NUTRIENTS AS BIOLOGICAL RESPONSE MODIFIERS
original article found in NATURAL MEDICINE JOURNAL,
Dec.1998, p.5
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written by Patrick Quillin, PhD,RD,CNS
Director of
Nutrition, Cancer Treatment Centers of America
author of BEATING CANCER
WITH NUTRITION
Imagine yourself starving to death while standing in the midst of a bountiful vegetable garden. Or imagine a chief scientist for NASA refusing to accept the law of gravity while working on a space launch program. This article will explain why both of these metaphors are very appropriate in examining our current "war on cancer" and our illogical and unproductive $1.2 trillion spent annually in America on what we euphemistically call "health care".
In December of 1971, then President Richard Nixon launched the "war on cancer" with high hopes of finding a "magic bullet" to cure cancer within 5 years. After spending $39 billion at the National Cancer Institute in the past 28 years, many experts say that we have lost this war and need to rethink our strategy. The quest for the "magic bullet" against cancer brought about the phrase "biological response modifier" around 1982, upon which great hopes were placed.
BIOLOGICAL RESPONSE MODIFIERS (BRM)
There are two basic approaches to altering the biochemistry of the disease process:
1) Cytotoxic, where the goal is to destroy the defective or invading cells, i.e. chemotherapy, radiation, and antibiotics.
2) Biological response modifiers where the goal is to re-regulate the cells or potentiate host defense mechanisms, i.e. immune modulation, cytokine stimulation, and prostaglandin alterations.
While both of these approaches have their advantages and disadvantages, Louis Pasteur on his deathbed admitted a basic flaw in his philosophy to Pasteurize or eliminate all bacteria on earth: "I have been wrong. The terrain is everything." The "terrain" is the body's innate non-specific host defense mechanisms, which are bolstered by BRM. While the phrase BRM was coined for therapies like thymosin alpha-1, interferon, interleukin, tumor-derived activated killer cells (TDAK), and other promising creations from biomedical research , nutrition factors also qualify under the definition of "non-toxic potentiators of the body's innate restorative functions." Many of these expensive and highly toxic BRM from biomedical research have been disappointing in their ability to reverse poor prognostic diseases, such as various cancers and AIDS. Meanwhile, many nutrition factors hold promise as non-toxic, and clinically-effective BRM to improve quality and quantity of life along with chances for complete remission from infectious and degenerative diseases. With the limited space available in this article, categories and examples of nutrients as BRM will be discussed, though this article is by no means a complete review of nutrients as BRM.
SECOND GENERATION OF NUTRITION SCIENCE
From around 400 BC until the later part of the 20th century, nutrition research centered around defining and relieving blatant clinical deficiency syndromes:
-niacin for pellagra
-vitamin D for rickets
-iodine for goiter
-vitamin C for scurvy and so on.
Recommended Dietary Allowances (RDA) were based upon nutrient intakes required to prevent symptoms of deficiencies. Multiple generations of American medical students were taught: "You can properly nourish any normal adult with the RDAs, which can be obtained from the 4 food groups, which can be obtained by any meal at a fast food restaurant. Now let's move on to more important subjects."
We are now entering the second generation of nutrition research in which we ask the question: "What is your endpoint? What is the purpose of giving this nutrient? Is it to prevent frank clinical deficiency symptoms? Is it to generate normal health? Or to induce optimal health and longevity?'
For instance, Bendich and colleagues conducted a pivotal experiment in which they found the "normal" amount of dietary vitamin E (7.5 mg/kg body weight) required to produce normal growth and spleen-to-body weight ratio in animals. However, when they doubled that intake of vitamin E (15 mg/kg), they found it prevented deficiency signs of myopathy and testis degeneration. Intake of 7 times "normal" (52.5 mg/kg) was able to prevent red blood cell hemolysis and at 27 times "normal" dosage (202.5 mg/kg) the rat immune system showed optimal T and B lymphocyte responses to mitogens.
We have found a similar dose dependent response curve in vitamin E for human consumption. While 10 mg/day is the RDA, a study looking at the vitamin E intake of 87,000 nurses found that 200 mg/day provided a 41% reduction in risk for coronary artery disease. Meydani and colleagues found in a placebo controlled trial that healthy older adults experienced a measurable improvement in immune parameters when provided 800 mg/day of vitamin E. Once again, we ask the question: "What is your endpoint? Are you looking for normal American health or optimal health?" There is considerable evidence of long term sub-clinical deficiencies of vitamin E in many Americans, as shown by widespread cataracts, macular degeneration, Alzheimer's, cardiovascular disease, immunosuppression, and cancer.
First generation nutrition scientists studied nutrients in isolation. We now know that nutrients work together in a complex network of biochemical production lines. For instance, you need less vitamin C if you are getting optimal amounts of vitamin E, because these two antioxidants "recharge" one another in the body. Requirements for vitamin E increase along with the intake of polyunsaturated fatty acids due to the vulnerability toward lipid peroxidation in PUFAs.
First generation nutritionists also looked at one specific function of a nutrient, i.e. vitamin K and blood clotting. We now know that nutrients take on a completely different function when consumed at higher dosages. At lower doses vitamin K assists in blood clotting, while at higher doses (above 1 mg/day), vitamin K assists in calcification of the bone matrix. At low doses, vitamin C aids in the generation of collagen and elastin, to keep the body "glued together". At higher doses, ascorbic acid becomes a potent anti-viral and antioxidant compound. At low doses, niacin provides adequate energy metabolism through nicotinamide adenine dinucleotide (NAD), while at higher doses, niacin first becomes a valuable vasodilator, then at higher doses a potent hypocholesterolemic agent endorsed in the Journal of the American Medical Association as the "first drug to be used" in hypercholesterolemia.
**(side bar) WHO IS THE FATHER OF BRM?
"If everyone is thinking alike, then no one is thinking." Ben Franklin
At the turn of the century, W.B. Coley, a surgeon at Sloan Kettering Hospital in New York noticed from hospital charts that cancer patients were more likely to go into complete remission if he or she developed a post-operative infection. Coley gathered a collection of pathogens and injected them into a few cancer patients and found that, if the patient survived the feverish infection period, he or she often emerged cancer free. Something about a fever upregulated or "turbo-charged" the immune system to recognize and destroy the invading tumor. We have since itemized a long list of cytokines, or messengers between immune cells, and signal transduction molecules that are reduced in quantity or effectiveness in cancer patients.
While Dr. Coley's "cocktail" was branded as quackery during his time, we might pay due homage to his creative spirit in moving us toward a more effective, less toxic and more rational approach to cancer treatment and other immune dysfunctions. "Chance favors the prepared mind." And Dr. Coley's prepared mind paved the road for BRM to come from both biomedical research and nutrition scientists.
NUTRIENTS AS BRM IN BOLSTERING HOST DEFENSE MECHANISMS
"What a piece of work is man! How noble in reason! How infinite
in faculties!
--William Shakespeare, Hamlet--
The average adult human body is a marvelous organism. 60 trillion cells working in harmony to produce dynamic equilibrium. Somehow, while our external environment changes constantly, our body is required to maintain a relatively static and dependable internal environment. Our heart pumps 55 million gallons of blood in our lifetime through 60,000 miles of blood vessels. The 20 trillion cells in the immune system are charged with the daunting task of recognizing self from non-self and destroying all invading pathogens or tumor cells. The average cell takes from 1000 to 10,000 DNA "hits" or potentially cancer-causing breakages per day. Somehow, amidst this storm of DNA wreckage, 2/3 of Americans do not develop palpable cancer in their lifetime. All of these mind boggling metabolic processes are built from, fueled by, and repaired by nutrients from our diet.
Everything that we put into our mouth becomes a BRM. While the Merck Medical Manual lists dehydration as a serious life-threatening disease, water is the potent BRM cure for dehydration. According to FDA regulations, water should be a prescription drug in that instance.
Although most Americans chose their foods for the reasons of taste, cost, convenience and emotional satisfaction, the real reason that any creature eats is to bring in the substrates, or raw materials to keep this BRM production line working smoothly. Diet pop, lite beer, chips, doughnuts, funnel cakes, Pop Tarts, Snackwells, cheese whiz, hot dogs, and white bread are the staples in the American diet--most of which are deficient in the essential BRM to keep metabolism functioning. Then, when the person inevitably develops the routine symptoms of mild depression, constipation, sinusitis, and lethargy; or encounters the routine killers and cripplers in America of heart disease, stroke, cancer, diabetes, arthritis, osteoporosis, senility, gout, and kidney stones; it is rare that the health care professional asks the patient about BRM in the diet. Given the known roles of nutrients as BRM, our health care system seems inappropriately and inefficiently designed and due for a major overhaul.
Among the major categories in which nutrients serve as BRM in the human body:
-Redox reactions. Reduction, oxidation. Antioxidants help to corral the destructive potential of unpaired electrons to minimize cellular damage and slow the aging process.
-Genetic expression. Nutrients (like folic acid, B-12, vitamins D & A) all serve to help repair the delicate DNA while downregulating the tumor expression process (p53 tumor suppressor gene), while also inducing apoptosis (programmed cell death) in the deviant cancer cells.
-pH balance. Healthy venous pH (potential hydrogens) level in humans is 7.41, which is partially regulated by foods in the diet, water intake, and balance of oxygen and carbon dioxide in the blood.
-Bioenergetics. The primary macronutrients required by nearly every human cell are oxygen, water, and energy from adenosine triphosphate (ATP). Nutrients provide the substrates for oxidation (carbohydrates, fats, protein, alcohol), the catalysts for sparking the foodstuffs (niacin, riboflavin, thiamin, biotin), and electron carriers to fully execute maximal ATP from foods (coenzyme Q-10, copper, iron). As an example for exploiting this area, tumors are "obligate glucose utilizers" or sugar feeders. In extensive research on human and animal tumors, cancer has a higher rate of anaerobic glycolysis. By starving the tumor of its required fuel, we can help to selectively slow down cancer growth. This can be done primarily through dietary manipulation, which may make food intake more important than chemotherapy in the treatment of many forms of cancer.
-Anti-proliferative factors. While all nutritionists agree to the need for various growth (proliferative) nutrients, there is mounting evidence that some nutrition factors control growth (anti-proliferative). In the negative feedback inhibition circuits in the body, some factor turns on and another factor turns off a reaction. Unregulated growth becomes cancer or auto-immune diseases. It has been suggested, though not yet proven, that selenium, garlic, fish oil, quercetin, vitamin E succinate, and many herbal ingredients work as anti-proliferative factors.
-Detoxification. Toxins enter the human body through our air, food, and water supply and are also created as by-products of metabolism (auto-intoxication). Nutrients like vitamin E, selenium, zinc, molybdenum, protein, glutathione, and others are responsible for assisting in phase 1 and phase 2 detoxification pathways. For a thorough review on detoxification, see Pizzorno & Murray, Natural Medicine Journal, p.6, May 1998
-Cell communication. There are elegant pathways of communication between cells (intercellular) and within cells (intracellular). Nutrients fuel these "telegraph" pathways that keep cells working in harmony. Signal transduction (membrane communication) goes awry in the cancer process. Major histocompatibility complex (MHC) is the communication network that allows the immune system to recognize self from non-self. There is evidence that other substances in our diet, such as glycoproteins (from vegetables and aloe) may augment cell communication and help to induce apoptosis in cancer cells. When this system is contaminated from toxins or inadequately nourished from the diet, auto-immune diseases, infections and cancer can be the result. Beta-carotene improves cell-to-cell communication , which partly explains why over 200 studies show that a diet rich in fruits and vegetables (hence bioflavonoids, carotenoids, and glyconutrients) lowers the risk for various cancers.
-Immune modulators. The immune system is crucial to protecting our bodies from infection, cancer, premature aging, and avoiding auto-immune diseases. There have been extensive reviews on the subject of nutritional influences on immunity, including the textbook by the New York Academy of Sciences and a chapter in the revered textbook MODERN NUTRITION IN HEALTH AND DISEASE. Essentially, a wide variety of malnutritive conditions, including:
-deficiencies (such as vitamin C, E, zinc, selenium, and EPA from fish oil),
-excesses (such as sugar, omega 6 fats, and toxic minerals)
-imbalances (such as B-6 to protein ratio or omega-3 to omega-6 ratio) can instigate compromised host defense mechanisms.
Nutrients may be our most valuable and potent immune modulators. In one study, advanced refractory cancer patients with solid tumors were given either fish oil or placebo as sole therapy in their treatment. The group receiving fish oil experienced an increase in CD4 helper immune cells and a statistically significant extension of lifespan. Why do we use an inexpensive and non-toxic therapy, such as fish oil, as the treatment of last choice reserved for hopeless cancer patients? Why not use fish oil as part of routine cancer treatment from the beginning?
-Platelet aggregation. There is evidence that our diet can strongly influence the "stickiness" of our cells, not just in prothrombin time for blood coagulation, but also in the adhesiveness of cells for stroke and cancer metastasis. For instance, one study injected melanoma cells (one of the more aggressive and poor prognostic of human cancers) into mice, then fed the mice either the control diet (mice chow) or mice chow along with varying levels of flaxseed (2.5%, 5%, and 10%). There was an inverse dose dependent response in this study: the more flaxseed meal that the animals consumed, the lower the number and size of lung metastases found in the animals.
-Prostaglandin regulation. Prostaglandins are hormone-like substances that were first discovered in the prostate gland, yet now are found to exert powerful influences throughout the body. The ratio of macronutrients in the diet (protein, carbohydrate, and fat) will direct serum levels of insulin and glucagon, which then regulate the branchpoint in metabolism of prostaglandins for producing either more PGE-1 (favorable) or PGE-2 (a "fight or flight" prostaglandins that opposes PGE-1). Note the pathway outlined below.
-Bioregulators. In the plant kingdom, there are certain herbal compounds that have been labelled "adaptogens", a term coined in 1957 by the Russian pharmacologist I. Brekhman to define substances that are: 1) innocuous or of low toxicity, 2) non-specific in activity, or able to influence a wide range of pathways in the body, and 3) a normalizer of functions, such as ginseng that will raise blood pressure in a hypotensive individual or lower blood pressure in a hypertensive patient. No allopathic agent can match the versatile and non-toxic effects of a bioregulator or adaptogen.
John Prudden, MD, PhD felt that bovine tracheal cartilage (BTC) was a bioregulator in its influence on cancer patients. Prudden found that 9 grams daily of BTC as sole therapy provided a 90% response rate in human cancer patients and a 35% long term cure rate. In personal discussions with Prudden, he felt that BTC was an immune regulator, inhibitor of angiogenesis (making of blood vessels from tumors), and anti-mitotic agent (inhibit cell replication in abnormal tissue). And yet paradoxically, when applied topically, BTC would accelerate wound healing even when the patient was using steroid hormones that normally inhibit wound healing. How can one substance increase cell growth in one environment and decrease cell growth in another situation? Our only possible explanation is that some nutrition substances take on this "bioregulator" role and become irreplacable as navigational guidance systems in the complex metabolic pathways of the body.
Another example of a potent yet humble bioregulator is fiber. Through human civilization, food vendors have been diligently at work trying to extend the shelf life of foods while enhancing the organoleptic qualities--making it taste and feel better in the mouth. Eliminating fiber has been a quest throughout the ages. In 17th century England, the wheat miller could provide you with "the Queen's white" or "peasant brown" wheat flour. Which do you think the people favored? In the mid 19th century, Sylvester Graham found that he could provide great relief to many nagging health symptoms merely by adding the lost wheat bran back to the bread. Graham crackers became a big hit with the constipated masses. The Kelloggs cereal empire in Battle Creek, Michigan had a similar beginning in providing desperately needed fiber to people suffering from a variety of ailments. When the Dutch settlers showed the people of Java how to remove the bran from rice, the thiamin disease beri-beri (literally: "I cannot, I cannot") was discovered in 1897 by Dr. Eijkman. Our many experiments at removing fiber from our diet have had disastrous consequences for our health.
In the 1950s, nutrition scientists proclaimed that fiber was indigestible plant matter, therefore could not cross the intestinal mucosa into the bloodstream, and therefore was nutritionally useless. Wholesale removal of fiber was then endorsed by medical and nutrition scientists, until Denis Burkitt, a medical missionary to Africa noticed the absence of the "diseases of civilization" where the locals had substantially higher fiber intake. My missionary friends tell me that Africans have an expression: "where the people have large stools, they have small hospitals."
Then researchers discovered that bacteria in the colon digest fiber into various by-products, including butyric acid, which has shown incredible promise as a bioregulator of apoptosis. Phase 1 trials are being conducted to examine the toxicity and tolerance of the "drug" butyrate as an anti-cancer agent. Meanwhile, we continue with wholesale stripping of fiber from our food supply.
Another disregarded plant component, phytic acid, has been found to contain inositol hexaphosphate, or IP-6, which has been studied extensively for its ability to act as a protective antioxidant, protect DNA, reduce inflammation, inhibit abnormal cell proliferation, bolster Natural Killer cell activity, and generally act as a "bioregulator" in the human body.
RESEARCHING THE ARCANE AND IGNORING THE OBVIOUS
Americans invest $12 billion annually at the National Institutes of Health on covert taxpayer support of patent drug development while we ignore the cornucopia of BRM from Nature that stare us in the face everyday. We ignore potent, non-toxic and inexpensive nutritional biological response modifiers, primarily because they are not patentable prescription medication. We struggle valiantly and brilliantly with a plethora of highly toxic agents, from chemotherapeutics, to radiation, to interferon and interleukin--ignoring the more promising agents that have been under our noses all along. We are starving to death in a plentiful vegetable garden.
We also ignore the "rules". The human body is a complex and dynamic collection of biochemical reactions, which are regulated by genes and our environment (nutrition, toxins, neuropeptides from thought, etc.). If Mrs. Jones has breast cancer because she is overweight, her ovaries are toxically burdened with xenoestrogens and therefore generating an imbalance between estrogen and progesterone, she is eating a half box of Oreos each day which plays havoc with her potent prostaglandins, she suffers from adrenal insufficiency after years of a stressful job and marriage, she gets no exercise which allows an accumulation of toxins in her liver and lymphatic ducts, and her recent divorce has triggered an avalanche of immuno-suppressive neuropeptides. Medical researchers somehow think that they can find a single patentable agent that will neutralize all of the negative vectors taking place in Mrs. Jones's body. We are ignoring the rules, just like the NASA scientist who refuses to learn or accept the laws of gravity while working on a space launch mission. Both of these projects are doomed to failure.
Meanwhile, Nature beckons us with a bewildering and enticing array of
biological response modifiers which are ladened with the potential to ease
human suffering and substantially reduce the intolerable expenses of our
current illogical medical system. 
PATIENT PROFILE: SPIRIT OVER NUTRIENTS
H.G. was a fun-loving, guy who loved cigarettes, lots of wine and a good laugh. He developed prostate cancer with bone metastasis while in his mid 50s. His doctor said: "Get your affairs in order." H.G. went to a psycho-neuroimmunology clinic to help him use his mind as a healing tool in his advanced untreatable cancer. He felt that he had been burdened with an endless procession of responsibilities, from high school to the Marines, to a profession, family and more. He wanted to be free of all of this. He left his wife and his cancer went into remission. Meanwhile, his wife, B.G. was a non-smoker, drank very little, hiked, was in good shape, and ate a very good diet. One year after H.G. left her, B.G. developed advanced brain cancer and died within 6 weeks of diagnosis. Nutrition is an important factor in cancer outcome. But as a nutritionist, I must admit that what's eating you is at least as important as what you are eating. Feed your mind good thoughts. Feed your heart good feelings. Feed your body the right nutrients. And you will recover from this disease.
