~Cancer Adjuvant Therapy, Part 4

COMPLEMENTARY THERAPIES, continued

Inositol hexaphosphate (IP-6)--activates natural killer cells, promotes differentiation, supports p53 activity, and normalizes the cell cycle by modifying signal transduction pathways

IP-6, a promising anticancer compound sold as a nutritional supplement, is a combination of inositol (a B vitamin) and phytic acid, also known as inositol hexaphosphate. According to Dr. A. Shamsuddin, M.D., Ph.D., who introduced IP-6 after more than 15 years of research, it works by enhancing the body's ability to defend itself against cancer, making it of equal importance as either a cancer preventive or therapeutic agent.

Inositol hexaphosphate is a sugar, very much like glucose, except it has six phosphates attached to its molecules. Every animal and plant species tested had varying levels of IP-6, but the highest amounts were found in rice, about 2% by weight: 100 grams of rice provide approximately 2 grams of IP-6, but even that amount is not readily available. Since the body is dependent upon digestive enzymes to break it down, only a meager amount is actually absorbed from foodstuffs. Thus, IP-6 in encapsulated or bulk forms should be of special interest to cancer patients and those desiring protection against cancer.

The following chemotherapeutic properties are assigned to the immune modulator:

  • IP-6 activates natural killer cells, cells that work without antibody participation (Baten et al. 1989).

  • IP-6 decreases cellular proliferation (Sakamoto et al. 1993; Shamsuddin et al. 1989b). Illustrative of its potential, IP-6 reduced large intestinal cancer (by regulating cell proliferation) in F344 rats even when the treatment was begun 5 months after carcinogenic induction (Shamsuddin et al. 1989a).

  • IP-6 promotes differentiation ("normalization") of cancer cells, that is, an unspecialized, atypical cell structure assumes the likeness of the tissue of origin, indicating the virulence of the malignancy is waning (Yang et al. 1995). IP-6 was shown to inhibit growth and induce differentiation in HT-29 human colon cancer cells, making it valuable as an adjunctive treatment in colon cancer. IP-6 also strongly inhibited growth and induced differentiation in human prostate cancer cells (PC-3) in both in vitro and in vivo studies (Shamsuddin et al. 1995).

  • IP-6 has been effective against every cancer cell tested (Shamsuddin et al. 1997; Grases et al. 2002).

  • After inducing cancer in laboratory animals, IP-6 administered either orally or by injection at the site of the tumor, or intraperitoneally, resulted in tumors two-thirds smaller than the controls. As tumors reduced in size, survival rate increased (Shamsuddin et al. 1989a).

  • IP-6 increases expression of the tumor suppressor gene p53 by up to 17-fold. p53 acts on cells under stress, such as those with DNA damage, reducing proliferation and encouraging apoptosis. When cancer arises, a mutation in p53 is commonly involved. Lastly, since loss of p53 function increases cancer cells' resistance to chemotherapeutic agents, the stimulating action of IP-6 on p53 makes it an attractive adjuvant chemotherapeutic agent (Shamsuddin et al. 1997; Saied et al. 1998).


Toxicity studies (dating back to 1958) showed that a daily dose of 9 grams of IP-6 for 3 years resulted in side effects, including lesser incidences of kidney stones and fatty liver, as well as lower cholesterol levels. It is important to note that IP-6 does not kill cancer cells, as most anticancer agents do; thus, hair loss and immune suppression do not occur. A suggested dosage of 1-3 grams a day is adequate for most individuals. For those requiring larger doses, a powder is available (1 scoop twice daily is equivalent to 16 capsules, supplying about 6.4 grams of IP-6).

Lactoferrin--is immunoregulatory, inhibits angiogenesis, and binds iron

Perhaps one of the most promising therapeutic uses of lactoferrin, a milk protein with bacteriostatic properties, may be as a nontoxic, anticancer agent. Lactoferrin, a minor fraction of whey, results in a significant reduction in the incidence of esophageal, lung, bladder, and colon cancer in laboratory rats (Ushida et al. 1999; Masuda et al. 2000; Tsuda et al. 2002).

Since evidence indicates milk products protect against colon cancer, researchers speculate that bovine lactoferrin, a natural ingredient in milk, may be the chemoprotective agent (Tsuda et al. 2000b). Rats treated with a carcinogen and supplemented with 2% bovine lactoferrin for 36 weeks had a reduced incidence of colon cancer (27% of that observed in a control group; rats receiving 0.2% bovine lactoferrin reduced incidence to 46%). A remarkable 43% reduction in spontaneous lung metastasis (compared to controls) occurred after implanting colon carcinoma 26 (Co 26 Lu) in lactoferrin-treated laboratory animals (Tsuda et al. 2000a).

In addition to inhibiting angiogenesis (the vascular network that sustains the tumor), lactoferrin maintains the integrity of the immune system (Yoo et al. 1997; Tsuda et al. 2002). Typically, bovine lactoferrin prompts an increase in the number of natural killer cells, as well as the cytotoxicity of white blood cells (Tsuda et al. 2000a). The antibiotic, anti-inflammatory, and immune-modulating properties of lactoferrin appear active against the gastritis-, ulcer-, and cancer-inducing bacterium Helicobacter pylori (Dial et al. 2002).

Lactoferrin, a natural iron-binding protein, scavenges free radicals in fluids and inflamed areas, suppressing free radical mediated damage. It decreases the availability of iron in neoplastic cells, depriving them of an iron supply (Khan et al. 2001; Weinberg 2001).

The suggested dosage is 300-900 mg a day of the superior apolactoferrin (iron-depleted) form of lactoferrin. Lactoferrin is a natural component of cows' and human mothers' milk, but is also found in the milk of sheep, goats, and pigs.

Melatonin--is an immune modulator that increases the survival time of most cancer patients

Some cancer patients are now taking melatonin, an immune-modulating neurohormone, as part of a comprehensive, nontoxic cancer treatment. The cone-shaped pineal body, a small but crucial gland located in the brain, produces melatonin, a hormone that influences sexual maturation but also appears to play an important role in cancer.

Melatonin supplementation appears to restore circadian rhythms, which diminish or disappear with age. When melatonin's circadian rhythm is abolished, the aging process is accelerated, life span is shortened, and an increase in spontaneous tumors occurs (Maestroni 1999). It has been shown that when the defense system is compromised due to disrupted rhythms, tumors grow two to three times faster (Filipski et al. 2002).

Melatonin also protects and restores normal blood-cell production caused by the toxicity of conventional treatments; a profile shared with the FDA-approved drugs Neupogen, a granulocyte colony-stimulating factor (G-CSF), and Leukine, a granulocyte-macrophage colony-stimulating factor (GM-CSF). A combination of melatonin and low-dose interleukin 2 (IL-2) neutralizes treatment-induced lymphocytopenia, a decrease in the numbers of lymphocytes in the peripheral circulation of cancer patients (Lissoni et al. 1993).

Researchers found the best way to amplify the antitumoral activity of low dose IL-2 is by not coadministering another cytokine but rather cosupplementing with the immune-modulating neurohormone melatonin (Lissoni et al. 1994a). This is hopeful news for a subset of cancer patients, because melatonin has been shown to cause tumor regression in neoplasms nonresponsive to IL-2 (Maestroni 1999).

The Division of Radiation Oncology of the San Gerardo Hospital (Milan) developed the following protocol for 80 patients with advanced metastatic tumors (Lissoni et al. 1994a). The patients were randomized to receive 3 million IU of IL-2, 6 days a week, for 4 weeks or IL-2 plus 40 mg a day of melatonin. A complete response was achieved in 3 of 41 patients treated with IL-2 plus melatonin and in none of the patients receiving only IL-2. A partial response occurred in 8 of 41 patients treated with IL-2 plus melatonin and in 1 of 39 patients treated with IL-2. Tumor regression rate was significantly higher in patients using IL-2 and melatonin compared to those receiving IL-2 (11/41 versus 1/39). The survival rate at 1 year was higher in patients treated with IL-2 and melatonin than in the IL-2 group (19/41 versus 6/39). Lymphocytic populations were consistently higher when melatonin accompanied the treatment and thrombocytopenia (a decrease in the number of circulating platelets) occurred less frequently.

For patients with bloodborne cancers, an IL-2/melatonin combination is also promising. Twelve patients (nonresponsive to standard therapies) evaluated the efficacy and tolerability of a combination of low-dose IL-2 plus melatonin in advanced malignancies of the blood, including non-Hodgkin's lymphoma, Hodgkin's disease, acute myelogenous leukemia, multiple myeloma, and chronic myelomonocytic leukemia. IL-2 was given 6 days a week for 4 weeks, along with oral melatonin (20 mg a day). Cancer was stabilized and did not progress in 8 of 12 (67%) participants for an average duration of 21 months. An additional benefit accrued as the melatonin/IL-2 therapy was well-tolerated (Lissoni et al. 2000).

Nonresectable brain metastasis remains an untreatable disease. Because of melatonin's cytostatic action (the ability to suppress the growth of cells) and its anticonvulsant activity, the pineal hormone may prove effective in the treatment of brain metastasis. In a study to test the theory, 50 patients with inoperable brain metastasis were given supportive care or supportive care plus 20 mg of melatonin nightly. Freedom from brain tumor progression and survival rates at 1 year were higher in patients who were treated with melatonin compared to those who received only supportive care (Lissoni et al. 1994b, 1996). Even when melatonin was unable to stop the progression of advanced, metastatic disease, it improved the performance status of patients (see Table 2).

Low melatonin levels play a role in escalating rates of breast cancer. As melatonin levels decrease, the secretion of estrogen increases. Nighttime production of melatonin inhibits the body's secretion of estrogen and decreases the proliferation of human breast cancer cells. Conversely, exposure to light during the night decreases melatonin production and increases cumulative lifetime estrogen levels, a sequence that may increase the risk of breast cancer.

In fact, two current studies show that women who work night shifts may increase their risk of breast cancer up to 60%. Blind women have a significantly lower risk (36% less) of breast cancer than normally sighted women because of consistently higher levels of melatonin (Kliukiene et al. 2001). Women, who are classed as only visually impaired, realize no protective effects in regard to breast cancer.

Table 2: Summary of Studies Using Melatonin (Lissoni's Phase II Randomized Clinical Trial Results)
        1-Year Survival  
Tumor Type Patient Number Basic Therapy Melatonin Dose Melatonin Placebo Level of Significance
Metastatic non-small cell lung 63 Supportive care only 10 mg 26% under 1% <0.05
Glioblastoma 30 Conventional radiotherapy 10 mg 43% under 1% <0.05
Metastatic breast 40 Tamoxifen 20 mg 63% 24% <0.01
Brain metastases 50 Conventional radiotherapy 20 mg 38% 12% <0.05
Metastatic colorectal 50 IL-2 40 mg 36% 12% <0.05
Metastatic nonsmall cell lung 60 IL-2 40 mg 45% 19% <0.05
&nbdp;
Compiled by Cancer Treatment Centers of America and published in the March 2002 issue of Life Extension Magazine.


It appears that melatonin may also reduce the number of estrogen receptors on breast cancer cells. Since estrogen effectively feeds the growth of hormone-responsive breast tumors, reducing the receptors might slow tumor growth. Science News reported that the amount of melatonin required to inhibit breast cell proliferation appears no greater than the amount commonly present in human blood at night (Science News 93; Moss 1995).

Electromagnetic fields (EMFs) are another inhibitor of melatonin production. There is evidence that ELF (extremely low frequency) magnetic fields can act at the cellular levels to enhance breast cancer cell proliferation by blocking melatonin's natural oncostatic action. The mechanism(s) of action is unknown and may involve modulation of signal transduction events associated with melatonin's regulation of cell growth (Liburdy et al. 1993)

Melatonin delivers another anticancer perk through its antioxidant values. Physicians who once credited glutathione and vitamin E as being antioxidants of choice have now given special honor to melatonin. The neurohormone appears to protect against tumors by shielding molecules (especially DNA) from oxidative stress. Melatonin exerts its antioxidant properties by detoxifying the highly reactive hydroxyl radical, as well as singlet oxygen, hydrogen peroxide, and peroxynitrite anions (Kim et al. 2000).

A typical dose for a healthy individual is 300 mcg-6 mg each night. Cancer patients often take between 3-20 mg each night.

Modified Citrus Pectin (MCP)--retards cancer growth and metastasis

Modified citrus pectin (MCP), also known as fractionated pectin, is a complex polysaccharide obtained from the peel and pulp of citrus fruits. Through pH and temperature modifications, the pectin is broken down into shorter, nonbranched, galactose-rich, carbohydrate chains. The shorter chains dissolve more readily in water, making them better absorbed than ordinary, long-chain pectin. The short polysaccharide units afford MCP its ability to access and bind tightly to galactose-binding lectins (galectins) on the surface of certain types of cancers. By binding to lectins, MCP is able to powerfully address the threat of metastasis (Strum et al. 1999).

In order for metastasis to occur, cancerous cells must first bind or clump together; galectin is thought responsible for much of cancer's metastatic potential by providing the binding site (Raz et al. 1987; Guess et al. 2003; Pienta et al. 1995). MCP appears small enough to access and bind tightly with galectins, inhibiting (or blocking) aggregation of tumor cells and adhesion to surrounding tissue (Kidd 1996). Deprived of the capacity to adhere, cancer cells fail to metastasize.

Men with prostate cancer who took 15 grams of MCP a day had a slowdown in the doubling time of their PSA levels. (Lengthening of doubling time represents a decrease in the rate of cancer growth.) Interestingly, rats injected with prostate adenocarcinoma and given MCP (in drinking water) showed a significant reduction in metastasis (compared to control animals), although the primary tumor was unaffected. According to Dr. Kenneth Pienta (leader of the Michigan Cancer Foundation), MCP may be the first oral method of preventing spontaneous prostate cancer metastasis (Pienta et al. 1995; Guess et al. 2003).

As with prostate adenocarcinoma, research shows that metastasis of breast cancer cell lines requires aggregation and adhesion of the cancerous cells to tissue endothelium in order for it to invade neighboring structures (Glinsky et al. 2000). To test the anti-adhesive properties of MCP, researchers evaluated (in an in vitro model) breast carcinoma cell lines MCF-7 and T-47D. The study concluded that MCP countered the adhesion of malignant cells to blood vessel endothelium and subsequently inhibited metastasis (Naik et al. 1995). MCP decreased metastasis of melanoma to the lung by more than 90% in laboratory animals (Platt et al. 1992).

Because MCP is a soluble fiber, no pattern of adverse reaction has been recorded in the scientific literature, apart from a self-limiting loose stool at high doses. MCP dosages are usually expressed in grams, with a typical adult dose ranging from 6-30 grams divided throughout the day. MCP’s apparent safety and proven antimetastatic action, and the lack of other proven therapies against metastasis appear to justify its inclusion in a comprehensive orthomolecular anticancer regimen (Kidd 1996). Pecta-Sol is the brand name of the original modified citrus pectin (MCP. The dosage for Pecta-Sol is about 15 grams a day.

N-acetyl-cysteine (NAC)--is an anticarcinogenic and antimutagenic agent; it inhibits IL-6 as well as invasion and metastasis of malignant cells

N-acetyl-cysteine (NAC) is the acetylated precursor of the amino acids L-cysteine and reduced glutathione. Historically, it is used as a mucolytic agent in respiratory illnesses as well as an antidote for acetaminophen hepatotoxicity, but more recently its credits have grown. Animal and human studies have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer (Bongers et al. 1995; van Zandwijk 1995).

The biological value of NAC is attributed to its sulfhydryl group, while its acetyl-substituted amino group offers protection against oxidative and metabolic processes (Bonanomi et al. 1980; Sjodin et al. 1989). In vitro studies showed NAC to be directly antimutagenic and anticarcinogenic; in vivo, NAC inhibited mutagenicity of a number of mutagenic materials (De Flora et al. 1986, 1992).

NAC has both chemopreventive and therapeutic potential in malignancies arising in the lung, skin, breast, liver, head, and neck (van Zandwijk 1995; Izzotti 1998). NAC is effective in inhibiting tumor cell growth in melanoma, prostate cells, and astrocytoma cell lines (the latter is a primary tumor in the brain) (Albini et al. 1995; Arora-Kuruganti et al. 1999; Chiao et al. 2000). Neovascularization (new blood vessel growth) is crucial for tumor mass expansion and metastasis. NAC inhibited invasion and metastasis of malignant cells by up to 80% by preventing angiogenesis (De Flora et al. 1996).

A number of cancers express IL-6 and other potentially dangerous cytokines. NAC inhibited (in a dose-dependent manner) the synthesis of IL-6 by alveolar macrophage (Munoz et al. 1996; Gosset et al. 1999).

Peak plasma levels of NAC occur approximately 1 hour after an oral dose; 12 hours after dosing, it is undetectable. Despite a relatively low bioavailability (4-10%), research has shown NAC to be clinically effective (Borgstrom et al. 1986). A suggested NAC therapeutic dosage is usually in the range of 600 mg per day.

Resveratrol--influences cancer at initiation, promotion, and progression stages

Resveratrol is one of a group of compounds (called phytoalexins) that are produced in plants during times of environmental stress, such as adverse weather or insect, animal, or pathogenic attack. Resveratrol has been identified in more than 70 species of plants, including mulberries and peanuts, and the skins of red grapes, which are a particularly rich source (Jang et al. 1999). According to Pezzuto, "Of all the plants we’ve tested for cancer chemopreventive activity, this one [resveratrol] has the greatest promise" (Pezzuto 1997).

Resveratrol was effective against cancer during all three phases of the cancer process: initiation, promotion, and progression. For example, resveratrol displayed antimutagenic and antioxidant activity, providing greater protection against DNA damage than vitamins C, E, or beta-carotene. Resveratrol restored glutathione levels, considered by some as the most essential of antioxidants (Jang et al. 1999). It increased levels of a Phase II detoxifying enzyme (quinone reductase), an enzyme responsible for metabolically disassembling carcinogens.

Resveratrol inhibited the activity of cyclooxygenase-2 (COX-2), reducing the inflammatory response in human epithelial cells (Subbaramaiah et al. 1999). Upregulation of COX-2 is associated with the physical manifestations of various human cancers, as well as other inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are thought to exert chemopreventive effects, particularly in the promotion stage of the disease.

Resveratrol prompted differentiation of human promyelocytic leukemia cells. The development of preneoplastic lesions in mouse mammary glands was inhibited by resveratrol (Kang et al. 2003; Asou et al 2002; Tsan et al. 2002).

The following studies illustrate the many pathways resveratrol employs to inhibit cancer:

  • Italian researchers recently determined that resveratrol exhibited a protective role against colon carcinogenesis, with the defense attributed to changes occurring in Bax protein, which encourages cell death (apoptosis), and p21 expression (Tessitore et al. 2000). Reduced Bax activity is associated with resistance to cytotoxic therapy (Bosanquet et al. 2002). p21 is able to arrest the cell cycle at the G1 phase by inhibiting DNA replication (Aaltomaa et al. 1999). Suppressing the growth cycle allows for a critical phase in cellular development referred to as differentiation, that is, an abnormal cell becomes more normal.

  • Resveratrol appears a promising anticancer agent for both hormone-dependent and hormone-independent breast cancers. At high concentrations, resveratrol caused suppression of cell growth in three breast cancer cell lines: estrogen-receptor (ER)-positive KPL-1 and MCF-7 and ER-negative MKL-F. Growth inhibition was credited in part to up-regulation of Bax protein and activation of caspase-3 (a key mediator of apoptosis in mammalian cells). Resveratrol was also able to lessen the growth stimulatory effects of linoleic acid, a fatty acid frequently over-consumed in Western diets (Nakagawa et al. 2001).

  • Resveratrol significantly reduced tumor volume (42%), tumor weight (44%), and metastasis (56%) in mice with highly metastatic Lewis lung carcinoma. Resveratrol was able to inhibit angiogenesis and reduce oxidative stress (Kimura et al. 2001; Kozuki et al. 2001).

  • Different wine polyphenols (catechin, epicatechin, quercetin) including resveratrol may be effective against prostate cancer. Prostate cancer cell lines (LNCaP and DU145) produce high concentrations of nitric oxide; PC3 produces low concentrations. Researchers propose that the anti-proliferative effects of polyphenols are due to their ability to adjust nitric oxide production (Kampa et al. 2000). Grape extract, a rich source of resveratrol, inhibited prostate cancer growth up to 98% in a dose- and time-dependent manner (Agarwal et al. 2000b).

  • Resveratrol appears to be promising in the control of acute monocytic leukemia (Tsan et al. 2000). Resveratrol induced apoptotic cell death in human leukemia cells (HL60) (Clement et al. 1998) and stopped the growth of lymphocytic leukemia cells during the S-phase of the growth cycle (the time of DNA replication) (Bernhard et al. 2000).

  • Resveratrol inhibits NF-kB, thus inhibiting cell proliferation and cytokine production (Gao et al. 2001). The inhibition of cytokine production by resveratrol was found to be irreversible.

    If using pure resveratrol, the suggested dosage is 7-50 mg a day. Beware of diluted supplements that provide very little active resveratrol. At the time of this writing, there were only a few sources of pure high-potency resveratrol available as dietary supplements.

    Continued . . .


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