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FUCOIDAN Induce Apoptosis in Cancer Cells, Enhance Immunity, Suppress Angiogenesis & Reduce Side Effects of Chemotherapy and Radiation Dr.Daisuke Tachikawa Preface I am happy that this booklet can be published in English. Actually I did not believe in any dietary supplements before; however Fucoidan made me change my idea about dietary supplements. I have been using Fucoidan as a cancer treatment in Japan. Since I have used Fucoidan, my patients began to smile again. The purpose of cancer treatment is not only to suppress or eliminate cancer, but also to maintain a good quality of life for patients and families. I am always pleased to see the smile back on their faces. Moreover, I am also very fortune to hear patients’s joyful feedbacks when their tumor is suppressed and reduced and the side effects of chemo and radiation therapy are decreased. It is very important to treat patients effectively, to eliminate or moderate side effects. Therefore I am very happy to introduce the wonderful supplement Fucoidan not only to Japanese people but also to people in the United States. Dr. Daisuke Tachikawa March 2007 Copyright © 2007 by Daisuke Tachikawa All right reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form without the prior written permission of the coppyright owner. The information in this book is for educational purposes only and is not recommended as a means of diagnosing or treating an illness. All matters concerning physical and mental health should be supervised by a health practitioner knowledgeable in treating that particular condition. Neither the publisher nor the author directly or indirectly dispenses medical advice, nor do they prescribe any remedies or assume any responsibility for those who choose to treat themselves. ISBN: 0-9771370-3-1 ISBN 13: 978-0-9771370-3-9 Printed in the United State of America Introduction OKINAWA – THE PREFECTURE BOASTING THE HIGHEST LONGEVITY IN JAPAN! Okinawa, the southernmost prefecture of Japan, is known as the “island boasting the highest longevity in Japan”. It is also where the mortality rate by cancer is the lowest in the nation. One of the reasons is considered the unique dietary habits of the eties of sea vegetables such as kombu (laminaria japonica), mozuku (nemacystus decipiens) and mekabu (the pleated section of wakame, or undaria pinnatifida, near the root). Kombu is usually produced in the northern sea around Hokkaido, but there is a reason people in Okinawa have come to eat kombu as part of their traditional diet. Japan began exporting kombu to Qing (the current China) during the middle of the Edo period (around the first half of the 18th century). Okinawa was a gateway port through which kombu was brought to Qing. This is why kombu became a popular food in Okinawa. While people on the island of Honshu (the largest island in Japan) often use kombu to make soup stock, Okinawans generally eat kombu directly. When consumed this way, all the natural nutrients can be accessed and absorbed. Okinawa is the largest consumer of kombu in Japan. Moreover, it is said that the amount of mozuku consumed in Okinawa is 10 times as much as the amount consumed in any other prefecture. We often associate mozuku with the small dish accompanying sake. In Okinawa, however, mozuku is commonly used in miso soup or zosui (Japanese porridge of rice and vegetables). Everyone must have heard somewhere that sea vegetables are good for the body, since it is abundant in vitamins as well as iodine, calcium, manganese, iron, zinc, potassium and other minerals. Sea vegetables absorb the abundant minerals dissolved in seawater as they grow, so naturally it is a rich source of minerals. In a sense, sea vegetables are concentrate of all the goodness found in the sea. Sea vegetables is classified by pigment composition into brown algae, red algae, green algae and blue algae. The brown algae group includes kombu, wakame, hijiki (hijiki fusiforme) and mozuku, while red algae includes tengusa (agar-agar) and amanori (porphyra). Green algae includes aonori (green laver) and aosa (sea lettuce), while blue algae includes kudamo (Lynbya confervoides) and higemo (Rivularia). Plants grow by means of photosynthesis, and sea vegetables in the ocean also conducts photosynthesis. Blue algae-which attaches itself to rocks and quay walls-and the green algae found in relatively shallow seas, grow where they can receive sufficient amounts of light. The red algae can conduct photosynthesis in the presence of relatively little light found in deeper waters, while brown algae often inhabits the intermediate depths. People of the modern age have an unbalanced diet lacking in vitamins and minerals, and this imbalance tends to invite the onset of diseases. However, kombu, mozuku and other varieties of sea vegetable replenish the body with vitamins and minerals. This is why sea vegetables are believed to be good for the health. Howwever, simply understanding the natural goodnes of sea vegetables do not reveal the secret of longevity long enjoyed by the people of Okinawa. The key to that secret lies in fucoidan. What is Fucoidan? Fucoidan is a recent discovery that has seized the attention of the medical communitu. Not a few people know that agaricus (agaricus blazei murill) is a type of mushroom having a cancer-healing effect. Yet fucoidan also enhances the body’s immunity, much like agaricus. In addition, fucoidan provides an anticancer effect by way of inducing apoptosis. Fucoidan is found in marine algae (brown algae) such as mozuku (nemacystus decipiens), mekabu (the pleated section of wakame, or undaria pinnatifida, near the root), and kombu (laminariaa japonica). The “simy” constituent of sea vegetable is a rich source of fucoidan, which is a general term referring to a group of polysaccharides containing sulfated fucose. Recent studies have found that “polysaccharides”, a class of dietary fiber contained in brown algae, have health benefits for human. Polysaccharides are constituted by monosaccharides such as glucose, xylose and galactose. They are considered “bioactive substances” that are drawing the attention of late. Many of you may have heard of the anticancer action of “ß-gluco” contained in agaricus and fomes yucatensis. This ß-glucan is also a polysaccharide. Konbu, mozuku, and mekabu (the accordion-like part of wakame found near the root), all have one common feature, which is that they are all slippery and gluey. The main substance that causes sea vegetable slippery is “fucoidan”, which is another polysaccharide constituted by multiple bonds involving a sugar called “fucose”. The key difference between fucoidan and other polysaccharides is that fucoidan contains a lot of sulfate groups (SO42-). From the word “sulfate group”, you might think of sulfuric acid (H2SO4), which is a liquid of strong acidity that melts all metals other than gold and platinum and also burns our skin. However, the sulfate group is an entirely different substance from sulfuric acid. It is what makes sea vegetable slimy. Three Main Powers of Sea vegetable “Fucoidan” Cause Cancer Cells to kill themselves THIS SLIPPERY SUBSTANCE CAUSES CANCER CELLS TO WEAKEN AND SHRINK NATURALLY. Let’s learn about the “three powers” of fucoidan. The secret of its incomparable “anti-cancer” power! Fucoidan has been shown to offer a variety of pharmacological actions. These results encouraged researches to carry out numerous experiments and studies on fucoidan in hopes of finding new functions of fucoidan that are effective in treating cancer. The findings of these experiments and studies using lab animals, etc.., have shown that fucoidan is indeed effective in treating cancer. Unlike traditional health supplements that claim to offer anticancer effects, the effectiveness of fucoidan is three-folds. The functions of fucoidan are: [1] Induce apoptosis in cancer cells [2] Enhance immunity [3] Suppress angiogenesis It is considered that these three functions cause cancer cells to naturally weaken and shrink and eventually die. So, let’s talk briefly about the “three anticancer powers” unique to fucoidan. Power [1] Amazing Apoptosis Inducing Action There are two ways in which cells die: one is “apoptosis”, and the other is “necrosis”. Necrosis refers to a form of cell death in which a cell is damaged and dies as a result. It is defined as pathological death of cells caused by external factors such as burn and bacterial infection. Necrosis causes the cell membrane to collapse. It also causes heat generation or inflammation in the surrounding tissues. On the other hand, apoptosis refers to a phenomenon in which the cell nucleus shrinks and the cell itself becomes smaller and eventually lowed and processed by phagocytic cells. Therefore, apoptosis does not cause inflammation or other damage to the surrounding tissues. Each cell is genetically programmed in its DNA to undergo apoptosis. It is lite or other drug, NK cell, or killer T cell, this program will be activated and the cell will undergo apoptosis. You may be surprised at learning that “all cells are programmed to die”. However, this mechanism of “selfdestruction of cells” is a very important phenomenon in the workings of nature. The hands and feet of a human fetus have the shape of a single, small plate, like the feet of a waterbird with webbed toes. At this time, the cells that had formed the webs between the fingers/toes naturally disappear due to apoptosis. When a tadpole grows and becomes a frog, it loses its tail. After a caterpillar undergoes metamorphosis into a butterfly, it no longer has the muscle cells and nerve cells that had controlled the peristalsis in the caterpillar stage. These processes occur through apoptosis. In addition to these visible changes, various invisible changes are occurring in our body every day due to apoptosis. In many cases, apoptosis is involved in the process of discharging from our body those old cells that are no longer necessary. Tissues that produce blood also undergo apoptosis. Our body produces a certain number of blood cells daily, but excessive erythroblasts, neutrophils and other white blood cells are removed from our body through the natural selection process by means of apoptosis. Apoptosis inducing action causes cancer cells to die naturally! Cells that have become cancerous are mutated forms of normal cells. If the mechanism of apoptosis is poperly at work, these cells ahould die naturally just like normal cells do. However, cancer cells do not die by themselves because their apoptosis system no longer functions properly. Normal cells have a certain life span and are said to remain alive almost indefinitely. The cells of “uterine cervix carcinoma” collected by a U.S laboratory in 1951 have been cultured at laboratories around the world and are still alive and growing. Today, these cells are used in various research. This strong vitality is what makes cancer treatment very difficult. Cancer cells also “travel” to all places throught the body, even to far away locations, through lympho nodes and blood vessels connected to the original site of cancer. After arriving at new locations, cancer cells take roots and start creating new lesions. This is the principle of “metastasis” of cancer. If cancer metastasizes to many locations, or to locations where the cancerous lesions cannot be removed by surgery, treatment will become significantly more difficult. Assume that all cancerous lesions have been removed by surgery. If even one cancer cell is left, that cell will replicate and metastasize again to eventually ruin our body. This is what we call “relapse” of cancer. Cancer is very different from other diseases in that it involves metastasis and relapse that can be repeated. If we can find a substance that eliminates these troublesome cancer cells by inducing their apoptosis, such substance will surely make a wonderful anticancer drug. Needless to say, however, this substance must not cause normal cells to undergo apoptosis. One of the very reasons why fucoidan is drawing such a ken attention today is the possibility that it can lead “only” cancer cells to apoptosis. There are concerns of side effects from drugs and supplements claiming to induce apoptosis. No such worries are necessary with fucoidan, as it is a natural substance produced in sea. You will never have health problems from overeating mozuku. Our body can ingest fucoidan safely. At the 55th General Conference of the Japanese Cancer. Association in 1996, one report attracted the audience’s attention. In this report, the researchs found that fucoidan not only caused cancer cells to self-destruct, but it also had virtually no negative effects on normal cells. This report triggered numerous experiments and studies by other researchers, and encouraging results have bên published one after another. Traditional cancer treatment in western medicine consists of “three key therapies” designed to “kill cancer cells using external means”, such as “surgery to remove cancerous lesions”, “anticancer drugs to weaken and destroy cancer cells”, and “radiation to target cancer cells for destruction”. These three therapies not only affect cancer cells, but they also damage normal cells to a certain degree. This is why these therapies are all associated with side effects, such as hair loss, nausea, emesis, loss of appetite and fatigue, as well as drop in QOL (Quality Of Life). On the other hand, the “apoptosis inducing action” of fucoidan causes only cancer cells to “kill themselves”. The medical community is paying ciated with traditional cancer treatments. Apoptosis is described as “programmed cell death”. It is a part of the growth mechanism of normal cells, whereby unnecessary cells or harmful cells are eliminated. Normal tissues remain homeostatic by maintaining a balance of cell growth and cell death caused by apoptosis. We have already learned that apoptosis is what causes a tadpole to lose its tail when it becomes a frog. With abnormal cells, however, “suppression of apoptosis” becomes a cause of tumorigenic transformation and metastatic infiltration. Studies are ongoing to understand the mechanism of how apoptosis wekens and shrinks cancer cells. This mechanism can be explained as follows based on the findings obtained to date: [1] An apoptosis inducing factor activates a self-destruction switch on a cancer cell and therefore inhibits DNA synthesis in the cell. [2] Perforin released by NK cells and T cells destroys the cell membrane of a cancer cell and causes the cancer cell to die. Also, granzyme released by T cells also lead cancer cells to apoptosis by destroying cancer genes. [3] Fucoidan activates caspase (= a proteolytic enzyme found in cells) in a cancer cell and therefore leads the cancer cell to apoptosis. Although how fucoidan specifically works on Fas (= cancer cell membrane receptor) for the activation of caspase is not yet reveled in details and research is still underway, the aforementioned reasons offer likely explanations as to why cancer cells kill themselves. Fucoidan has been shown by a series of recent studies to have a strong role in the mechanism of leading cancer cells to apoptosis. Fucoidan in mozuku exhibits strong apoptosis inducing action LEADING CANCER CELLS TO APOPTOSIS… So, how can we confirm that this is really happening? Professor Hiroshi Taguchi of Mie University’s Facully of Bioresources (Molecular and Cellular Biology) conducted an experiment that helps answer this question. In this experiment, a solution consisting of fucoidan dissolved in saline solution was mixed with a culture solution containing human cancer cells. A saline solution without fucoidan was preparedas a control and similarly mixed with human cancer cells. When the samples were observed, cancer cells in the fucoidan solution soon began losing their outer profile and most cancer cells died and disappeared within 24 hours. Professor Taguchi explains about this outcome as follows: “Cancer cells lost their shape, weakened, and broke into small pieces. This is a typical pattern of cell death due to apoptosis”. Why do cancer cells kill themselves due to apoptosis? There are two mechanisms at work here. On is that fucoidan issues a cue that triggers a self-destruction switch on the surface of a cancer cell, thereby leading the cancer cell to apoptosis. The other is that “perforin” released from NK cells and T cells make holes in the membrane of a cancer cell and destroys the cell nucleus, while “granzyme” released from T cells also destroys the genes in a cancer cell. Both substances have the effect of inducing apoptosis. (NK cells and T cells will be explained later). Cancer cells in which apoptosis has been triggered will have the helical structure of their genes (DNA) broken down, while their cucleus will also become fragmented into pieces. Eventually, the cells will die. Cancer cells undergoing natural death by means of apoptosis experience DNA fragmentation. In experiments aimed at studying the apoptosis inducing capability of substances, the researchers generally calculate the rate of cell fragmentation just like Professor Taguchi of Mie University did. There is an experiment in which the researchers studied three substances to see if they had “apoptosis inducing action” against two types of cancer cells – cancer cells of human ovarian cancer and those of premyelocytic leukemia. The substances studied were: [1] fucoidan from Okinawa mozuku, [2] fucoidan from kombu, and [3] agaricus. In solutions containing the respective substances at specified concentrations, two types of cancer cell strains were introduced and rates of DNA fragmentation were measured. (Refer to the graphs on the next page) The results found that with both the samples of fucoidan from Okinawa mozuku and fucoidan from konbu, the rate of fragmentation increased as the fucoidan concentration in the solution increased. With the agaricus sample, on the other hand, fragmentation was virtually absent even when the concentration was raised. When the samples of fucoidan from Okinawa mozuku and fucoidan from konbu were compared in the experiment, the rate of fragmentation was higher with the sample containing Okinawa mozuku by 40 to 50 percent compared to the sample containing fucoidan from konbu. This result suggests that different varieties of fucoidan have different apoptosis inducing capabilities and that fucoidan from Okinawa mozuku would have stronger power to induce apoptosis. There is still an unanswered question, which is whether fucoidan directly contributes to apoptosis induction, or induces apoptosis indirectly by activating NK cells, or has both effects. We must wait for further experiments and studies for the answer. However, one thing is clear, and that is fucoidan causes cancer cells to kill themselves. This mechanism will certainly cast a new light on cancer treatment. Power [2] Enhancing “Immunity” to Destroy Cancer! Our body has a natural mechanism to eliminate foreign substances entering our body, such as pathogens and viruses, and make them harmless. This is called the “immune system”. In a sense, immunity is a system that differentiates external substances from internal substances and eliminates external substances. We know people who easily get a cold and who don’t. What’s the difference between these two groups of people? When a cold virus enters our body, our body can eliminate the virus if we have strong immunity. If we have a poor health and our immunity is weak, however, the body cannot eliminate the virus and we will fall ill as a result. To our body, cancer cells are also foreign substances. There are groups of cells that control immunity in our body. They are called “T cells” (= killer T cells that destroy foreign substances, helper T cells that enhance immunity, etc.) and “B cells” among lymphocytes found in our blood streams. “Macrophages” and “natural killer cells” (= NK cells) also have a hand in our immunity system. These immune cells act like guards to defend against and attack foreign substances. SO, HOW does this “IMMUNE SYSTEM” Work? Lymphocytes are classified into “T cells” and “B cells” produced from stem cells in our bone marrow. B cells produce antibodies (immune globulins) and mainly attack bacteria, virus and other foreign substances. T cells do not produce antibodies. “Helper T cells” produce a bioactive substance called “lymphokine” and act upon B cells to produce antibodies. When the target foreign substance has been removed, “suppressor T cells” instruct the attack to be stopped. If the attack in the body. “Killer T cells” directly attack cancer cells and other foreign substances. These lymphocytes are not the only cells that attack foreign substances. “Macrophages” also act as switches to active our immune system. Macrophages can take foreign substances into themselves and kill them, and hence their name (macrophage means “bieg eater”). In addition to “eating” foreign substances, macrophages also have the effect of informing T cells of the existence of foreign substances by releasing enzymes and cytokines (interferons, interleukins and other bioactive substances). This action is called “antigen presentation”. On the other hand, “natural killer cells (NK cells)” act without being instructed or commanded by other cells. They are literally ”killers” who immediately attack foreign substances as soon as they are found. Although it takes a long timer after a cell becomes cancerous until a group of cancer cells turn into a tumor, NK cells are able to eliminate abnormal cells that have just begun turning cancerous. OUR IMMUNITY DECREASES WITH AGE… “Immunity” is a natural defense mechanism we have in our body. As long as the immune cells explained above remain active and functioning properly, they can protect us from diseases even when various viruses, bacteria or pathogens enter our body, or when cells mutate and turn cancerous. If everyone has “immunity”, then why do some of us get cancer? Does immunity not work on cancer? A simple answer is because our immunity decreases with age. The functions of human body will peak at around 20 years of age and gradually weaken thereafter. For example, if you find that a scar is healing much more gradually, you cannot see as must as before or your potency is decreasing, it is a sign that “aging” process has begun. Regrettably, immune cells also age and therefore as we get older, our body becomes prone to various diseases. All of you must have seen some signs of decreasing immunity. Have you had a small injury that didn’t heal as quickly as before? Do you feel it takes a longer time to recover from a minor cold or flu? Aging is not the only cause that decreases our immunity. Immune cells may decrease in number or their function to eliminate harmful “active oxygen” may weaken for other reasons. Representative factors include contamination of food and environment due to numerous chemical substances, and stress of modern society. These factors accumulate and cause the immunity of today’s people to drop. Fucoidan activates NK cells Dr. Makoto Fujii of Kagoshima University is conducting animal studies and other research on fucoidan, believing that it can be used effectively in treatment, mice were hypodermically implanted with cancar cells (tumor cells called “sarcoma 180”). The mice were then divided into two groups: one fed with a feed containing fucoidan. The two groups were observed and changes were examined after 20 days. ▪ The tumor weight was around 1.06g with the mice fed with a feed not containing fucoidan, but the tumor weight had decreased substantially to approx. 0.24g with the mice fed with a feed containing fucoidan. (Refer to the top graph on the next page). ▪ When the while blood cell count in the mouse’s spleen was checked as an indicator of NK activity level, the mice fed with fucoidan axhibited higher levels of NK activity. (Refer to the bottom graph on the next page). What do these results mean? We have approx. 60 trillion cells in our body, where old cells die and are replaced with new cells. It is said that all cells in our body are renewed in 200 days. However, not all renewed cells are healthy. According to studies, more than 3000 abnormal cells are produced in our body each day. Although our body can eliminate these abnormal cells as long as we are healthy, if some of them remain in the body for some reason they will start growing and become “cancerous”. Immune cells called “natural killer cells (NK cells)” are lymphocytes that monitor our body for production of abnormal cells. When a cell mutates for some reason, these NK cells will detect the mutation and attack the mutated cell. In other words, NK cells have the function to detect cells that have turned cancerous, travel to positions adjacent to these cancer cells, and then introduce a substance called “granzyme” into the cancer cells. Given granzyme, the cancer cells will soon “self-destruct”. Self-destruction of cells is called “apoptosis”. When NK cells are active, they will induce apoptosis in cancer cells. This mechanism is substantiated by the result of Dr. Fujii’s experiment, in which the mice fed with fucoidan showed elevated activity levels of NK cells and reduced weights of tumors. At the 8th Meeting of the Society for Natural Immunity held in the Netherlands in April 2004, I (Dr. Tachikawa) presented the result of my study entitled, “Cancer Suppression Effects of Foods Containing Fucoidan”. The content of this study sparked keen interest in the audience. In my presentation, I reported on one animal study, details of which are explained below. In this study, mice hypodermically injected with sarcoma 180 were divided into five groups and fed with different feeds containing: [1] normal feed (control group), [2] mozuku fucoidan, [3] mekabu fucoidan, [4] agaricus mycelium extract powder, and [5] Fucoidan Mix. They were fed with the respective feeds for 23 days, after which the “NK cell activity” and “tumor weight” of each group were compared. They analysis and comparison of “tumor weight” among the respective groups found that the tumor weights in all groups had decreased by nearly one-third except for the control group fed with a normal feed. The mice in all groups from [2] to [5] demonstrated reduced tumor weights. (Refer to the top graph on the next page). When the “NK cells” of tested groups were analyzed and compared, the mice in all groups from [2] to [5] exhibited high levels of NK cell activity. Among others, however, the group fed with feel containing Fucoidan Mix showed the highest levels of NK cell activity. (Refer to the upper graph on the next page). Currently many researchers are conducting various experiments on fucoidan, and cases have been reported where cancer cells disappeared or became smaller. In many of these studies, the researchers concluded that the disappearance or reduction of cancer cells were due to the effects of fucoidan to increase immunity in the tested animals and attack cancer cells in their body. Enhance immunity and kill cancer cells – the statement sounds familiar, as it is the exact claim of agaricus, fomes yucatensis and other mushrooms said to be effective in treating cancer. Studies have shown that fucoidan also has the same function Fucoidan has also been shown to enhance the production of “interleukin-12 (IL-12)” and “interferon-g (IFN-g)”. Interleukin-12 is produced by macrophages and B cells, and has the effect of activating T cells and NK cells and thereby enhancing the effectiveness of attack against cancer cells. Interleukin-12 also activates the production of interferon-g by T cells and NK cells. Interferon-γ is a lymphokine (bioactive substance) produced by lymphocytes. It is a “hard worker” that not only attacks viruses and cancer cells effectively, but also activates macrophages and NK cells. For your reference, interferon-γ is used widely as a drug to treat chronic hepatitis C and kidney cancer. Fucoidan activates “intestinal immunity” As explained earlier, our “immune system” attacks and defends against harmful external substances through the synergistic actions of various immune cells and bioactive substances such as NK cells, mcrophages and interferons. In our body, the bone marrow, thymic gland, spleen, lymph nodes and blood vessels are representative organs that contribute to the immune system. Besides these, the intestinal tract is also a key-and the largest-organ that provides immunity in our body. The immune function provided by the intestinal tract is called “intestinal immunity”. You have already learned that immunity prevents harmful substances such as viruses, pathogens and molds from being introduced into our body. The intestinal tract provides the last bastion against intrusion of foreign substances. Around 60% of all lymphocytes in our body concentrate in the intestinal tract. If foreign substances get past the intestinal tract, they will have serious consequences on our body. In this sense, “intestinal immunity” is literally the last bastion. The surface of the small intestines is covered by 30 million “villi”. The surface of these villi in turn consists of “epithelial cells”, and “T cells” exist between epithelial cells. It is believed that these T cells monitor epithlial cells that frequently metabolize and detect if they have become cancerous. Once cancer cells are found, T cells will eliminate them right away. Capillaries run immediately below epithlial cells, and the “proper mucous membrane” is found around these capillaries. The proper mucous membrane is where macrophages, T cells, B cells and other “lymphocytes” are found, and therefore it constitutes an immune system in its own right. B cells exist in the greatest number among all lymphocytes found in the proper mucous membrane, and B cells are believed to have the function to synthesize IgA is secreted in large quantities into the viscous membranes of the intestines. It neutralizes foreign substances including harmful bacteria and viruses and makes them harmless, while also suppressing abnormal growth of inner-intestinal bacteria. In the small intestines, three is an immune tissue called the “Peyer’s patch”. The Peyer’s patch is the control tower of intestinal immunity that controls the immune functions of the intestinal tract. Epithelial cells that cover the Peyer’s patch include “M cells”. Everything that enters the small intestines is carried to the Peyer’s patch by M cells. In the Peyer’s patch. Macrophages check each substance to determine if it can be forwarded to the large intestines. If the substance is found harmful, macrophages inform helper T cells that are standing by around them. Helper T cells then release cytokine and inform lymphocytes such as macrophages, NK cells, killer T cells and B cells, which all attack the substance. Lymphocytes also create a barricade to prevent pathogens from traveling any further. In a way, they provide what we call an “iron defense”. SO, HOW does this INTESTINAL IMMUNITY Work when fucoidan enters the small intestines? Fucoidan is first introduced into the M cells in the Peyer’s patch. Macrophages standing by in the Peyer’s patch mistakenly determine fucoidan as a harmful substance. This is because fucoidan is a polysaccharide made of monosaccharide bonds. Because of this structure, fucoidan is not broken down in the stomach, etc.., and arrives in the small intestines virtually intact. Accordingly, all lymphocytes attack fucoidan. This is not actually bad, because it has the effect of activating lymphocytes and conquently enhancing our body’s defense power against other pathogens. In recent years, researchers studing fucoidan are making the assumption that a protein called the “TLR” (Tolllike Receptor: a receptor essential for the body’s natural defense against mycotic infection), which is found at the surface of cells that provide the antigen presentation function, is also involved in intestinal immunity. In other words, researchers are thinking that when fucoidan, which is a polysaccharide, stimulates intestinal immunity and activates its immune system, this TLR promotes the process of signal transmission to T cells to cause them to attack other pathegens, which will consequently increase the effect of immunity. The key point here is that fucoidan is a polymer that can stimulate intestinal immunity. For us to remain healthy, it is important that our body maintains resistance to pathogens and viruses and keeps high level of immunity at all time. The same thing can be said for cancer. It goes without saying that, for us to remain cancer-free, we must increase our immunity. Why fucoidan’s immunity activation fucoidan shrinks cancer cells Now, we will give you a brief explanation of the immunity activation function of fucoidan (although the mechanism of how this function works is actually very complex). (Note that the information provided here is based on the latest theory and some parts are still based on hypothesis). There are various cells that control our immunity. Representatives of such cells include granulocytes, macrophages, NK cells and lymphocytes, which all work together to enhance our immunity and attack and repel cancer cells. Among these cells, macrophages, NK cells and “T cells”, which are types of lymphocyte, are particularly important. “T cells” include helper T cells, suppressor T cells and killer T cells. In terms of immunity in the context of cancer treaetment, “helper T cells” and “killer T cells” are of particular interest. “Helper T cells” are classified into type 1 (=Th1) and type 2 (=Th2). When macrophages release IL-12 (=interleukin-12), type 1 helper T cells (Th1) are activated. NK cells, or natural killer cells, differentiate tumor cells and release perforin at identified tumor cells to destroy their cell membrane and consequently kill the cancer cells. This action of NK cells is activated by IL-2 (=interleukin-2; 1 T cell growth factor) released form Th1. As you can see, many players are involved and work in an intricate manner to provide in our body. In addition, the immune responses due to “intestinal immunity” and “TLR” (= Toll-Like Receptor) also stimulate macrophages to released and NK cells and cytotoxic T cells are activated. This way, the “apoptosis inducing action” and “immunity activation action” of fucoidan produce synergistic effects to provide signficant functions that contribute to cancer treatment strategy. As shown in the illustration above, IFN-γ released from Th1 reduces IgE antibody. On the other hand, IL-4 (=interleukin-4; a B cell growth factor) released from Th2 enhances IgE antibody. Th2 is dominant in patients suffering from cancer or allergy. How to dissociate Th2 and make Th1 dominant represents an important strategy for cancer treatment. “Th1” is the name of helper T cells among T lymphocytes that release IL-2, IFNγ and other cytokines. The IL-2 level is low in cancer patients. IL-2 is a factor that induces CTL (cytotoxic T cells). In other words, the two most importan factors in cancer treatment strategy is to increase “immune response” by activating the ability to produce IFN-γ and IL-2 and thus the responses of IFN-γ and IL-2 in order to activate CTL and NK cells, and also to “induce apoptosis”. Fucoidan creates a Th1 dominant environment and enhances the responses of IL-2 to induce CTL and also activate NK cells. This is why fucoidan is extremely effective in treating cancer. Power [3] Suppression of Angiogenesis by Stripping Cancer Cells of Nutrients As explained above, fucoidn first causes cells to kill themselves (by inducing apoptosis). Next, fucoidan activates to maximum levels macrophages, NK cells and other immune cell that constitute our natural immune system to allow them to attack cancer effectively. However, these are not the only powers of fucoidan. Fucoidan also has the third weapon, which is “angiogenesis suppression action”. Cancer cell take roots in tissues throughout our body and start forming tumors. Once the cancerous lesion grows to a certin size, the cancer cells will require a supply of nutrients and oxygen. To solit and grow, cancer cells will generate new blood vessels around them to have nutrients and oxygens transported to them. These “new blood vessels” also serve as the routes through which cancer cells metastasize. Generation of new blood vessels associated with cancer is called “angiogenesis”. Researchers are developing various new drugs to suppress angiogenesis. If we can suppress angiogenesis associated with cancer, we can block the supply routes for cancer cells and consequently eliminate cancer. Studies have shown that fucoidan has this “angiogenesis suppression action”. At 12th International Congress on Immunology held in Canada in July 2004, data was released regerding a study where the efffects of fucoidan to inhibit lumen formation associated with human umbilical vein endothelial cells (HUVEC) were examined. In this experiment, both mozuku fucoidan and mekabu fucoidan were found to offer high inhibition effect against lumen formation associated with HUVEC. (Refer to the graphs on the preceding page). In other words, fucodian has the effect of blocking the generation of new blood vessels through which cancer cells receive nutrients and oxygen and also metastasize. Studies have shown that in patients not taking fucoidan, cancer cells grow at a constant speed at first and their growth speed accelerates once new blood vessels are generated around them. These studies have also shown that patients taking fucoidan do not exhibit such change in the growth speed of cancer cells. These results clearly indicate that fucoidan is inhibiting the generation of new blood vessels. Let’s summarize what we have learned so far: [1] Fucoidan induces apoptosis in cancer cells [2] Fucoidan enhances immunity [3] Fucoidan suppresses angiogenesis The synergistic effects of these “three anticancer powers” are simply amazing. This is why fucoidan is much talked about on the media and drawing the keen interest of the medical community not only in Japan but around the world. Interview with Cancer Clinician Dr. Tachikawa Clinical Case [1] Stomach Cancer Fucoidan enables quality medicine --- You have handled many cases. Do you remember any patients who demonstrated particulary impressive results? I remember one patient who visited our hospital in February 2004. This patient A was in his 50s. He had all his stomach removed five years ago due to “stomach cancer”. He also has his spleen and gallbladder removed by surgery and undergone lymphadenectomy, as well. His cancer was in stage IIIa. He had not received chemotherapy after the surgeries, and suffered repeated cased cased of “intestinal obstruction”. His condition deteriorated at the beginning of 2004 and when he received examination at a hospital, they found stricture of rectum due to peritoneal metastasis (Schnizler metastasis), with the descending colon and sigmoid colon also having strictures. He was diagnosed with “cancerous peritonitis”. The hospital even thought about putting an artificial anus and began chemotherapy using TS-1. However, after realizing that he had “hepatopathy”, they decided to use Taxotere, an anticancer drug, instead. --- So he was in a fairly bad state. “Intestinal obstruction” prevented him from eating normally. He first visited us to continue with his treatment with Taxotere. However, we decided that Taxotere was producing little effect. After discussing with him and obtaining an infermed consent, we decided to use TS-1 together with fucoidan for suppressing side effects. We also used “high-pressure oxygen therapy” to enhance the effectiveness of chemotherapy for improvement of intestinal abstruction. --- How was the result? TS-1 was administered in the cycle of four weeks of administration and two weeks of rest. After the first cycle, he was already able to eat. We were satisfied with the gradual improvement in strictures in his rectum and colons. He also benefited from virtual absence of side effects caused by the anticancer drug. He took approx.4g of fucoidan, corresponding to 20 capsules, every day. Eventually the strictures improved to a level where he no longer needed an artificial anus. He was discharged in May. --- How is he doing now? He is continuing his outpatient once every month, and has recovered very well. The strictures have been corrected, which indicates a considerable shrinkage of cancerous lesions. He could not eat at all before the treatment and could not use the anticancer drug without suffering from side effects. It is amazing how he to see us once a month. Clinical Case [2] Ovarian Cancer --- How about other patients? There is this case involving female patient B in her 30s. she received examination at a university hospital in October 2003 after experiencing a bloated feeling in the abdomen. She was diagnosed with “left ovarian cancer”. She also had cancerous peritonitis and cancerous ascites. She was advised to undergo surgery, chemotherapy and radiotherapy. However, she refused to all treatment options and came to our hospital in November 11 to get a second opinion and also receive consultation on fucoidan. After examining her, I also recommended surgery, chemotherapy and radiotherapy just like the doctors at the university hospital did. Still she refused to do the surgery or receive any traditional treatment. She thought about her course of treatment for a week, and came back. This time, she was accompanied by her husband and parents. We disscussed the options thoroughlt, but she still wanted to avoid surgery or chemotherapy. We respected her wishes and began treatment bassed solely on fucoidan therapy. She took approx.8g of fucoidan orally in liquid form. --- How is she progressing after the treatment? We treated her ascites by opening a hole in her abdominal cavity to release the fluid. We drew around 3000 to 4000 cc of fluid at a time. Although the quantity was slightly high based on clinical experience, we decided on this level in consideration of cosmetic (appearance) reasons. She used to have the paracentesis produre once a month at the beginning, but the inteval has since become longer and now she receives the procedure only once every 1.5 months to 2 months. The tumor size also shrank. The tumor, which was around 11 cm at the beginning, became 7cm, and now it is only 6cm. The center part of the cancerous lesion began to undergo necrosis, and we believe this is either because “angiogenesis” is suppressed (refer to p.30 to 33) or cancer cells are undergoing apoptosis. --- So her treatment was very effective. Yes. Although ascites remains at the same level of class VI based on cytodiagnosis, her cancerous lesion is shrinking and she living normal life except for visiting us once every 1.5 months to 2 months. It is amazing. She has not received any treatment other than taking fucoidan. Clinical Case [3] prostate Cancer --- It is true that not only anticancer drugs but also hormone drugs have side effects? Hormone drugs are commonly used in the treatment of “breast cancer” and “prostate cancer”, and it is true that they are not free from side effects. However, fucoidan has the effect of reducing side effects from hormone drugs. I give you an example of patient E in his 70s who was diagnosed with “prostate cancer”. He was diagnosed with prostate cancer in 2003 and a surgery was scheduled. However, he developed inflammation and the surgery was postponed. As a temporary measure, he received hormone therapy. However, his PSA tumor marker did not stabillize and he was also suffering from strong malaise throughout his body, probably as a side effect of his hormone therapy. Not only that, he began experiencing impotence. Accordingly, he stopped the hormone therapy and visited our hospital in February 2004. he had a strong desire to maintain his male function and treat his cancer without resorting to surgery or hormone therapy. Respecting his desire, we decided to treat him by combining fucoidan with an aglycon-type isoflavone. Although it has a chemical structure resembling that of estrogen, isoflavone does not have strong hormonal effect. He began his outpatient treatment once every 1.5 months to 2 months, and we had a very good result. His PSA level dropped from 10.0 before the treatment to 0.96 in two months, and subsequently dropped to a level of 3.74 to 3.62, well below the normal level of 4.0. CT images also clearly show that his tumor has shrunk. He is continuing with his treatment without experiencing any drop in QOL, because his male function is not affected. Other amazing power of Fucoidan Not surprisingly, fucoidan also provides great benefits in the curing of many adult diseases other than cancer. For example, fucoidan is effective for patients suffering from heart diseases, arteriosclerosis, stroke, diabetes, gastric ulcer and various allergies. The experiments conducted by Kagoshima University and animal experiments carried out by Fucoidan Research Lab (Fukuoka), for example, have shown that fucoidan has the following pharmacological effects and actions: [1] anticancer effect and antitumor effect, [2] immunity activation action, [3] apoptosis inducing action, [4] angiogenesis suppression action, [5] action to suppress blood coagulation, [6] cholesterol lowering action, [7] action to suppress rise in blood pressure, [8] action to suppress rise in blood sugar level, [9] anti-Helicobacter pylori action, antiucler action and aaction to improve discomfort in stomach, [10] action to ease hay fever, atopic conditions and other allergies, [11] antiviral action and antibacterial action, [12] antioxidative action, and [13] hair growth action. These for anti-tumor action of Fucoidan These below are excerpted in American National medical Library PubMed publication articles, and can confirm these articles below in www.pubmed.gov in more detail. Also it can be confirmed by inputting the words, fucoidan and cancer, as a key word. Institute of Japanese National Cancer Center (2003) Fucoidan has been attracted attention as the safe ingredient which can decrease damage of gastritis and stomach cancer that are caused by Helicobacter Pylori. French Pharmaceutical College (Faculte de Pharmacie) Paris (2005) Fucoidan suppresses neoplastic cells to adhere on to healthy human cells. (Metastasis inhibition of cancer cells). Keio University Japan medical department (2005) Fucoidan suppresses a cell strain increase of lymphoma (lymphcancer) and induces apoptosis (suicide of cancer cells). Korea Yoense University (Doctor Hwang) (2005) Fucoidan is the active material of lymph and macrophages (immune cells) to attack cancer cells. (Immunoregulation activity of Fucoidan and Arabinogalactan outside of the living body) Fukuoka University Facility of Pharmaceutical Science Japan (2003) Confirmed Fucoidan restrained a vascularization of cancer and contributed to effect of anti-tumor action. General Questions about Fucoidan Q1. What is Fucoidan? Fucoidan is a water solved food fiber as a constituent of the “sliminess” which is contained in sea vegetables such as mozuku (nemacystus decipiens) and mekabu (a pleated section of wakame). The chemical component of Fucoidan is a general term referring to a group of polysaccharides containing sulfated fucose. Also as comparing with other sea vegetables such as wakame, Okinawa mozuku has the most content of Fucoidan. Professor Kylin.H.Z of Swedish Uppsala (Uppsala) University discovered Fucoidan in a slimy ingredient of kombu in 1993, but named fucoidin in those days. After that, it started to be called Fucoidan by the international glucide naming agreement. Q2. How much fucoidan should I take each day? To maintain health on a daily basis, you should take at least one gram of fucoidan per day. If you have a “lifestyle-related” disease such as diabetes or high blood pressure and want to improve the conditions related to that ailment, take at least two or three grams a day. If you have cancer or other serious disease, it is recommended that your daily dose be a mininum of 3 to 6 grams. Q3. Can I take other drugs while I use fucoidan? Remember, fucoidan is not a drug. It is a natural ingredient found in mozuku (Nemacystus decipiens) and mekabu (the pleated section of wakame (Udaria pinnatifida)). There should be no harmful effect when taking prescribed drugs together with fucoidan, since it would be the same as taking those drugs after eating sea vegetables. Q4. Is there a particular way of taking fucoidan that makes it fight cancer even better? To maximize the cancer-fighting action of fucoidan, it is recommended that you take the product four times each day: in the morning, at noon, in the ivening and then at bedtime. The body’s natural immunity is greatest during the daytime when we’re active, and it decreases when the body is at rest (while we sleep). Contrastingly, cancer cells are most active when the body is at rest. So, it’s very important to take your fucoidan before going to bed. Don’t worry about consuming too much fucoidan, however. It is essentially the same as eating sea vegetables. Q5. Are there any side effects? Fucoidan is derived from mozuku and mekabu. It is a natural product, so there are no side effeccts. Unlike synthetic drugs, fucoidan will not produce side effects even when taken in large doses. Q6. Is fucoidan only for those suffering from illness? Fucoidan surely has functions and effects. Many cases have been reported where fucoidan has been improved by the patients who suffer from a gastric ulcer and high blood pressure, diabetes. Therefore healthy people can also benefit from fucoidan. If healthy people consume fucoidan, it is useful for preventing cancer and adult diseases effectively. Q7. What kind of effects will appear if you take fucoidan? For some people, a soft stool will appear for three or four days. The reason is that fucoidan is a vegetable fiber therefore, it cleans the bowels. A couple of days later, it will return to normal again. A soft stool is not diarrhea. In other works an abnormal symptom in the bowel such as constipation is relived and the bowels movement is improved. In general, the patients will experience long term benefits: * Condition of the body improves and saliva is sweeter. * Sense of taste returns and digestive function improves. * Moderate the side effects of chemotherapy and pain caused by cancer. * Reinforce immunity. * Show the clinical tendency of lowering tumor makers or reducing the cancer cells. Such phenomenon has individual; however, if healthy people consuming fucoidan, will see physical improvement. Especially, in the case of women, they will have improvement in their skin complexion and the effects of menstruation. Q8. What is the mechanism of Fucoidan that elininates Helicobacter Pylori that causes stomach cancer and gastric ulcer? Pylori bacteria “attaches to sulfate groups”. Usually this occurs with the sulfate groups in gastric mucous membranes; once fucoidan enters the stomach the sulfate groups in fucoidan attact the plori bacteria. The pyloi bacteria attached to the sulfate groups in fucoidan will be carried to the intestines and subsequently discharged from the body along with fucoidan. Q9. Is fucoidan effective on diseases of the liver, too? Cases have been reported where heavy drinkers with liver damage experienced rapid improvements in liver function after fucoidan. These results are probablly attributable to the immune-enhancing action of fucoidan. <<References>> 1. Gansaibo Dake wo Jisatsuni Oikomu “Kaiso Fucoidan”!! (“Seaweed Fucoidan”” Causes Only Cancer Cells to Kill Themselves!!), edited/written by “Sea Vegetable Fucoidan” Investigation Team (Aoyama Shoseki) 2. Fucoidan de Gansaibo ga Kieta! (Fucoidan Made Cancer Cells Disappear!), Hiroyuki Abe (Fukumori Shuppan) 3. Kaiso Power no Himitsu (The Secret of Seaweed Power), Hiromi Kita (Editorial Supervisor) (Seishun Publishing). 4. Gansaibo wo Jimetsusaseru Konbu no Fucoidan (Fucoidan in Konbu Causes Cancer Cells to Destroy Themselves), Hiromi Kita (Heart Shuppan) 5. Makkigan mo Naosu Kogan Shokuhin – Saikyo no Kumiawasekata (Best Combinations of Anticancer Foods that Cure Even Terminal Cancer), Hiromi Kita (Metamor Publishing). 6. Ishi ga Kakushinshita Gan wo Odorokuhodo Naosu Muttsu no Kogan Shokuhin (Six Anticancer Foods Having Amazing Effects on Cancers that Even Doctors are Convinced of), Myosei Shimizu (Metamor Publishing). 7. “Kaiso Fucoidan” de Gansaibo wa Jisatsusuru!! (“Sea Vegetable Fucoidan” Causes Cancer Cells to Self-Destruct!!), Daisuke Tachikawa (Editorial Supervisor) (Shiki Shuppan). 8. Iryogenba de Jissho! Gan Rinshoi ga Mitometa “Kaiso Fucoidan” no Koryoku!! (Proven in Clinical Fields! Effects of “Sea Vegetable Fucoidan” Even Cancer Clinicians Acknowledge!!) Daisuke Tachikawa (NOA Shuppan) Profile of Daisuke Tachikawa Dr. Daisuke Tachikawa graduated from School of Medicine at Fakuoka University in Japan. He started his career as a Medical Faculty member at the Department of Orthopaedics/ Plastic Surgery in Fukuoka University and later he joined the Department of Surgery at the Fukuoka University Tsukushi Hospital. In 1999 he received doctorial degree with Major in Pathological Structure from Fukuoka University. He was honored with the Fukuoka University Medical Association Award same year. Later he served at Matsuzaki Memorial Hospital and in 2003. He was honored to be the Vice Principal of Matsuzaki Memorial Hospital. In 2006, he found his own hospital in Fukuoka.