Fermented wheat germ extract
From Wikipedia, the free encyclopedia
 |
Please see the discussion on the talk page. |
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 approved 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, FWGP also is under study 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 of FWGP in conditions at such widely distant points on the spectrum of abnormal immune system function as cancer and autoimmune conditions occurs because compounds in the extract called substituted benzo-quinones have been shown to modulate immune system function and cell metabolism away from the extremes of inactivity on the one hand, or over-activity on the other, supporting normal and protective ranges of function.
FWGP is derived from the germ (endosperm, or seed) of the wheat plant, and is a by-product of milling of wheat kernals to produce flour. FWGP 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. FWGP (trade names Avemar, Avé) is identified in some research studies by the laboratory code name MSC.
Like other naturally-occuring substances extracted from plants, FWGP was historically mainly the provence only of naturopathic doctors, holistic health practitioners, and herbalists. Today, however, such substances are increasingly of interest to more conventionally-trained physicians who study them for use them in those instances in which adequate, peer-reviewed published research has demonstrated substantial and quantifiable benefit.
[edit] Summary of laboratory and clinical research results
Results of cell studies, animal studies, and human clinical trials focused on cancer showed that FWGP has exhibited significant anti-cancer effects in a broad variety of cancer types.
[edit] Human clinical trials
FWGP improved survival, and reduced new recurrences and metastases in colorectal cancer patients. When used in a controlled study of 170 post-surgical colorectal cancer patients also receiving standard of care therapy such as chemotherapy, and/or radiation, addition of FWGP 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). [1]
In pediatric cancer patients with various cancer types, FWGP substantially reduced the risk of life-threatening infections accompanied by high fever, 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, enhanced immune system regulation, and helped white blood cells to cross through blood vessel walls and into tumors. [2]
In a melanoma study, of patients with advanced-stage (Stage III) melanoma skin cancer, FWGP 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. [3]
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 may be exploitable 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. [4] In another study, therapeutic effects of some conventional treatments used in combination with FWGP were increased, e.g., reduced metastasis, [5] 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. [6] In quality of life (QOL) tests, FWGP improved cancer patients’ quality of life, chiefly by boosting the activity of the immune system.
[edit] FWGP and automimmune diseases
Results of early research using FWGP in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) suggest FWGP may be of use in these diseases primarily for its antioxidant properties and for its ability to reduce inflammatory cytokines and rebalance the activity of Th1 and Th2 lymphocytes. [7] Clinical trials are underway to learn more about FWGP’s effects in SLE.
[edit] Animal studies
In animals with transplanted human lung cancer, FWGP added to chemotherapy increased survival markedly. [8]
In rats exposed to a substance known to cause colon cancer (AOM), giving the rats FWGP 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. [9]
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. [10]
Toxicity studies with the substance showed no toxicity at levels several times above the amounts recommended for use.
[edit] Cell studies
In a colon cancer cell study, FWGP caused 22% of the cancer cells to die due to apoptsis, and 28% due to direct cell-killing by FWGP. [11]
In estrogen-positive breast cancer cells, adding FWGP to Tamoxifen treatment killed more breast cancer cells than Tamoxifen alone, mainly by increasing apoptosis, (also referred to as programmed cell death or “cell suicide”). [12]
In T-cell and B-cell lymphoma cells, FWGP increased destruction of cancerous cells via forcing more cells into apoptosis. [13]
In tests against leukemia cells, FWGP controlled cell growth and proliferation, mainly by inhibiting enzymes needed to make new DNA to support replication of leukemic cells and by triggering apoptosis. [14]
In cell studies of pancreatic cancer, FWGP limited the creation of new pancreatic cancer cells by limiting cancer cells’ access to glucose, needed to make DNA and RNA for new cancer cells. [15]
In human and animal myeloid leukemia cells, and human cervical cancer cells, researchers found FWGP limited the growth and decreased the survival of the cancer cells, mainly by increasing the quantities of specific beneficial cell hormone-like substances called cytokines, such as tumor necrosis factor (TNF), which harm cancerous cells but not normal cells. [16]
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 most active natural compounds in FWGP, and ascorbate. The researchers believed the elimination was likely due to the interaction of the acites cells and very short-lived free radicals produced by the combination. [17]
Work by Szent-Gyorgyi and colleagues in 1985 showed the compound’s effects against the acites tumor cells was likely due to one of the active ingredients in FWGP causing a loss of NAD(P)H reducing power in the cells. [18]
[edit] How FWGP works
[edit] Against initiation of cancer (carcinogenesis)
In reducing the risk of cancer developing after exposure to cancer-causing substances, research done to date on FWGP suggests that it is the ability of the substance to maintain normal glucose metabolism that is most responsible for the increased protection against cancer in animals given the substance after or during exposure to cancer-causing substances. Cancer cells use many times more glucose (a sugar in the blood produced by digesting food) than normal cells do, a phenomenon known as the Warburg Effect. By using a different biochemical pathway than normal cells, cancer cells are able to use the extra glucose to rapidly they obtain to make large amounts of ribose, a five-carbon sugar that forms the backbone of DNA. DNA is needed to help form the nuclei of new cells. With the large amounts of ribose that cancer cells make rapidly with the extra glucose they use, they can divide to make new cancer cells very rapidly, enlarging tumors and fueling spread of the cancer. FWGP interferes with activity on the abnormal ribose-making pathway cancer cells use for this purpose, preventing their making enough ribose quickly to grow and divide rapidly.
[edit] Against cancer that is already established
Promotion of Immune Surveillance: Against already-established cancer, FWGP seems to have its most significant effects cancer through stimulating the immune system to better recognize and more vigorously attack cancer cells. The immune system mainly fights “foreign” molecules – microorganisms that originate outside the body. But cancer cells are abnormal cells that developed from normal cells, so like virtually all cells in the body, they have proteins on their surface called major histocompatibility complex, class 1 (MHC-1) proteins. Natural compounds in FWGP suppress the display of the MHC-1 proteins on the surface of cancer cells, making it easier for the immune system to recognize them as abnormal. FWGP compounds also spur an attack on cancer cells by natural killer (NK) cells, which can directly attack and destroy cancer cells. The increased recognition also the immune system’s T-cells respond more robustly to cancer, and help the immune system’s B-cells to produce more antibodies to attack the cancer.
Promotion of cancer cell apoptosis: Normally, cells with DNA too damaged to be repaired are forced into apoptosis, also known as programmed cell death. But cells can use an enzyme called poly(ADP-ribose), or PARP for short, to repair the DNA damage common to cancer cells. FWGP reduces PARP levels substantially, forcing many cancer cells into apoptosis, in which they are destroyed.
Restriction of cancer cell synthesis of ribose: FWGP’s ability to restrict cancer cell access to glucose for making ribose contributes much to its anti-carcinogenic effects, and is significant in slowing growth and spread of cancer that has already developed.
Increased ICAM levels: FWGP increases the production of a cell hormone-like substance called ICAM (intracellular adhesion molecule), which helps T-cells and macrophages to travel through the blood and invade and attack tumors.
Increased tumor necrosis factor alpha (TNF-a): FWGP boosts the production of), boosting the attack on cancer cells by macrophages, which can attack cancer cells directly.
Boosting of Immune System Cell Mobility: FWGP increases the activity of genes responsible for producing the cytokines interleukin-1-alpha, interleukin-alpha-beta, interleukin-5 and interleukin-6, important cytokines that increase the number of immune system cells and their mobility.
[edit] 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 biomedical properties of fermented wheat germ was initiated by the Hungarian biochemist Albert Szent-Gyorgyi, winner of the Nobel Prize in Physiology or Medicine in 1937 for his groundbreaking work in the discovery of vitamin C. In the later years of his career, Szent-Gyorgyi turned the focus of his research to cancer, a disease that had taken the lives of his first wife and his daughter, and other close family members.
An expert in cellular respiration and metabolism, Szent-Gyorgyi was also 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 begin investigating the biological properties of wheat germ to learn if it might be useful against cancer. By the time he began his cancer research, it had been discovered that cancer cells use huge amounts of glucose, compared to normal cells – a biochemical phenomenon known as the [Warburg effect]. Aware that cells’ overuse of glucose supports cancer cell growth and proliferation, Szent-Gyorgyi looked for substances in whole grains that might explain the anti-cancer effects of eating whole grains that he saw in his epidemiological observations.
In a series of early papers on wheat germ properties published in research journals, Szent-Gyorgyi laid out results of his studies 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 would concentrate the most effective metabolism-regulating quinones such as 2,6-DMBQ, he noted, so they could be taken as a supplement without the need to consume impractically large amounts of wheat germ.
However, large-scale fermentation processes were not sufficient at that time to produce enough quantities of the powder, and so Szent-Gyorgyi found himself with the same problem that he faced at one time in his work 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, still remained to be solved. Those problems remained unsolved at the time of Szent-Gyorgyi’s death in 1986.
Szent-Gyorgyi’s work was taken to fruition in the 1990s by a team led by Hungarian biochemist Mate Hidvegi, PhD. Hidvegi’s group used improved large-scale food industry fermentation processes to produce enough extract, and developed lab techniques to standardize the amount of active substances in any given amount of the powder. With initial cell and animal studies showing cell metabolism normalizing effects and pro-apoptotic effects important in combating cancer, human clinical trials were initiated. Currently, FWGP is approved in Hungary and several other European Union (EU) nations as a medical nutriment in support of cancer therapy, and is gaining increasing interest and use in the US as a dietary supplement.
[edit] Summary
Fermented Wheat Germ Powder (FWGP) is a powdered form of a plant extract, approved for use as a medical nutriment for support of therapy for cancer in Europe, and approved in the US as a dietary supplement. Identification of the specific active constituents in the extract dates back to the mid-twentieth century work of the Hungarian biochemist Albert Szent-Gyorgyi, famous for his discovery of vitamin C. More recent research has shown FWGP to be useful in supporting immune system modulation and cell metabolic regulation, promoting NK cell targeting ability and coordination of immune system activities such as the responses of macrophages, B-cell and T-cells, and helping to maintain healthy cellular and humoral (Th1 and Th2) balance. Beneficial 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 very important. Research with the substance continues at academic and medical institutions in the US, the EU, and in Asia.
[edit] 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.
