Natural Therapies: Tocotrienols Tocotrienols When vitamin E was isolated from plant oils, the term tocopherols was used to name the initial four compounds that shared similar structures. Their structures have two primary parts--a complex ring and a phytyl (long-saturated) side chain--and have been designated as alpha, beta, delta, and gamma tocopherol. Tocopherols (vitamin E) are important lipid-soluble antioxidants that can protect the body against free radical damage. There are numerous studies demonstrating vitamin E's role in reducing the risk of developing heart disease and other debilitating illnesses. However, there are four additional compounds related to tocopherols--called tocotrienols--that are less widely distributed in nature. The tocotrienol structure, three double bonds in an isoprenoid (unsaturated) side chain, differs from that of tocopherols. While tocopherols are found in corn, olive oil, and soybeans, tocotrienols are concentrated in palm, rice bran, and barley oils. Therefore, vitamin E is the term used to describe eight naturally occurring essential fat-soluble nutrients: alpha, beta, delta, and gamma tocopherols plus a class of compounds related to vitamin E called alpha, beta, delta, and gamma tocotrienols. Tocotrienols have been shown to elicit powerful antioxidant, anticancer, and cholesterol-lowering properties, and studies have confirmed tocotrienol activity to be much stronger than that of tocopherols. In fact, while tocotrienols have only marginal vitamin E activity, their antioxidant effects are ranked as one of the most important classes of nutritional compounds for the prevention and treatment of disease. Tocotrienols provide more efficient penetration into tissues such as the brain and liver. Because of the double bonds in the isoprenoid side chain, tocotrienols move freely and more efficiently within cell membranes than tocopherols, giving tocotrienols greater ability to catch and fight free radicals. This greater mobility also allows tocotrienols to recycle more quickly than alpha-tocopherol. Studies have revealed that tocotrienols produced superior distribution in the fatty layers of the cell membrane and demonstrated greater antioxidant and free-radical-scavenging effects then that of vitamin E (alpha tocopherol) (Serbinova et al. 1991; Theriault et al. 1999). Tocotrienol's antioxidant function is also associated with lowering DNA damage, tumor formation, and other parameters of cell damage. A study focusing on breast cancer revealed that animals exposed to carcinogens that were fed corn oil- or soybean oil-based diets had significantly more tumors than those fed a tocotrienol-rich palm oil diet. The results clearly noted that the tocotrienol-rich palm oil did not promote chemically induced breast cancer (Sundram et al. 1989). Tocotrienols possess the ability to stimulate the selective killing of cancer cells through programmed cell death (apoptosis) to reduce cancer cell proliferation while leaving normal cells unaffected (Kline et al. 2001). One of the mechanisms by which tocotrienols are thought to suppress cancer is related to the isoprenoid side chain. Isoprenoids are plant compounds that have suppressed the initiation, growth, and progression of many types of cancer in experimental studies (Block et al. 1992). They are common in fruits and vegetables, which may explain why diets rich in these foods have consistently been shown to reduce the incidence of cancer. The antiproliferative effect of isoprenoids is thought to be due to suppression of the mevalonate pathway, through which mutated ras proteins transform healthy cells into cancer cells. Mutated ras is the most common cellular defect found in human cancers. The mevalonate pathway escapes regulatory control in tumor tissue but remains highly sensitive to regulation by toco-trienols. Tocotrienols are at least five times more powerful than farnesol, the body's regulator of the mevalonate pathway ( Elson et al. 1994). Interestingly, human breast cancer cells have been shown to respond very well to treatment with tocotrienols. Tocotrienols provide growth inhibition of breast cancer cells in culture that is independent of estrogen sensitivity and have great potential to be a significant aid in the prevention and treatment of breast cancer (Nesaretnam et al. 1998). A number of in vitro studies have demonstrated the effectiveness of tocotrienols as inhibitors of both estrogen-receptor-positive (estrogen-responsive) and estrogen-receptor-negative (nonestrogen-responsive) cell proliferation. Researchers tested the effect of palm tocotrienols on three cell lines of estrogen-responsive and estrogen-nonresponsive human breast cancer cells (MCF7, MDA-MB-231, and ZR-75-1). They found that tocotrienols inhibited cell growth strongly in both the presence and absence of estradiol, the major estrogen in the body. The researchers also demonstrated that tocotrienols enhanced the effect of tamoxifen. The gamma- and delta-fractions of toco-trienols were most effective at inhibiting cell growth, while alpha-tocopherol was ineffective in doing so ( Nesaretnam et al. 2000). Among the tocotrienols, delta-tocotrienol was shown in another study to be the most potent inducer of apoptosis (programmed cell death) in both estrogen-responsive and estrogen-nonresponsive human breast cancer cells, followed by gamma and alpha-tocotrienol (beta-tocotrienol was not tested). Interestingly, delta-tocotrienol is more plentiful in palm tocotrienols than in tocotrienols derived from rice. Of the natural tocopherols, only delta-tocopherol showed any apoptosis-inducing effect, although it was less than a tenth of the effect of palm and rice delta-tocotrienol (Yu et al. 1999). Similar results were obtained when mammary cancer cells from mice were studied ( McIntyre et al. 2000). While tocopherols had no inhibitory effect on cancerous cell growth, alpha, gamma, and delta-tocotrienols effectively arrested the cell cycle and triggered cell death. Highly malignant cells were most sensitive to the antiproliferative effects of tocotrienols, whereas less aggressive precancerous cells were the least sensitive. Tocotrienols were found to be far more effective than alpha-tocopherol in inhibiting breast cancer cell growth ( Guthrie et al. 1997). The tocotrienol concentration needed was less than 1/20 of alpha-tocopherol in estrogen-responsive cells and less than 1/10 in cells unresponsive to estrogen. Tocotrienols in combination with tamoxifen were more inhibitory than either compound alone in both estrogen-responsive and nonresponsive breast cancer cells. The authors pointed out that the synergism between tamoxifen and tocotrienols may allow for the use of lower doses of tamoxifen and reduce its risk of adverse side effects. While tocotrienols are considered important antioxidants, it may be that they are the most potent of all of the lipid-soluble antioxidants available. From decreasing platelet aggregation (clumping of blood) to anti-inflammatory action to anticancer activity, tocotrienols are a significant nutritional compound. Therefore, a daily dose of 240 mg of tocotrienols should be considered as an adjuvant breast cancer therapy. Preventing Breast Cancer Cell Metastasis
Bisphosphonates are analogs of a naturally occurring compound, called pyrophosphate, that serves to regulate calcium and prevent bone breakdown. The study and development of bisphosphonates as a major class of drugs for the treatment of bone diseases began only three decades ago. The first report of the biological characteristics of bisphosphonates was published in 1968. At that time, scientists discovered that bisphosphonates have a marked ability to inhibit bone resorption. Bisphosphonates are considered standard care for tumor-associated hypercalcemia and have been shown to reduce bone pain, improve quality of life, and to delay and reduce skeletal events. Bone Remodeling The renewal of bone is responsible for bone strength throughout our life. Old bone is removed (resorption) and new bone is created (formation). This process is called bone remodeling. Healthy bone is continually being remodeled. Two main types of cells are responsible for bone renewal: the osteoblasts involved in bone formation and the osteoclasts involved in bone resorption. There are several stages involved in bone remodeling. The first is activation. This process involves preosteoclasts that are stimulated and differentiated under the influence of cytokine and growth factors to mature into active osteoclasts. The next step is resorption, in which osteoclasts digest mineral matrix (old bone). The third step is reversal, which ends resorption and signals for the final phase, formation. During this stage, osteoblasts are responsible for bone matrix synthesis (collagen production). Two other noncollagenous proteins are also formed: ostocalcin and osteonectin. Together they form new bone. Bone Metastases Affects Remodeling In patients with bone metastases, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increased amounts in the patient's blood serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia. Normally, the activity of the osteoclasts and osteoblasts is well balanced, with the osteoclasts cleaning out the fatigued bone and the osteoblasts rebuilding new bone. In metastatic cancer, there is an increase in osteoclast activity that is caused by factors called osteoclastic activating factors (OAFs). These OAFs are known to be released by tumor cells and include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines. Among the known inhibitors of osteoclast activity, the bisphosphonates are the most promising drugs. At the 22nd Annual San Antonio Breast Cancer Symposium in San Antonio, TX in 1999, Dr. Ingo Diel (Assistant Professor of Medicine, University of Heidelberg, Germany) summarized the evidence in favor of giving bisphosphonates to women with breast cancer who have a high risk of advancing cancer. He explained that bisphosphonates interrupt the "vicious cycle" of bone metastases. Cancer researchers have found that treatment with bisphosphonates can also prevent the destruction of bone by cancer metastases and even cause those metastatic tumors to shrink. The latest finding demonstrates that bisphosphonates may stop bone metastases from occurring at all if they are included at the onset of treatment (ONI 2000). In an editorial in the New England Journal of Medicine, Delmas (1996) pointed out that bisphosphonates are useful as an adjuvant therapy to decrease bone pain and the risk of fractures and hypercalcemia in patients with multiple myeloma and bone metastases and may be useful as agents to delay the occurrence of bone metastases. Delmas indicated that bisphosphonates inhibit bone turnover by decreasing the resorption of bone. They do so directly, he states, by inhibiting the recruitment and function of osteoclasts and indirectly by stimulating osteoblasts to produce an inhibitor of osteoclast formation. Bisphosphonates are indicated for the treatment of a variety of metabolic bone diseases characterized by increased bone resorption. A study in the same issue of the New England Journal of Medicine reported that monthly infusions of pamidronate in 382 women with Stage IV breast cancer and bone metastases significantly reduced the incidence and prolonged the median time of skeletal complications (Hortobagyi et al. 1996). These data, says Delmas (1996), suggest that bisphosphonates may also be useful to delay the occurrence of bone metastases in women with breast cancer who do not yet have such metastases. Earlier studies with a new bisphosphonate, risedronate, suggest that these agents do slow the progression or inhibit the development of bone metastases in breast cancer patients. They probably do so either by inhibiting the resorption of bone, which would reduce the release of growth factors stored in the bone matrix that provide a favorable microenvironment for breast cancer to metastasize, or by inhibiting the adhesion of breast cancer cells to bone matrix (Delmas 1996). A Cochrane Review article published in November 2001, Bisphosphonates for Breast Cancer, systematically reviewed high-quality evidence regarding the effect of bisphosphonates on skeletal events, bone pain, quality of life, and survival in women with early and advanced breast cancer by identifying, describing, and summarizing the results. The reviewers (Pavlakis et al. 2002) concluded that in women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal-event rate, as well as increasing the time to skeletal event. Bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases. Bisphosphonates are now in their third generation and are often used in lytic bone metastasis because they inhibit the osteoclast activity that causes elevation of the blood calcium level and that causes some of the problem in osteolytic bone weakening. Osteolytic lesions are holes that form as the cancer eats away at the bone, making it prone to fracture. A very detailed and authoritative discussion of this important area of oncology is presented in the journal of the H. Lee Moffitt Cancer Center (Cristfanilli et al. 1999). Researchers are now considering the use of these agents in the adjuvant setting, that is to say given upon inception of treatment, perhaps to prevent breast cancer bone metastasis. In addition to treating osteolytic bone metastasis of breast cancer, the new agents zoledronate and ibandronate manage tumor-induced hypercalcemia, Paget's disease of the bone, and multiple myeloma-associated bone resorption. These new drugs are three logarithms more potent than the first-generation drugs etidronate, clodronate, and tilundronate. Patients newly diagnosed with lytic bone metastasis of breast cancer are offered bisphosphonate therapy, such as intravenous pamidronate every 3 or 4 weeks, as long as it proves effective. Oral clodronate offers equivalent results but is less well tolerated. Women with primary breast cancer who receive chemotherapy, hormone therapy, aromatase therapy, or oophorectomy may experience ovarian failure or early menopause, leading to a loss of bone mineral density. In an editorial article in the Annals of Internal Medicine (1998), Dr. Robert P. Heaney of Creighton University (Omaha) writes: McClung and colleagues' report that modest doses of the bisphosphonate alendronate reduce or block entirely the bone loss that would otherwise occur in early postmenopausal women. . . . All bone loss occurs because of an excess of the resorptive component of remodeling over the formative component, and it is to be expected that such an agent as a bisphosphonate, which suppresses remodeling, would thereby reduce bone loss. Moreover, because the bisphosphonates act on the resorptive side of remodeling (affecting both the differentiation and the work of osteoclasts), they effectively act as antagonists of parathyroid hormone action on bone and evoke a calcium-conserving increase in production of parathyroid hormone. Thus, one would expect not just a slowing of bone loss but, at the right dose, full protection of bone mass and even a modestly positive bone remodeling balance, as has been described for the therapeutic use of bisphosphonates. One of the strengths of McClung and colleagues' study is that it was dose-ranging. Alendronate at 1 mg/d reduced, but did not completely eliminate, estrogen- deficiency bone loss; 5 mg/d effectively blocked bone loss; and 10 and 20 mg/d may have produced slight bone gains. (The manufacturer of alendronate has sought U.S. Food and Drug Administration approval of the 5-mg/d dosage for use as protection against menopausal bone loss.) The molecular mechanisms by which tumor cells degrade bone involve tumor-cell adhesion to bone, as well as the release of toxic chemicals from tumor cells that stimulate osteoclast-induced bone degradation. Bisphosphonates inhibit cancer-cell adhesion to the bone matrix and inhibit osteoclast activity. By preventing tumor-cell adhesion, bisphosphonates are useful agents for the prophylactic treatment of patients with cancer that is known to preferentially metastasize to bone. There is evidence that growth factors, such as insulin-like growth factor and transforming growth factor, are released when the bone matrix is degraded. These growth factors could stimulate tumor-cell proliferation throughout the body and may serve as a beacon, calling cancer cells to the degraded bone ripe for colonal development, which may be a reason that early use of bisphosphonates significantly improved survival and may ward off metastasis. Based upon the mounting research, as evidenced in this article, it is strongly recommended that the use of bisphosphonates be considered, especially in light of the fact that bisphosphonates may stop bone metastases from developing at all, if included at the onset of breast cancer treatment. Patients are urged to discuss the use of bisphosphonates with their physicians. Note: Administration of bisphosphonate therapy should be accompanied by an adequate intake of a bone supplement that supplies all the raw materials to make healthy bone. These include calcium, magnesium, boron, silica, vitamin D, and vitamin K. Do not take vitamin K with Coumadin or other anticoagulant drugs. Bone Loss and Fatty Acids While people often use omega-3 fatty acids to reduce the inflammation associated with arthritis, these fatty acids may actually help prevent bone loss. French researchers found in a group of 105 patients that high levels of proinflammatory omega-6 fatty acids were strongly associated with bone loss. However, the use of omega-3 supplements--360 mg a day of eicosapentaenoic acid (EPA) and 240 mg a day of docasahexanoic acid (DHA)--appeared to decrease production of proinflammatory prostaglandin E2 in bone and significantly stopped bone loss (Requirand et al. 2000). Diet Cancer has an appetite for sugar. Tumors are primarily obligate glucose metabolizers. Simply stated, cancer requires sugar for survival. In fact, insatiable sugar cravings have been reported by those with breast cancer, which would be logical because sugar plays an active role in reducing the immune response and energizes cancer. There is a relationship between lactic acid, insulin, and angiogenesis. In tumors, hypoxic conditions occur through both inflammation, which reduces blood flow, and the chaotic development of blood vessels within tumors. These hypoxic conditions alter the pathways by which immune cells and tumor cells burn fuel (glucose) for energy, creating excessive lactic acid. In an oxygen-rich (aerobic) environment, glucose is burned in an efficient process that produces a maximum amount of energy and a minimal amount of lactic acid. However, tumor cells in chronic hypoxic conditions produce excessive lactic acid and inefficient utilization of glucose. Thus, there is a vicious cycle in which the reduced energy output stimulates the tumor cells to burn more glucose, which in turn produces more lactic acid. Tumor cells consume glucose at a rate three to five times higher than normal cells, creating a highly stimulated glycolysis (glucose-burning) pathway. This glucose consumption can waste the cancer patient's energy reserves, and the increased production of lactic acid can stimulate increased production of angiogenic factors. Lactic acid itself is an angiogenic factor that causes macrophages, the predominant immune cells at tumor sites, to produce other angiogenic factors, and of these TNF (tumor necrosis factor) may be the most active. A common belief is that immune activities will inhibit cancer; however, this does not accurately describe what occurs within the body. The macrophage-mediated angiogenesis creates a complex interplay between opposing regulators. It is believed that when normal wound healing has concluded, the macrophages responsible for promoting angiogenesis switch modes and inhibit angiogenesis. However, at tumor sites, the signals that cause the angiogenesis-promoting mode to switch to an angiogenesis-inhibiting mode appear to be lacking, and the angiogenesis-promoting mode continues unabated. Insulin plays an active roll in promoting angiogenesis. Insulin is a growth factor that stimulates glycolysis and the proliferation of many cancer-cell lines. Insulin is thought to facilitate angiogenesis by increasing lactic acid production in hypoxic tumor cells and by stimulating the proliferation of vascular cells. In cancer patients, elevated levels of insulin are common in cancerous tissue and blood plasma. It would follow that obesity, and early stages of Type-II noninsulin-dependent diabetes mellitus (NIDDM), have been implicated as risk factors in a variety of cancers. Therefore, based upon cancer's sugar dependency , a sugar-deprivation diet is strongly recommended. An effective tool in eliminating sugar is the Glycemic Index. The index is a list that rates the speed at which different foods are digested and raise blood sugar levels. The ratings are based upon the rate at which a measured amount of pure glucose affects the body's blood sugar curve. Glucose itself has a rating of 100, and the closer a food item is to a rating of 100, the more rapidly it raises blood glucose levels. Only foods with very low Glycemic Index values, such as vegetables and protein, and to a lesser extent whole grains and beans, are suggested (please refer to the Obesity protocol for specific information about low glycemic foods). With regard to depleting sugar from one's diet, the following ideas should be considered:
As discussed earlier in the protocol, estrogen is a growth factor for most breast cancers. High-fat diets and associated increases in fat tissue can increase estrogen availability in a number of ways:
Another consideration when discussing diet and breast cancer is the reduction of dietary estrogen. Several foods contain naturally occurring hormones (found in animal sources); synthetic hormone additives that can mimic estrogen in the human body (found in commercially packaged meat, poultry, and dairy products); or naturally estrogenic qualities that can encourage the body's production of estrogens (natural foods such as soy). Regardless of the source, try to avoid all commercial animal products (including, but not limited to, meats, poultry, and dairy). Also avoid the use of soft plastic food-storage products that can give off large amounts of polymers (e.g., by leaching into food contents), thought by environmentalists and some researchers to be a possible cause of breast cancer. In order to reduce estrogen, a breast cancer patient should consider increasing dietary intake of fish high in omega-3 fatty acids, whey, eggs, and nuts, occasionally including hormone-free poultry and hormone-free, low-fat dairy products. Blood Testing Monthly blood tests should include complete blood chemistry, with tests for liver function and serum calcium levels, prolactin, parathyroid hormone, and the tumor marker CA 27.29 (or CA 15.3). Additional blood tests to consider are the CEA and GGTP tests. These tests monitor the progress or failure of whatever therapies are being used and also are able to detect toxicity from high doses of vitamin A and vitamin D3. The patient should insist on obtaining a copy of their blood workups every month. Continued . . . |
FREE AIR MAIL SHIPPING IN THE UNITED STATES!  The statements made here have not been evaluated by the FDA. The foregoing statements are based upon sound and reliable studies, and are meant for informational purposes. Consult with your medical practitioner to determine the underlying cause of your symptoms. Copyright 1997-2009 Life Extension Vitamin Supplies and Life Extension Institute, Inc. All rights reserved. |