Fermented wheat germ extract

Fermented wheat germ extract (FWGE), also called fermented wheat germ powder (FWGP) is a concentrated extract of wheat germ fermented by baker's yeast, used primarily for its ability to stimulate and modulate immune system function.

FWGP is approved as a medical nutriment for supportive therapy of cancer in Hungary and is used for that purpose in other nations of the European Union (EU), and in parts of the Middle East and Asia. It is used in the US as a dietary supplement.

In addition to its use in support of treatments for cancer, in which immune system function usually is impaired prior to and/or following cytotoxic treatment, FWGE has also been studied for use in conditions in which the immune system is inappropriately over-active, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

The use and study of FWGE in conditions at such widely distant points on the spectrum of abnormal immune system function as cancer -- in which immune system function often is impaired -- and autoimmune conditions -- in which immune system function is inappropriately overactive -- occurs because the extract has been shown to support normal immune system function and normal cell metabolism.

FWGE is derived from the germ (endosperm, or seed) of the wheat plant, and is a by-product of milling of wheat kernels to produce flour. FWGE differs from ordinary wheat germ in that it is fermented to concentrate the substituted benzo-quinones, which are biologically active. Concentration allows the immunomodulatory effects of the substituted benzo-quinones to be obtained without the consumption of impractically large amounts of wheat germ. FWGE (trade names Avemar, Avé) is identified in some research studies by the laboratory code name MSC. In proprietary formulations, the extract is standardized (formulated to always contain a specific amount of substituted benzo-quinones in a given amount of extract).

Like many other naturally occurring substances extracted from plants, FWGE was historically mainly the provence only of naturopathic doctors, holistic health practitioners, and herbalists. Currently, such substances are increasingly of interest to more conventionally trained physicians who study them for use in those instances in which adequate, peer-reviewed published research has demonstrated substantial and quantifiable benefit.

ummary of laboratory and clinical research results

Results of cell studies, animal studies, and human clinical trials focused on cancer show that FWGE has exhibited significant anti-cancer effects in a broad variety of cancer types and also positive effects in auto-immune diseases [http://www.herbalgram.org/wholefoodsmarket/herbclip/review.asp?i=44660] .

Human clinical trials

FWGE improved survival, and reduced new recurrences and metastases in colorectal cancer patients. When used in a study of 170 post-surgical colorectal cancer patients also receiving standard of care therapy such as chemotherapy, and/or radiation, addition of FWGE reduced new recurrences by 82%, metastases by 67%, and deaths by 62%, compared to use of radiation and chemotherapy alone. It also lengthened the time it took for cancer to become measurably active again after primary therapy (surgery) and adjuvant therapy (chemotherapy and/or radiation treatment). [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12888813&query_hl=9&itool=pubmed_docsum]

In pediatric cancer patients with various cancer types, FWGE substantially reduced the risk of infections accompanied by high fever (febrile neutropenia), primarily by boosting immune system cell populations and activity. In pre-clinical tests specifically looking at immune effects, FWGP accelerated recovery of immune function following radiation and chemotherapy, inhibited immune suppression, improved NK cell recognition of target cells, and supported normal immune system function that helps white blood cells to cross through blood vessel walls and into tumors. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15454833&query_hl=11&itool=pubmed_docsum]

In a melanoma study, of patients with advanced-stage (Stage III) melanoma skin cancer, FWGE added to chemotherapy resulted in a 1-year relapse-free survival rate of 54.5%, compared to 38.9% for those getting only chemotherapy.

Pre-clinical research done earlier may explain some of the compound’s antimetastatic effects; it inhibited cell proliferation and cell adhesion, and demonstrated promotion of apoptosis and antioxidant effects. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10850313&query_hl=12&itool=pubmed_DocSum]

In an oral cancer study, FWGP used as supportive therapy for patients undergoing standard anticancer therapies (SAT) for locally advanced squamous cell carcinoma of the mouth, FWGP reduced the risk of cancer progression by 85%.

Because opportunities to exploit the mechanisms of action through which FWGP works (limiting access to pathways preferred by tumor cells for ribose synthesis, for example) may exist in many types of cancer, research is ongoing to learn if the results seen in colorectal cancer, melanoma skin cancer, and pediatric cancers will occur in other types of cancer.

In pre-clinical tests to determine whether FWGP might interfere with conventional therapy, the compound did not lessen the therapeutic benefit of any conventional therapy. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15285880&query_hl=6&itool=pubmed_docsum] In another study, therapeutic effects of some conventional treatments used in combination with FWGP were increased, e.g., reduced metastasis, [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12888813&query_hl=8&itool=pubmed_docsum] and in some cases those effects were accompanied by lessened frequency and severity of common side effects of conventional treatments, such as nausea, fatigue, weight loss and immune suppression. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15454833&query_hl=11&itool=pubmed_docsum] In quality of life (QOL) tests, FWGP improved cancer patients’ perception of their quality of life.

FWGP and automimmune diseases

Results of early research using FWGE in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) suggest FWGE may be of use in these diseases for its ability to reduce inflammatory cytokines and rebalance the activity of Th1 and Th2 lymphocytes. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16126993&query_hl=3&itool=pubmed_docsum] Clinical trials are underway to learn more about FWGP’s effects in SLE.

Animal studies

In animals with transplanted human lung cancer, FWGE added to chemotherapy increased survival markedly. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10850313&query_hl=12&itool=pubmed_docsum]

In rats exposed to a substance known to cause colon cancer (AOM), giving the rats FWGE reduced by 46% the number of animals developing colon cancer and reduced the size and number of tumors in those rats that did develop colon cancer. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11577004&query_hl=14&itool=pubmed_docsum]

In mice with a variety of cancer types (highly metastatic lung cancer; melanoma, and human colon cancer), FWGP administered with vitamin C reduced metastasis (spread) of the cancers. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9703878&query_hl=14&itool=pubmed_docsum]

Toxicity studies with FWGE showed no toxicity at levels several times above the amounts recommended for use.

Cell studies

In a colon cancer cell study, FWGE caused 22% of the cancer cells to die due to apoptosis, and 28% due to direct cell-killing by FWGP. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15673563&query_hl=20&itool=pubmed_docsum]

In estrogen-positive breast cancer cells, adding FWGP to tamoxifen treatment killed more breast cancer cells than tamoxifen alone, mainly by increasing apoptosis. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15665622&query_hl=22&itool=pubmed_docsum]

In T-cell and B-cell lymphoma cells, FWGP increased destruction of cancerous cells via forcing more cells into apoptosis. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11836569&query_hl=25&itool=pubmed_docsum]

In tests against leukemia cells, FWGE controlled cell growth and proliferation, mainly by inhibiting enzymes needed to make new DNA to support replication of leukemic cells and by triggering apoptosis. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12351627&query_hl=27&itool=pubmed_docsum]

In cell studies of pancreatic cancer, FWGE limited the creation of new pancreatic cancer cells by limiting cancer cells’ access to glucose, needed to make the sugar ribose for DNA and RNA for new cancer cells. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11484916&query_hl=29&itool=pubmed_DocSum]

In human and animal myeloid leukemia cells, and human cervical cancer cells, researchers found FWGE limited the growth and decreased the survival of the cancer cells, mainly by increasing quantities or activity of specific cell hormone-like substances called cytokines, such as tumor necrosis factor (TNF), which harm cancerous cells but not normal cells. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16126992&query_hl=31&itool=pubmed_docsum]

In a 1983 study done by Szent-Gyorgyi and colleagues, Erlich tumor cell acites were eliminated from mice using a combination of DMBQ, one of the naturally occurring compounds in FWGP, and ascorbate. The study authors said they believed the elimination was likely due to the interaction of the acites cells and very short-lived free radicals produced by the combination. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=6296861&query_hl=33&itool=pubmed_DocSum]

Work by Szent-Gyorgyi and colleagues in 1985 showed the compound’s effects against the acites tumor cells was likely at least partly due to one of the active ingredients in FWGE causing a loss of NAD(P)H reducing power in the cells. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3856273&query_hl=33&itool=pubmed_docsum]

History of Development of FWGP

FWGP is approved as a medical nutriment in support of therapy for cancer in Hungary, where it was first developed. It is used throughout Europe, and in parts of the Middle East and Asia, which have a history of use of foods and food-derived factors as medically beneficial that is older than in some other parts of the world.

Investigation into the biological properties of fermented wheat germ was initiated by Hungarian biochemist Albert Szent-Gyorgyi (Nobel Prize in Physiology or Medicine in 1937: discovery of vitamin C). In the later years of his career, Szent-Gyorgyi focused his research on causes of and possible treatments for cancer, a disease that had taken the lives of his first wife, his daughter, and other family members.

An expert in cellular respiration and metabolism, Szent-Gyorgyi was a strong proponent of Hippocrates' concept of using foods as medicine. His observation that people eating refined grains developed chronic diseases such as cancer more often than those who ate whole grains led Szent-Gyorgyi to investigate biological properties of wheat germ to learn if it might be useful against cancer. Scientists already knew that cancer cells use huge amounts of glucose, compared to normal cells [the Warburg effect] . Aware that rapid metabolism of glucose could support development, growth and proliferation of cancer cells, Szent-Gyorgyi looked for substances in the wheat plant that might help explain the lower cancer rates among those eating whole grains.

In a series of early papers on wheat germ published in research journals, Szent-Gyorgyi showed results and anaylses suggesting that certain natural compounds called quinones, specifically methoxy-sustituted benzoquinones, naturally present in wheat germ, could help regulate cell metabolism, and possibly prevent the kind of overuse of glucose that supports cancer cell growth and replication.

Fermenting wheat germ with baker’s yeast concentrated the most effective metabolism-regulating quinones such as 2,6-DMBQ, Szent-Gyorgyi noted, so they could be taken as a supplement without the need to consume impractically large amounts of wheat germ.

But large-scale fermentation processes were insufficient then to produce large quantities of the powder, so Szent-Gyorgyi had the same problem he'd faced earlier working to isolate vitamin C: not enough isolated concentrate to use in further lab tests. And the problem of how to standardize the compound’s content, to ensure the same amount of active molecules in each given amount of the powder remained to be solved. Those problems remained unsolved at the time of Szent-Gyorgyi’s death in 1986.

Szent-Gyorgyi’s work was later picked up by a new generation of Hungarian scientists, starting in the 1990s. These researchers used new industrial-scale fermentation processes to produce large quantities of extract, and succeeded in standardizing the amount of active substances in any given amount of it. When initial cell and animal studies showed slowed tumor cell growth, increased cancer cell death by apoptosis, reduced metastasis, and other apparent benefits, human clinical trials were initiated. Currently, FWGE is approved in Hungary and several other European Union (EU) nations as a medical nutriment in support of cancer therapy, and is in use in the US as a dietary supplement.

ummary

Fermented Wheat Germ Extract (FWGE) is a powdered concentrate of a fermented plant extract, approved in Europe as a medical nutriment for support of therapy for cancer, and used in the US as a dietary supplement. Research has shown FWGE to support normal immune system and cell metabolic function, to support NK cell targeting ability and coordination of immune system activities such as the responses of macrophages, B-cell and T-cells, and to support cellular and humoral (Th1 and Th2) balance. Effects seen in cell, animal, and human clinical cancer research studies may explain its use in the US and Europe in a wide variety of conditions in which support of normal, as opposed to abnormal, metabolism and immunity, are viewed as important. Research with the substance continues at academic and medical institutions in the US, the EU, and in Asia.

References

*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.
*Tompa A, Kocsis Zs, Marcsek Z, Jakab M, Szende B & Hidvégi M: Chemoprevention with Tamoxifen and Avemar by Inducing Apoptosis on MCF-7(ER+) Breast Cancer Cells, Proceedings of the 2nd Congress of the World Society for Breast Health, Budapest, June 24-28, 2004.
*Fajka-Boja R, Hidvégi M, Shoenfeld Y, Ion G, Demydenko D, Tömösközi-Farkas R, Vizler Cs, Telekes A, Resetár Á, Monostori É: 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 20: 563-570, 2002.
*Comín-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 277: 46408-46414, 2002.
*Boros LG, Lapis K, Szende B, Tömösközi-Farkas R, Balogh Á, 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 23: 141-147, 2001.
*Kiss-Toth E, Qwarnstrom EE, Dower SK, Hidvégi M, Duda E, Nagy T: Synergistic effect of Avemar on proinflammatory cytokine and ras mediated cell activation. 1st Congress of the Hungarian Society of Clinical Oncology, Budapest, Hungary, 10 - 11 November, 2000.
*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.
*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.
*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 26 (10), October 2004.
*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.: A medical nutriment has supportive value in the treatment of colorectal cancer, Br J Cancer 2003 Aug 4;89(3):465-9.
*Demidov LV, Manzjuk LV, Kharkevitch GY, Artamonova EV, Pirogova NA: Antimetastatic effect of Avemar in high-risk melanoma patients. 18th UICC International Cancer Congress, Oslo, Norway, 30 June – 5 July, 2002. (Abstract). Int J Cancer 2002; 100(S13): 408.
*Jakab F, Mayer F, Hoffman A, Hidvegi M: First Clinical Data of a Natural Immunomodulator in Colorectal Cancer, Hepato-Gastroenterology 2000; 47:393-395.
*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;1051:529-542.
*Telekes A, Kiss-Toth E, Nagy T, Qwarnstrom EE, Kusz E, Polgar T, Resetar 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.
*Sukkar SG, & Edoardo R: Oxidative stress and nutritional prevention in autoimmune rheumatic diseases, Autoimmunity Reviews 3 (2004) 199–206.
*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.
*Cascante M, Boros LG, Comin-Anduix B, Atauri P, Centelles JJ, Lee W-NP: Metabolic control analysis in drug discovery and disease. Nature Biotechnol 20: 243-249, 2002.
*Boros LG, Lee W-NP, Go VLW: A metabolic hypothesis of cell growth and death in pancreatic cancer. Pancreas 24: 26-33, 2002.
*Boros LG, Cascante M, Lee W-NP: Metabolic profiling of cell growth and death in cancer: applications in drug discovery. Drug Discovery Today 7(6), 18-26, 2002.
*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 of Tumor-Bearing Mice, Cancer Biother Radiopharm Volume 19, Number 3, 2004.
*Zalatnai A, Lapis K, Szende B, Rásó E, Telekes A, Resetár Á, Hidvégi M: Wheat germ extract inhibits experimental colon carcinogenesis in F-344 rats. Carcinogenesis 22: 1649-1652, 2001.
*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 10: 622-627, 2001.
*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 14: 277-289, 1999.
*Hidvégi M, Rásó E, Tömösközi-Farkas R, Lapis K, Szende B: Effect of MSC on the immune response of mice. Immunopharmacology 41: 183-186, 1999.
*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.
*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.

External links

* [http://www.avemarresearch.com/TOC.html Avemar Published Research, online references]
* [http://www.mskcc.org/mskcc/html/69418.cfm Summary info on fermented wheat germ as cancer-treatment botanical/nutritional complement] , by Memorial Sloan-Kettering Cancer Center's Website