Chapter 10: IRT Nutraceuticals for Cancer Control

At Oasis of Hope, we employ a broad spectrum of safe nutraceuticals. They are used as components of the in-hospital therapy and for continuing use when patients return home. These agents are intended to modulate cell signaling pathways in ways that should provide a diverse array of benefits such as sensitizing cancers to cytotoxic chemotherapies or intravenous vitamin C, slowing the growth of tumors, blocking the process of metastasis, inhibiting the angiogenic response required for tumor growth, boosting or disinhibiting the immune system's capacity to attack the cancer, protecting normal tissues from the toxicity of chemotherapies, and helping to control so-called "paraneoplastic" syndromes that erode bones or decrease muscle mass. Here are the chief nutraceuticals we use with the explanation of why and how they are used.

Melatonin

Melatonin is a natural hormone produced primarily by the pineal gland at the base of the brain. Secretion of melatonin is regulated by light exposure. Also, a burst of melatonin secretion occurs at nighttime during the onset of sleep. One of the primary roles of melatonin is to synchronize endocrine and nervous system rhythms in line with day-night cycles. For this reason, melatonin is traditionally given at bedtime so that natural biorhythms are reinforced rather than disrupted.

Melatonin exerts a range of physiological effects, some of which are of direct relevance to cancer therapy. Of particular interest is its ability to boost the function of NK cells and helper-T lymphocytes. These components of the immune system can help to control the growth and spread of many tumors (1,2). NK cells usually have little impact on large pre-existing tumors, but they do a better job of controlling the small nests of tumor cells that can give rise to new metastases (3,4). NK cell activity tends to decline as people age. This is at least partially attributable to the fact that the pineal’s production of melatonin tends to decline during the aging process(5).

Melatonin also functions as a major antioxidant. Although melatonin itself can function as a free radical scavenger, this effect is probably of little physiological significance because natural concentrations of melatonin are quite low. The major impact of melatonin on antioxidant defenses reflects its ability to boost the production of many antioxidant enzymes in many tissues (6,7). This antioxidant effect of melatonin can provide protection when cancer patients receive cytotoxic drugs that can damage healthy tissues by inducing oxidant stress. In experimental studies, melatonin administration has been shown to lessen the adverse effects of drugs such as doxorubicin and cisplatin, without lessening the therapeutic impact of these drugs (8-11). The heart, kidneys, and peripheral nervous system are among the vital organs that melatonin protects.

Melatonin also functions to support the growth and survival of bone marrow cells that give rise to circulating neutrophils, lymphocytes, monocytes, which are immune cells, and platelets, which are required for proper blood clotting. It apparently does this by boosting the marrow’s production of certain key growth factors (12,13). This effect is of evident relevance to cancer therapy since many cytotoxic cancer drugs are highly toxic to the bone marrow. The resulting decline in blood levels of white cells or of platelets can increase risk for infection or bleeding complications, and may require chemotherapy to be terminated or postponed. This would impair its therapeutic efficacy.

Melatonin has been tested in clinical trials in a wide range of cancers. Sometimes it is used as a stand-alone therapy in patients for whom further chemotherapy would be inappropriate, and sometimes as a adjuvant to standard chemotherapy or radiotherapy regimens. In general, the results of these studies have been remarkably consistent (14-18). With or without concurrent chemotherapy, the patients receiving melatonin tended to survive significantly longer. When chemotherapy was administered, therapeutic response, defined as objective remission or stable disease, tended to be significantly greater in those getting the melatonin. Furthermore, side effects of chemotherapy tended to be less severe in the melatonin group. In particular they were less prone to severe bone marrow depression. Chemotherapy with melatonin was also less likely to damage the heart or peripheral nervous system. Also, the patients receiving melatonin were less prone to cachexia, the severe loss of muscle mass that often complicates advanced cancer (19). Given the scope of these benefits, it is remarkable that nocturnally administered melatonin appears to be virtually free of side effects. Some people report that melatonin helps them to remember their dreams more vividly. Aside from this, it tends to be well tolerated, and some people find that it helps them to get a restful night’s sleep. Moreover, in light of the age-related fall-off in melatonin secretion, supplemental melatonin may be particularly beneficial to the overall health of people who are middle-aged or older. It supports improved immune and antioxidant defenses.

Cancer patients at Oasis of Hope frequently report that their experiences with chemotherapy tend to be less harsh and traumatic than were their previous chemotherapy regimens at other hospitals. We suspect that our inclusion of melatonin in the IRT protocols has a lot to do with this.

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Fish Oil

Fish oil is a uniquely rich source of the long-chain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). A small structural difference distinguishes these fatty acids from the omega-6 fatty acids found in plant-derived oils. Within our bodies, a portion of ingested omega-6 fatty acids are converted to the compound arachidonic acid. This in turn is the precursor for a wide range of hormone-like compounds, known as prostanoids, that play a key role in inflammatory processes. EPA and DHA are very similar in structure to arachidonic acid, and, when consumed in adequate amounts, they can act in various ways to antagonize the production of active prostanoids. For this reason, diets rich in fish oil tend to have anti-inflammatory effects in rheumatoid arthritis and certain other chronic inflammatory disorders (20). Furthermore, one of the prostanoids whose production is antagonized by fish oil is thromboxane, which plays a role in blood clot formation by promoting aggregation of the platelets. This discovery led to speculation that the relatively low risk for heart attack among aboriginal Eskimos may reflect their high consumption of seafood rich in EPA and DHA (21). Also, omega-3 fats reduce the risk to develop dangerous cardiac arrhythmias.

EPA and DHA have a valuable role to play in cancer treatment. A number of studies show that a diet rich in fish oil tends to slow tumor growth (22-25). At least part of this effect can be attributed to a suppressive effect of fish oil on angiogenesis. Remember that angiogenesis is the process by which new blood vessels develop to enable the growth and spread of tumors (24-27). EPA has been shown to decrease the expression of a key receptor required for response to the pro-angiogenic compound vascular endothelial growth factor (VEGF) (28).

Another key factor in angiogenesis is the enzyme Cox-2, which produces prostanoids required for vascular tube formation during the angiogenic process (29). A high intake of fish oil has the potential to antagonize the role of Cox-2 in the angiogenic process by decreasing the production of Cox-2-derived prostanoids.

Fish oil also has the potential to act directly on tumor cells to slow their proliferation. In some tumors, prostanoids produced by Cox-2 or other enzymes known as lipoxygenases can promote the multiplication and spread of cancer cells and/or protect them from apoptosis (30,31). Fish oil can antagonize the pro-proliferative activity of these prostanoids by suppressing their synthesis.

Fish oil has the ability to fend off cachexia, the severe loss of muscle mass that often complicates late-stage cancer (32-35). Although cachexia usually entails a loss of appetite that can contribute to weight loss by decreasing calorie intake, the life-threatening selective loss of muscle mass often seen in cancer reflects a very specific inflammatory process in muscle fibers that is not seen in healthy dieters. It has been discovered that EPA interferes with the inflammatory mechanisms that cause loss of muscle mass.

Finally, a number of experimental studies demonstrate that fish oil, particularly DHA, can boost the responsiveness of cancer cells to chemotherapy and radiotherapy (36,37). The mechanism of this effect is not well understood, but it is suspected that DHA, which is polyunsaturated and highly susceptible to oxidative damage, serves to amplify oxidative stress in cancer cells assaulted by cytotoxic chemicals or radiation. Cell culture studies suggest that normal healthy cells are less susceptible to this sensitizing effect of DHA for reasons that remain unclear. The potential impact of DHA on response to chemotherapy is one reason why fish oil is included in the in-hospital supplementation regimen for cancer patients at Oasis of Hope.

Most of us have a lot of fat in our bodies, including the omega-6 fats for which EPA and DHA serve as functional antagonists. For that reason, it usually takes at least several months for fish oil intake to achieve its maximal physiological effects. The ratio of omega-3 to omega-6 in the body’s tissues is a key determinant of the efficacy of fish oil supplementation. A given daily dose of fish oil will presumably have a greater and faster impact in people who are maintaining their total daily fat intake low.

In summary, the ample EPA/DHA intake provided with the Oasis of Hope IRT protocols is intended to: suppress the angiogenic process required for the growth and spread of tumors; act directly on some susceptible cancers to slow their proliferation; help prevent loss of muscle mass (cachexia); and improve the responsiveness of cancers to certain chemotherapeutic agents or radiation.

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Vitamin D

Growing evidence confirms that good vitamin D status not only decreases risk for many prominent cancers, but also can improve the results of chemotherapy and lengthen survival in people who already have cancer. Vitamin D is often called "the sunshine vitamin" because the skin manufactures it when rays of ultra violet (UV) light interact with a cholesterol precursor in the skin. The resulting compound is then quickly transformed in the liver to a derivative, calcidiol, which circulates in the blood. Calcidiol can also be produced from vitamin D obtained from supplements or foods. Calcidiol, per se, has little physiological activity. In order to do its metabolic job, calcidiol must be further transformed to calcitriol, which can bind to vitamin D receptors in the nucleus of cells. Most of the calcitriol found in the blood is produced in the kidneys.

Just within the last few years, scientists have learned that many types of epithelial cells (type of cells that give rise to most of the dangerous solid tumors) are capable of converting calcidiol to calcitriol and the rate of this conversion is proportional to blood calcidiol levels (38,39). In other words, epithelial cells can make more calcitriol when vitamin D status is improved by effective sun exposure or with supplemental vitamin D. Increased calcitriol levels in epithelial cells reduce the risk that these cells will give rise to malignant tumors. This reflects the fact that calcitriol works in various ways to slow down the cell multiplication while also increasing the propensity of mutated cells to "commit suicide" (40).

People's vitamin D status tends to vary a great deal, primarily owing to the fact that the skin’s capacity to manufacture vitamin D is influenced by a number of factors (41). The UV content of sunlight declines during the winter and in northern latitudes the winter sunlight is virtually devoid of UV. Certain types of air pollution that absorb UV also decrease the UV content of sunlight. Furthermore, skin production of vitamin D is lower in people who fail to get much sun exposure, who are darkly complected, or who use artificial sunscreens to prevent UV-mediated skin damage. Most natural foods are essentially devoid of vitamin D unless it is included as an additive. Traditional supplemental doses of vitamin D, typically 400 IU daily, are so low that they are just sufficient to prevent rickets. Neither food nor supplementation has had much impact on vitamin D status in most people. Consider the fact that, with optimal UV exposure, people can make up to 10,000 -20,000 IU of vitamin D daily (42).

Since UV exposure is the chief determinant of vitamin D status for most people, it should follow that, if vitamin D activity has a major impact on cancer risk, logic would dictate that there would be a greater incidence for many cancers in parts of the world where UV exposure is often low. This, in fact, is precisely what epidemiologists have been demonstrating over the last decade (43-48). In other words, people who have spent most of their lives in sunny regions, tend to be at lower risk for cancer than people who live in northern latitudes. It has been estimated that sub optimal UV exposure is responsible for over 23,000 premature cancer deaths per year in the U.S. alone (38,49). The types of cancer whose risks are influenced by vitamin D status include cancers of the breast, colon, rectum, ovary, prostate, pancreas, stomach, and uterine endometrium, as well as non-Hodgkin’s lymphoma.

But what does this have to do with therapy of pre-existing cancers? Fortunately, some of the cancers that arise from epithelial cells capable of making calcitriol retain the capacity to make calcitriol and express vitamin D receptors (38,50). In these cancers, an increase in blood levels of calcidiol, achieved by better UV exposure or supplemental vitamin D, leads to an increased production of calcitriol in the tumor. This calcitriol can slow the proliferation of the cancer cells while increasing their ability to commit suicide (51-53). Moreover, the impact of calcitriol on capacity for apoptosis can sometimes render these cancers more susceptible to cytotoxic chemotherapy or radiotherapy (54-57).

Recently, epidemiologists around the world have noted that cancer patients diagnosed during summer typically survive longer than patients diagnosed in winter (58-60). This presumably reflects the fact that, in those cancers still capable of making calcitriol, the relatively good vitamin D status during summers renders the cancers more sensitive to chemotherapy and/or slows the growth of the cancer. At Oasis of Hope, we make sure that our patients are being treated "in summer" by giving them 10,000 IU of vitamin D daily.

One pioneering study from Toronto has examined the influence of supplemental vitamin D (2,000 IU daily) on prostate cancer patients whose PSA levels remained measurable following surgery or radiotherapy (61). During this supplementation, the rate of tumor growth, assessed by PSA measurements, slowed markedly in 14 of the 15 subjects enrolled in the study.

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Silibinin

Milk thistle extract has been used for many decades in the treatment of liver disorders. Approximately 80% of this extract consists of silymarin, a mixture of several compounds known as flavonolignans. Silibinin, the most prominent of these compounds, accounts for about 60% of the weight of silymarin, and is believed responsible for most of the liver-protective activity of silymarin and milk thistle extract. Just within the last decade, scientists have learned that silibinin has considerable potential for preventing and treating cancer.

In concentrations that may be feasible to achieve with high-dose clinical regimens, silibinin has been shown to have growth inhibitory effects on a wide range of human cancer cell lines including cancers arising from the prostate, breast, colon, lung, liver, bladder, and cervix (62-69). Silibinin can suppress the proliferation of these cells, while at the same time increasing the rate at which they die by apoptosis. In addition, silibinin can sensitize cancer cell lines to the killing effects of certain cytotoxic chemotherapeutic drugs (70). Thus, silibinin may have potential both for retarding the growth and spread of cancer and for boosting the response of cancers to chemotherapy.

The mechanisms responsible for these effects have been studied most intensively in human prostate cancer cells (71). It should first be noted that these studies show that concentrations of silibinin, which retard the growth of these prostate cancers, do not influence the growth of cells from healthy normal prostate. In other words, the effects of silibinin on cell oliferation appear to be specific to cancer cells. The anti-proliferative effects of silibinin on prostate cancer cells have been traced to decreased function of the epidermal growth factor receptor (EGF-R). This is a key mediator of growth signals in prostate cancer and in many other types of cancer (72). Silibinin binds to this receptor and prevents it from interacting with hormones that activate it. Some of these are produced in prostate cancers. Furthermore, silibinin induces prostate cancer cells to make more of a compound, known as IGFBP-3, that binds to and inhibits the activity of insulin-like growth factor-I (IGF-I), a key growth factor for many cancers (73).

Silibinin has also been shown to decrease the activation of NF-kappaB (74,75), a protein complex that, when activated, tends to make cancer cells more aggressive and renders them less sensitive to chemotherapy or radiotherapy (76,77). In many prostate cancers, and indeed in many other types of cancer, NF-kappaB is continuously active. The effect of silibinin on NF-kappaB helps to rationalize silibinin’s ability to increase the sensitivity of cancers to certain chemotherapy drugs. The effects of silibinin on growth factor signals, which promote cancer cell survival, also contribute in this regard.

The impact of orally administered silibinin on the growth of human tumors in immunodeficient mice has been studied with three different types of tumor – prostate, lung, and ovarian (78,79). In each case, silibinin has been found to have a substantial and dose-dependent suppressive effect on tumor growth in doses that had no apparent toxicity to the treated animals.

Examination of the silibinin-treated tumors revealed that they had a much less developed vasculature than control tumors. In other words, there were less blood vessels in the tumor to provide nourishment and oxygen (78,79). Follow-up studies showed that in some cancers silibin could suppress secretion of a compound known as vascular endothelial growth factor (VEGF), which plays a key role in inducing the growth of new blood vessels into tumors (78,80,81).

Furthermore, other studies show that clinically feasible concentrations of silibinin have a direct effect on endothelial cells. Silibinin can suppress the proliferation of these cells and reduce their ability to migrate, invade tissues, and roll themselves into tubes, which is how new blood vessels are formed (74,80). These findings suggest that the growth-slowing impact of silibinin on tumors reflects the interaction of at least three phenomena: a direct proliferative effect on cancer cells; a suppression of VEGF production by these cells; and a direct inhibitory effect on the capacity of endothelial cells to build new blood vessels.

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Selenium

The use of selenium in cancer therapy is motivated, in part, by substantial evidence that good selenium nutrition can reduce cancer risk (82). Dr. Larry Clark, and colleagues, conducted a massive double blind clinical study that recruited over 1,300 American subjects known to be at high risk for skin cancer, but free of any serious cancers at the time of enrollment (83). For over a decade, these volunteers received either selenium (200 mcg daily) or a matching placebo. Although the supplemental selenium failed to reduce subsequent risk for skin cancer, the researchers were encouraged to find that the cancer death rate in the selenium-supplemented group was only half as high as that in those receiving the placebo, 29 vs. 57. Indeed, the researchers were forced to terminate the study earlier than planned, as they considered it unethical to continue with the placebo supplementation. The lower cancer death rate in the selenium group was primarily attributable to a substantial reduction in the incidence of new serious cancers in the lungs, colon, and prostate. (84,85).

Epidemiological studies have also pointed to decreased risks for certain cancers in people who have relatively high selenium intakes, or who live in regions of the world where soil selenium levels are relatively high (84,85) One reason why people with poor selenium nutrition may be at increased cancer risk is that selenium is an important antioxidant nutrient that supports the production of enzymes that protect our cells against oxidant stress (86). Since oxidants can damage DNA, leading to potentially carcinogenic mutations, good selenium status clearly has anti-mutagenic potential.

Of course, preventing cancer and treating cancer are two different things. In animal studies, selenium isn’t as effective for controlling pre-existing cancers as it is for preventing cancer. But, the ability of selenium to prevent cancer in carcinogen-treated animals suggests that selenium administered in conjunction with chemotherapy may well reduce the chance that treatment with DNA-damaging cytotoxic agents could ultimately give rise to new cancers.

Furthermore, although selenium alone usually isn’t effective as a cancer therapy, there is exciting recent evidence that, as an adjuvant to high doses of intravenous vitamin C, chemotherapy or radiotherapy, supplemental selenium can render cancer cells more sensitive to these measures, while simultaneously protecting normal healthy tissues (87,88). By using selenium in conjunction with chemotherapy, scientists achieve higher cure rates in rodents with transplanted tumors. This is because the tumors become more sensitive to the chemotherapies, and because the researchers can use higher doses of the drugs without producing life-threatening toxicities. Clinical studies are now in progress at Roswell Park Memorial Hospital evaluating supplemental selenium as an adjuvant to chemotherapy regimens. Preliminary reports indicate that the selenium is helping to maintain effective white cell counts, reduce the need for transfusions, and decrease side effects such as nausea, vomiting, and hair loss (89). The Roswell researchers are giving their chemotherapy patients 2,000mcg selenium daily prior to and during chemotherapy.

One recent study demonstrates that selenium protects normal cells from cytotoxin-mediated DNA damage by boosting the ability of a protective protein known as p53 to trigger DNA repair mechanisms in cells (89). Since the p53 protein is absent in most advanced cancers, this might explain why the protective benefit of selenium is confined largely to normal cells. A further reason for using selenium in cancer therapy is that high intakes of this mineral have been shown to boost immune responses. In particular, the types of immune cells involved in cancer control, cytotoxic T lymphocytes and NK cells, function more effectively with increased intakes of selenium (90,91).

In summary, the likely benefits of selenium in clinical cancer therapy, especially when used as an adjuvant to chemotherapy, are: improved response of cancers to chemotherapy and high doses of intravenous vitamin C; a reduction in chemotherapy side effects; increased capacity of the immune system to fight cancer spread; and reduced risk that chemotherapy may eventually give rise to a new cancer.

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Synerpax

Synerpax is a multi-ingredient nutritional supplement used in conjunction with both the in-hospital and at-home IRT regimens. It provides a blend of phytochemicals: green tea polyphenols, curcumin, piperine, resveratrol, and grape seed extract. These have demonstrated cancer retardant efficacy. Synerpax also includes Selenium and Zinc, which are important elements in the fight against cancer.

Green Tea Extract

Perhaps the most clinically significant of these ingredients is green tea extract. The extract employed is highly potent, comprising 98% polyphenols, the most prominent of which is the compound epigallocatechin-gallate, better and more conveniently known as "EGCG". Recent research shows that EGCG can achieve worthwhile inhibition of an important receptor on endothelial cells in concentrations that can feasibly be reached after oral administration. The receptor in question responds to a crucial stimulant of angiogenesis, vascular endothelial growth factor (VEGF). Many cancer cells produce VEGF. It is such a key mediator of angiogenesis that several new hyper expensive cancer drugs target the bioactivity of VEGF. The strategy employed by Oasis of Hope is to attack angiogenesis from as many angles as feasible, in the hope that the cumulative effect will be a clinically worthwhile retardation of tumor growth (92-96.)

Curcumin

Another intriguing phytochemical supplied by Synerpax is curcumin – the agent that makes turmeric yellow. Curcumin has slowed growth, promoted cell death by apoptosis, and increased responsiveness to chemotherapy drugs in a wide range of cancer cell lines (97-101). Oral curcumin may indeed prove to have value for prevention of colon cancer (102), which reflects the fact that curcumin taken up by the mucosal cells lining the colon can exert a worthwhile effect in these cells before it is metabolized.

Piperine

To expedite the absorption of curcumin and perhaps other constituents of this supplement, Synerpax includes piperine, also known as Bioperine®. It is a compound found in black pepper. Piperine has been shown to enhance the absorption of numerous phytochemicals and drugs, in part because it is a potent inhibitor of a protein "pump" that pushes a wide range of chemicals out of intestinal cells (103). A clinical study assessing absorption of curcumin found that concurrent administration of piperine improved absorption about 20-fold (104). A favorable effect on piperine on absorption of EGCG in mice has also been reported (105).

Grape Seed Extract

Synerpax also provides grape seed extract and resveratrol. These agents, like EGCG and curcumin, have exerted favorable effects on cancer cells in culture. Grape seed extract is rich in antioxidant flavonoids known as proanthocyanidins. Recent studies show that a high oral intake of grape seed extract can markedly inhibit the growth of human colorectal and prostate cancers implanted in mice (106,107). These findings suggest that, at some sufficiently high intake, grape seed extract may prove useful in clinical cancer therapy.

Resveratrol

Resveratrol is an antioxidant phytochemical found in red wine. Resveratrol, like curcumin, has potential to block the activation of NF-kappaB, a protein complex that makes many cancers more aggressive and resistant to chemotherapy (108).

Zinc

A nutritional dose of zinc is included in Synerpax since this mineral plays a key role in effective function of the immune system. It is desirable to insure that the zinc nutrition of cancer patients is at least adequate (109).

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Boswellic Acids

Boswellic acids are a group of closely related compounds found in salai guggul, a resinous extract from the tree Boswellia carteri traditionally used in Ayurvedic (Indian) medicine as an anti-inflammatory agent (110). In the early 1990s, German researchers discovered the mechanistic basis for salai guggul’s anti-inflammatory efficacy. Boswellic acids are very potent inhibitors of the enzyme 5-lipoxygenase (5LPO), which plays an essential role in the generation of a family of hormone-like pro-inflammatory compounds known as leukotrienes (111).

There is increasing evidence that 5LPO is often expressed by many types of cancer, and that this enzyme generates compounds that have potent growth factor activities for these cancers (112-114). Inhibiting 5LPO typically retards the growth of cancer cell lines dependent on 5LPO, and often increases the rate at which these cells die by apoptosis. Human cancer cell lines derived from prostatic, pancreatic, breast, esophageal, colorectal, bladder, gastric, and renal cancers, as well as mesotheliomas and leukemias, have shown 5LPO dependency (115-122). Not all such cancers are 5LPO dependent.

The impact of 5LPO activity on the sensitivity of cancers to chemotherapy or radiotherapy has so far received little attention. However, one fascinating recent report indicates that, concurrent expression of 5LPO is associated with substantial protection from the cytotoxicity of chemotherapeutic cancer drugs (123). Conversely, suppression of 5LPO in these cancers greatly enhances their sensitivity to these drugs. This implies that 5LPO inhibitors, administered prior to and during chemotherapy, should enhance the responsiveness of a high proportion of human cancers.

Zileuton, a drug approved for treatment of asthma, works by inhibiting 5LPO, and has shown cancer-retardant activity in hamsters with pancreatic cancer (124). However, we have chosen to use boswellic acid-rich extracts in Oasis of Hope IRT regimens because they are considerably less expensive and can be presumed to be safe based on centuries of use in traditional medicine. Moreover, a number of cell culture studies indicate that boswellic acids, most notably one known as acetyl-11-keto-beta-boswellic acid, can slow the proliferation and boost the death rate of various human cancer cell lines (125-129). The only published clinical experience with boswellic acids in the treatment of cancer dealt with the use of these agents in patients with progressing brain cancers (130,131). Although some of the children experienced improved neurological function during this treatment, this might have reflected an anti-inflammatory effect of leukotriene suppression rather than tumor regression. Nonetheless, the observed benefit was worthwhile. In rats transplanted with gliomas, treatment with boswellic acids could more than double survival time (132). In the in-hospital IRT protocol and at-home regimen, we include a potent dose of boswellic acids.

GPG

GPG is a nutraceutical, developed by Oasis of Hope scientists, that features Glycine, Modified Citrus Pectin and Glutamine. Recent research has demonstrated that these three active ingredients have the potential to: slow the growth and spread of cancer by blocking the processes of metastasis and angiogenesis, enhance the immune system, help prevent cachectic loss of muscle mass, and protect healthy tissues from the toxic effects of chemotherapy.

Glycine

Glycine is a non-essential amino acid that has a pleasant sweet flavor. Glycine doesn’t target a tumor directly, but rather inhibits the process of angiogenesis (133-135).

Modified Citrus Pectin

Another key component of GPG is Modified Citrus Pectin (MCP). Pectin is a soluble fiber found in citrus fruits. MCP is a special form of pectin that has been partially hydrolyzed so that it is less branched and more absorbable.

Studies have shown that orally administered MCP can impede the metastatic spread of implanted tumors (136). In order for metastasis to occur, cancer cells in the bloodstream must first attach themselves to the walls of small blood vessels. This binding is achieved by membrane proteins known as galectins (137,138). Modified Citrus Pectin binds to galectins, blocking their ability to promote adherence of cancer cells to vessels walls (139).

Galectins also play a role in the angiogenesis process by helping endothelial cells to roll up into tubes so that they can form new vessels (140). In a recent clinical trial in patients with prostate cancer, the rate of tumor growth slowed significantly when the patients received MCP (141). In studies with rodents, MCP showed the ability to block formation of new metastases.

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Glutamine

The last ingredient of GPG is the amino acid glutamine. This amino acid serves as an important source of food calories for immune cells as well as the gastrointestinal tract. Skeletal muscle constantly generates and exports glutamine to aid the nutrition of these tissues (142).

Glutamine also has the potential to protect immune and gastrointestinal cells from damage by radiation and/or chemotherapy (143-145). A recent study observed that supplemental glutamine helps the white blood cell count (neutrophils) to recover faster following chemotherapy (146).

The potential benefits of supplemental glutamine to cancer patients are multi-faceted: reducing some of the dangerous side effects of radiation and/or chemotherapy, without protecting tumor cells (143-147); boosting the capacity of natural killer cells to attack the tumor, thereby helping to control the spread of cancer, particularly new metastases; and helping to prevent the severe loss of muscle mass (cachexia), a common complication of advanced cancer.

Biotin

Most tumors have a rather haphazard blood supply that leaves some regions of the tumor poorly perfused and low in oxygen. It has long been known that when cancer cells are in a hypoxic environment, they tend to be less sensitive, not only to radiotherapy, but also chemotherapy. The basis of this phenomenon has not been fully clarified, but scientists recently have proposed an intriguing explanation (148-151). Most tumors generate a gaseous compound known as nitric oxide, which has a range of important physiological effects. Synthesis of nitric oxide can be substantially reduced in hypoxic tumor regions, since oxygen is required for the production of this compound (152,153). Researchers have reported that adding small amounts of nitric oxide (or rather chemicals like glyceryl trinitrate, which generate this volatile compound) to cancer cells incubated in low oxygen, can substantially boost the ability of cytotoxic chemotherapy drugs to kill these cells. Conversely, in cancer cells that are normally oxygenated, administration of drugs which inhibit production of nitric oxide reduces the sensitivity of these cells to cytotoxic chemicals – in effect, mimicking the impact of low oxygen exposure. Thus, it is now believed that the reduction in tumor production of nitric oxide associated with tumor hypoxia is largely responsible for the diminished sensitivity of cancer cells to chemotherapy in hypoxic tumor regions.

Importantly, adding a source of extra nitric oxide to cells that are normally oxygenated does not seem to alter their sensitivity to cytotoxic chemotherapy (148). Evidently, whereas a small amount of nitric oxide is needed for optimal chemosensitivity, excess amounts do not further boost this sensitivity. Thus, clinical strategies which increase levels of nitric oxide throughout the body or which mimic the physiological effects of this compound, would not be expected to increase the toxic impact of chemotherapy on normally oxygenated healthy tissues.

One of the chief physiological effects of nitric oxide is to activate the enzyme guanylate cyclase, which generates an important regulatory compound known as cyclic GMP. This appears to be the main mediator of the main mediator of nitric oxide’s favorable impact on cancer chemosensitivity (148). Thus, measures which boost cyclic GMP production in hypoxic cancer cells increase their chemosensitivity the way that nitric oxide does.

How should this new knowledge be applied in cancer therapy? One recent study shows that the ability of doxorubicin, a cytotoxic chemotherapy drug, to control the growth of a transplanted human prostate cancer in mice, is significantly enhanced if the mice are concurrently treated with glyceryl trinitrate patches that boost levels of nitric oxide throughout the body (151).

Although it would probably be feasible for us to use similar patches in conjunction with chemotherapy, we have chosen a somewhat more elegant, more natural, and less expensive approach – high-dose biotin. Biotin is a physiologically essential B vitamin. However, in concentrations roughly ten-fold higher than physiological levels, biotin acts as a direct activator of guanylate cyclase (154). In other words, biotin mimics the impact of nitric oxide in this regard, boosting production of cyclic GMP. In light of the fact that biotin appears to be quite safe, even in high doses, we have decided to use mega-dose biotin as a nitric oxide mimetic, in an effort to boost the chemotherapeutic responsiveness of poorly-oxygenated cancer cells.

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