiotic and antipyretic therapy used in the two groups.
RESULTS: During the treatment (follow-up) period, there was no progression
of the malignant disease, whereas at end-point the number and frequency
of febrile neutropenic events significantly differed between the two groups:
30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%)
in the control group (Wilcoxon signed rank test, P < 0.05). CONCLUSIONS:
The continuous supplementation of anticancer therapies with the medical
nutriment MSC helps to reduce the incidence of treatment-related febrile
neutropenia in children with solid cancers.
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Cancer Biother
Radiopharm. 2004 Jun;19(3):343-9.
Szende B, Marcsek Z, Kocsis Z, Tompa A.
National Institute of Chemical Safety, Jozsef Fodor National Center for
Public Health, 1450 Budapest, Hungary.
Effect of
simultaneous administration of Avemar and cytostatic drugs on viability
of cell cultures, growth of experimental tumors, and survival tumor-bearing
mice.
Avemar, a wheat germ preparation with immunomodulant and antimetastatic
activity, was applied simultaneously with cytostatic drugs of different
modes of action, in vitro and in vivo, in order to find out whether this
simultaneous administration exerts an antagonistic or a synergistic effect
on the viability of cell cultures, tumor growth, and survival of animals,
inoculated with a transplantable mouse tumor (3LL-HH). In vitro, Avemar
did not influence the effect on the viability of MCF-7, HepG2, or Vero
cells, exerted by Dacarbazine, 5-fluorouracyl, or Adriblastina. In vivo,
Avemar, combined with Endoxan, Navelbine, and doxorubicin, did not prevent
the tumor growth inhibitory effect of the cytostatic drugs. The combination
of Avemar with the cytostatic drugs did not increase the toxicity of the
cytostatic compounds, and did not exert any toxic effect. Avemar may be
administered together with cytostatic drugs, without the risk of increasing
toxicity or decreasing antiproliferative activity.
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Br J Cancer.
2003 Aug 4;89(3):465-9.
Jakab F, Shoenfeld Y, Balogh A, Nichelatti M, Hoffmann A, Kahan Z, Lapis
K, Mayer A, Sapy P, Szentpetery F, Telekes A, Thurzo L, Vagvolgyi A, Hidvegi
M.
Department of Surgery and Vascular Surgery, Uzsoki Teaching Hospital of
Budapest, Hungary.
A medical
nutriment has supportive value in the treatment of colorectal cancer.
MSC (Avemar) is a medical nutriment of which preclinical and observational
clinical studies suggested an antimetastatic activity with no toxicity.
This open-label cohort trial has compared anticancer treatments plus MSC
(9 g once daily) vs anticancer treatments alone in colorectal patients,
enrolled from three oncosurgical centres; cohort allocation was on the
basis of patients' choice. Sixty-six colorectal cancer patients received
MSC supplement for more than 6 months and 104 patients served as controls
(anticancer therapies alone): no statistical difference was noted in the
time from diagnosis to the last visit between the two groups. End-point
analysis revealed that progression-related events were significantly less
frequent in the MSC group (new recurrences: 3.0 vs 17.3%, P<0.01; new
metastases: 7.6 vs 23.1%, P<0.01; deaths: 12.1 vs 31.7%, P<0.01).
Survival analysis showed significant improvements in the MSC group regarding
progression-free (P=0.0184) and overall survivals (P=0.0278) probabilities.
Survival predictors in Cox's proportional hazards were UICC stage and
MSC treatment. Continuous supplementation of anticancer therapies with
MSC for more than 6 months is beneficial to patients with colorectal cancer
in terms of overall and progression-free survival.
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Int J Oncol.
2002 Mar;20(3):563-70.
Fajka-Boja R, Hidvegi M, Shoenfeld Y, Ion G, Demydenko D, Tomoskozi-Farkas
R, Vizler C, Telekes A, Resetar A, Monostori E.
Lymphocyte Signal Transduction Laboratory, Institute of Genetics, Biological
Research Center of the Hungarian Academy of Sciences, Szeged, Hungary.
Fermented
wheat germ extract induces apoptosis and downregulation of major histocompatibility
complex class I proteins in tumor T and B cell lines.
The fermented wheat germ extract (code name: MSC, trade name: Avemar),
with standardized benzoquinone content has been shown to inhibit tumor
propagation and metastases formation in vivo. The aim of this study was
to understand the molecular and cellular mechanisms of the anti-tumor
effect of MSC. Therefore, we have designed in vitro model experiments
using T and B tumor lymphocytic cell lines. Tyrosine phosphorylation of
intracellular proteins and elevation of the intracellular Ca2+ concentration
were examined using immunoblotting with anti-phosphotyrosine antibody
and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM
and FuraRed-AM, respectively. Apoptosis was measured with cytofluorimetry
by staining the DNA with propidium iodide and detecting the cell population.
The level of the cell surface MHC class I molecules was analysed with
indirect immunofluorescence on cytofluorimeter using a monoclonal antibody
to the non-polymorphic region of the human MHC class I. MSC stimulated
tyrosine phosphorylation of intracellular proteins and the influx of extracellular
Ca2+ resulted in elevation of intracellular Ca2+ concentration. Prominent
apoptosis of 20-40% was detected upon 24 h of MSC treatment of the cell
lines. As a result of the MSC treatment, the amount of the cell surface
MHC class I proteins was downregulated by 70-85% compared to the non-stimulated
control. MSC did not induce a similar degree of apoptosis in healthy peripheral
blood mononuclear cells. Inhibition of the cellular tyrosine phosphatase
activity or Ca2+ influx resulted in the opposite effect increasing or
diminishing the Avemar induced apoptosis as well as the MHC class I downregulation,
respectively. A benzoquinone component (2,6-dimethoxi-p-benzoquinone)
in MSC induced similar apoptosis and downregulation of the MHC class I
molecules in the tumor T and B cell lines to that of MSC. These results
suggest that MSC acts on lymphoid tumor cells by reducing MHC class I
expression and selectively promoting apoptosis of tumor cells on a tyrosine
phosphorylation and Ca2+ influx dependent way. One of the components in
MSC, 2,6-dimethoxi-p-benzoquinone was shown to be an important factor
in MSC mediated cell response.
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Pancreas.
2002 Jan;24(1):26-33
Boros LG, Lee WN, Go VL
Harbor-University of California Los Angeles Research and Education Institute,
UCLA School of Medicine, Torrance, California 90502, USA
A metabolic
hypothesis of cell growth and death in pancreatic cancer.
INTRODUCTION: Tumor cells, just as other living cells, possess the potential
for proliferation, differentiation, cell cycle arrest, and apoptosis.
There is a specific metabolic phenotype associated with each of these
conditions, characterized by the production of both energy and special
substrates necessary for the cells to function in that particular state.
Unlike that of normal living cells, the metabolic phenotype of tumor cells
supports the proliferative state. AIM: To present the metabolic hypothesis
that (1) cell transformation and tumor growth are associated with the
activation of metabolic enzymes that increase glucose carbon utilization
for nucleic acid synthesis, while enzymes of the lipid and amino acid
synthesis pathways are activated in tumor growth inhibition, and (2) phosphorylation
and allosteric and transcriptional regulation of intermediary metabolic
enzymes and their substrate availability together mediate and sustain
cell transformation from one condition to another. CONCLUSION: Evidence
is presented that demonstrates opposite changes in metabolic phenotypes
induced by TGF-beta, a cell-transforming agent, and tumor growth-inhibiting
phytochemicals such as genistein and Avemar, or novel synthetic anti-leukemic
drugs such as STI571 (Gleevec). Intermediary metabolic enzymes that mediate
the growth signaling pathways and promote malignant cell transformation
may serve as high-efficacy nongenetic novel targets for cancer therapies.
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Pancreas
2001 Aug; 23(2): 141-147.
Boros LG, Lapis K, Szende B, Tomoskozi-Farkas R, Balogh A, Boren J, Marin
S, Cascante M, Hidvegi M.
UCLA School of Medicine, Harbor-UCLA Research and Education Institute,
Torrance, California 90502, USA.
Wheat germ
extract decreases glucose uptake and RNA ribose formation but increases
fatty acid synthesis in MIA pancreatic adenocarcinoma cells
The fermented wheat germ extract with standardized benzoquinone composition
has potent tumor propagation inhibitory properties. The authors show that
this extract induces profound metabolic changes in cultured MIA pancreatic
adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the
single tracer with biologic gas chromatography-mass spectrometry. MIA
cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent
decrease in cell glucose consumption. uptake of isotope into ribosomal
RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct
glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent
increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of
cell palmitate and the 13C enrichment of acetyl units were also significantly
increased with all doses of wheat germ extract. The fermented wheat germ
extract controls tumor propagation primarily by regulating glucose carbon
redistribution between cell proliferation-related and cell differentiation-related
macromolecules. Wheat germ extract treatment is likely associated with
the phosphorylation and transcriptional regulation of metabolic enzymes
that are involved in glucose carbon redistribution between cell proliferation-related
structural and functional macromolecules (RNA, DNA) and the direct oxidative
degradation of glucose, which have devastating consequences for the proliferation
and survival of pancreatic adenocarcinoma cells in culture.
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Update Medical Publishing S.A., Athens- Stuttgart Hepato-Gastroenterology
2000;47:393-395
F. Jakab, A. Mayer, A.Hoffmann, M. Hidvegi
First Clinical Data of a Natural Immunomodulator in Colorectal Cancer
Background/Aims:
MSC (trade-name AVEMAR) is a per os applicable complex of multiple, biologically
active molecules obtained from fermented wheat-germ extract. Preclinical
studies suggest potent anti-metastatic activity and it has a favourable
toxicity profile. It has been aimed in a pilot-scale, phase II clinical
study to document whether or not MSC as a support to surgery or plus chemotherapy
adds any therapeutic benefit compared to the same combination without
MSC in colorectal cancer. Methodology: From 1998 to June 1999, 18 control
patients and 12 consecutive colorectal cancer patients respectively, were
enrolled into this study. All patients underwent curative surgery. The
control group (18 patients) received no other therapy or adjuvant chemotherapy
alone. The MSC group (12 patients) received MSC alone or plus adjuvant
chemotherapy. Until now, the median follow-up has been 9 month. Results:
Interim data of the study document that the MSC group no new metastases,
neither hepatic no other, have occurred, so far. On the contrary, several
new metastases have developed in the control group. Conclusion: Orally
administered MSC is a potent candidates to be regarded as a supportive
therapy to surgery or plus chemotherapy for colorectal canter patient.
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AVEMAR is
a natural immunomodulator in colorectal cancer
Clinical
data shows that Avemar has an antimetastatic effect
BACKGROUND: AVEMAR is a per os applicable complex of multiple, biologically
active molecules obtained from fermented wheat-germ extract. Preclinical
studies suggest potent anti-metastatic activity and it has a favorable
toxicity profile. It has been aimed in a pilot-scale, phase II clinical
study to document whether or not AVEMAR as a support to surgery or plus
chemotherapy adds any therapeutic benefit compared to the same combination
without MSC in colorectal cancer. METHODOLOGY: From 1998 to June 1999,
18 control patients and 12 consecutive colorectal cancer patients respectively,
were enrolled into this study. All patients underwent curative surgery.
The control group (18 patients) received no other therapy or adjuvant
chemotherapy alone. The AVEMAR group (12 patients) received AVEMAR alone
or plus adjuvant chemotherapy. Until now, the median follow-up has been
9 months. RESULTS: Interim data of the study document that in the AVEMAR
group no new metastases, neither hepatic nor other, have occurred, so
far. On the contrary, several new metastases have developed in the control
group. CONCLUSIONS: Orally administered AVEMAR is a potent candidate to
be regarded as a supportive therapy to surgery or plus chemotherapy for
colorectal cancer patients.
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Immunopharmacology
1999 Apr;41(3):183-186
Hidvegi M, Raso E, Tomoskozi Farkas R, Lapis K, Szende B.
Birochem, Budapest, Hungary.
Effect of
MSC on the immune response of mice
The supposed immunostimulatory actions of MSC, a new fermented wheat germ
extract standardized to its benzoquinone composition (trade name: AVEMAR)
were studied examining blastic transformation of peripheral blood lymphocytes
of mice treated with MSC. It was found that MSC significantly increased
the degree of blastic transformation caused by Concanavalin A. Using the
B10LP to C57Bl skin graft system, MSC (0.03 and 3.0 g kg(-1) applied orally)
acted in favour of restoring the immune function. On the other hand, 2,6-dimethoxy-p-benzoquinone
(DMBQ), applied in equivalent doses (0.012 and 1.2 mg kg(-l)), did not
shorten the rejection time of skin grafts. The immune restoring effect,
as well as the blastic transformation enhancing potential of MSC may be
exploited in various cases of decreased immune response.
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Hepatogastroenterology
2000 Mar-Apr;47(32):393-5
Jakab F, Mayer A, Hoffmann A, Hidvegi M.
Department of Surgery, Uzsoki Teaching Hospital, Budapest, Hungary.
First clinical
data of a natural immunomodulator in colorectal cancer
BACKGROUND/AIMS: MSC (trade-name AVEMAR) is a per os applicable complex
of multiple, biologically active molecules obtained from fermented wheat-germ
extract. Preclinical studies suggest potent anti-metastatic activity and
it has a favorable toxicity profile. It has been aimed in a pilot-scale,
phase II clinical study to document whether or not MSC as a support to
surgery or plus chemotherapy adds any therapeutic benefit compared to
the same combination without MSC in colorectal cancer. METHODOLOGY: From
1998 to June 1999, 18 control patients and 12 consecutive colorectal cancer
patients respectively, were enrolled into this study. All patients underwent
curative surgery. The control group (18 patients) received no other therapy
or adjuvant chemotherapy alone. The MSC group (12 patients) received MSC
alone or plus adjuvant chemotherapy. Until now, the median follow-up has
been 9 months. RESULTS: Interim data of the study document that in the
MSC group no new metastases, neither hepatic nor other, have occurred,
so far. On the contrary, several new metastases have developed in the
control group. CONCLUSIONS: Orally administered MSC is a potent candidate
to be regarded as a supportive therapy to surgery or plus chemotherapy
for colorectal cancer patients.
-------------------------------------------------------------------------------
Cancer Biother
Radiopharm 1999 Aug; 14(4):277-289.
Hidvegi M, Raso E, Tomoskozi-Farkas R, Szende B, Paku S, Pronai L, Bocsi
J, Lapis K.
1st Institute of Pathology and Experimental Cancer Research, Semmelweis
Medical University, Budapest.
MSC, a new
benzoquinone-containing natural product with antimetastatic effect
An orally applicable fermentation product of wheat germ containing 0.04%
substituted benzoquinone (MSC) has been invented by Hungarian chemists
under the trade name of AVEMAR. Oral administration (3 g/kg body weight)
of MSC enhances blastic transformation of splenic lymphocytes in mice.
The same treatment shortens the survival time of skin grafts in a co-isogenic
mouse skin transplantation model, pointing to the immune-reconstructive
effect of MSC. A highly significant antimetastatic effect of MSC has been
observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic
effect of MSC--besides the immune-reconstitution--may also be due to its
cell adhesion inhibitory, cell proliferation inhibitory, apoptosis enhancing,
and antioxidant characteristics, also observed in our in vitro experiments.
It is even more noteworthy that combined treatment with MSC and one of
the following antineoplastic agents (5-FU and DTIC)--both in wide use
in every day clinical practice--exhibited a significantly enhanced antimetastatic
effect in appropriate metastasis models (established from C38 mouse colon
carcinoma and B16 mouse melanoma respectively) as compared to the effect
elicited by any component of these therapeutic compositions (MSC + 5-FU
and MSC + DTIC) administered alone. The results show that the fermented
wheat germ extract (MSC) has more than an additive effect and synergistically
enhanced the metastasis inhibitory effect of both antineoplastic agents
studied till now. It is also worthy of mention that the synchronous treatment
with MSC profoundly decreased the toxic side effects of the applied antineoplastic
agents (decreased weight loss etc). Based on the biological effects of
MSC--shown to be non-toxic by subacute toxicology studies--this product
may be used as an adjuvant in the therapy of malignant neoplasia and other
diseases caused by or following immune-deficiency.
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Birochem
Ltd., Budapest, Hungary.
Hidvegi M, Raso E, Tomoskozi-Farkas R, Paku S, Lapis K, Szende B.
Anticancer Res 1998 Jul-Aug;18(4A):2353-8
Effect of
AVEMAR and AVEMAR + vitamin C on tumor growth and metastasis in experimental
animals
Because of the observed immunostimulatory actions of a new fermented wheat
germ extract--with standardized benzoquinone composition--we have investigated
the eventual tumor growth- and metastasis-inhibiting effects of this preparation
(AVEMAR) applied alone or in combination with vitamin C. Tumor models
of different origin [a highly metastatic variant of the Lewis lung carcinoma
(3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon
carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice
were applied. The metastasis-inhibiting effects of the treatments have
been studied both in the presence and in the absence (following surgical
removal) of the transplanted primary tumors. Combined treatments with
AVEMAR and vitamin C--administered synchronously--profoundly inhibited
the metastasis formation in all the applied tumor models while, treatments
with vitamin C alone did not exert such an inhibiting effect on the metastasizing
process. The degree of the observed metastasis inhibition in certain models
was significant, while in others--although it was meaningful--did not
prove to be significant. It is noteworthy that treatment with AVEMAR alone
in certain models exerted a more pronounced inhibiting effect on metastasis
formation than the synchronous combined treatment with AVEMAR and vitamin
C. Furthermore, if the time schedule of the combined treatment was changed
(vitamin C--instead of being administered synchronously--was given one
hour after the treatments with Avemar), the vitamin C rather decreased
the metastasis inhibiting effect of AVEMAR. It should be mentioned however,
that in the case of rat nephroblastoma, a different response was observed:
while, in the case of synchronous combination significant inhibition of
metastasis formation was observed, treatment with AVEMAR alone did not
produce metastasis-inhibition. It is noteworthy that in this model the
metastasis-inhibiting effect of the synchronous combination treatment
proved to be even more pronounced if AVEMAR was administered in a 100
times smaller dose than its regularly applied dosage. Treatment with AVEMAR
and vitamin C--administered in combination or separately--in the majority
of experimental models (with the exception of rat nephroblastoma) did
not inhibit the growth of the primary tumors. It is reasonable, therefore,
to suppose that in the observed metastasis-inhibiting effect the eventual
proliferation inhibiting effect of these remedies does not play an important
role. According to the results of other experiments--carried out in our
laboratory in parallel with those described here--AVEMAR proved to have
a meaningful immunostimulatory effect. It might therefore be suggested
that the observed metastasis-inhibiting effect of this preparation may
be mainly due to its immunostimulatory properties. The possible therapeutic
benefits of AVEMAR and AVEMAR plus vitamin C are also discussed.
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Anticancer research 18:2353-2358 (1998)
Mate Hidvegi, Erzsebet Raso, Rita Tomoskozi-Farkas, Sandor Raku, Karol
Lapis, Bela Szende
Hungary and Department of Biochemistry and Food Technology, Budapest Technical
Univeristy; First Institute of Pathology and Experimental Cancer Research,
Semmelweis University of Medicine; Budapest, Hungary
Effect of
Avemar and Avermar + Vitamin C on Tumor Growth and Metastasis in Experimental
Animals
We have investigated the effect of Avemar on liver colony formation from
3LL-HH cells implanted into the spleen of immunocompetent C57B1/6 mice
and from human colon carcinoma xenograft (HCR 25) implanted into the spleen
of immunosuppressed CBA/CA mice. In the 3LL-HH spleen-liver model Avemar
+ Vitamin C significantly reduced the number of metastases in the group
treated continuously after inoculation of 3 x 10 cells. A slight decrease
in the metastasis number was also observed in the couprs inoculated with
lower number of tumor cells or treated with Avemar+ Vitamin C prior to
tumor inoculation. Increasingly, where the inhibition of metastasis formation
was the highest the primary tumor weight increased . To test the effect
of Avemar on the growth and metastatization of human cancer, human colon
carcinoma tutor line (HRC25) established in our laboratory was used. Growith
of the primary splenic tumor was markedly inhibited, that was paralleled
by significant reduction of number of liver metastases. Compared to the
grontrol group the treatment also cause deduction of the side of liver
colonies. Removal of the primary tumor resulted in lower number of metastases
in the control group. That was further reduced by treating the mice with
Avemar. Using the B16 melanoma tumor line (muscle-ling model), in the
first experiment the mice were treated after tumor inoculation in the
presence of primary tumor (Table III). Marked inhibition of metastasis
formation in the lung was observed in the group treated with Avemar alone.
The inhibition was 85% in the Avemar treated group, whereas vitamin C
alone had no effect. Avemar + vitamin C treatment also caused a slight
reduction in the primacy tumor weight. Interestingly, no inhibition of
metastasis formation was observed at an other model where the primary
tumor was removed 10 days after tumor inoculation. Wilms’ tumor is
one of the most frequent childhood tumors. It’s transplantable rat
analog, developed by some of us, is able to produce lung metastases when
transplanted under the renal capsule. Avemar +vitamin C showed a strong
inhibitory effect on the primary tumor C showed a strong inhibitory effect
n the primary tumor growth as well as on the formation of lung metasteses.
Primary tumor weight and the number of metastases decreased even more
significantly when Avemar + vitamin C was administered in a diluted form.
Interestingly, Avemar alone was ineffective in this model, whereas vitamin
C reduced both primary tumor weight and the number of metastases.
--------------------------------------------------------------------------------
8th European
Congress on Biotechnology
Rita Tomoskozi-Farkas, Mate Hidvegi
Budapest, Hungary, 17-21 August 1997
OPTIMIZATION
OF CEREAL GERM FERMENTATION
One of the most important problems of cancer therapy is preventing metastasis.
In the last few years researchers have been devoting more attention to
immunostimulants and drugs of natural origin. Albert Szent-Gyorgyi worked
on compound - 2,6-dimethoxy-p-benzoquinone (2,6-DMBQ) and 2-methoxy-benzoquinone
(2MBQ) - which have anticancer and bacteriostatic effect as well. The
aim of our work is to produce a drug of natural origin rich in 2-MBQ and
2,6-DMBQ which may suitable for in vivo experiments. By the reason of
our previous studies we tried to increase the concentration of 2-MBQ and
2,6-DMBQ in wheat germ by yeast fermentation. To reach the optimal parameters
of fermentation we used factorial design method. The simultaneous effect
of reaction parameters and component concentrations on the 2,6-DMBQ formation
was investigated.For the determination of the optimal 2,6-DMBQ formation
the fermentation time was varied between 5 and 24 hours. The temperature
range used was 25- 35 oC. The substrate - yeast ratio, the dried material
- water ratio were varied between 1.5-3.5 and 5-10. We examined the effect
of defatting of wheat germ, the intensity of mixing and light.
--------------------------------------------------------------------------------
Patologiai
es Kiserleti Rakkutato Intezet, Semmelweis Orvostudomanyi Egyetem, Budapest.
Szende B, Raso E, Hidvegi M, Tomoskozine FR, Paku S, Pronai L, Bocsi J,
Lapis K. I.
Orv Hetil. 1998 Nov 29;139 (48):2893-7.
A new benzoquinone-containing
antimetastatic product
An orally applicable fermentation product of wheat germ containing 0.04%
substituted benzoquinone (MSC) was invented by Hungarian chemists under
the trade--name of AVEMAR. The following biological effects of this product
were observed. Oral administration (3 g/kg body weight) of MSC enhances
blastic transformation of splenic lymphocytes of mice. The same treatment
shortens the survival time of skin grafts in co-isogenic mouse skin transplantation
model, which points to immune-reconstructive effect of MSC. Highly significant
anti-metastatic effect of MSC was observed in three metastasis models
(3LL-HH, B16, HCR-25). The antimetastatic activity of MSC--besides the
immune reconstitution--may also due to the cell-adhesion inhibitory, cell
proliferation inhibitory, apoptosis-enhancing and antioxidant effects,
which were also observed in our in vitro experiments. Based on the biological
effects of MSC--which is non-toxic, according to subacute toxicology studies--this
product may be used as an adjuvant in the therapy of malignant neoplasia
and other diseases caused by or following immunedeprivation.
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