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Cancer Adjuvant Therapy
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.
Selenium--is protective against many types of cancers, promotes apoptosis, is a powerful antioxidant, and improves quality of life during aggressive cancer therapies
Many animal studies have been conducted to evaluate the effects of super nutritional levels of selenium on experimental carcinogenesis using chemical, viral, and transplantable tumor models. Two thirds of these studies found that high levels of selenium reduced the development of tumors at least moderately (14-35% compared to controls) and, in most cases, significantly (by more than 35%) (Whanger 1998).
The impact of selenium supplementation on basal cell carcinoma was studied on 1312 subjects (18-80 years of age, 75% of whom were men) (Clark et al. 1996). Within 6-9 months, the group receiving 200 mcg a day of selenium realized about a 67% increase in plasma selenium levels. The non-supplemented group, although judged "normal" in regard to plasma selenium levels, experienced twice the rate of cancer as those receiving selenium. Researchers concluded that higher amounts of dietary selenium than the amount recommended by the FDA are needed to prevent cancer.
Although the study failed to show the effectiveness of selenium in altering the course of either basal or squamous cell carcinoma, selenium impacted the incidence of other types of malignancies with amazing success. The overall reduction in cancer incidence was 37% in the selenium-supplemented group; a 50% reduction in cancer mortality was observed over a 10-year period (Clark et al. 1996).
The following are the site-specific reductions in cancer incidence observed in the study: colorectal cancers (58%), lung cancer (46%), and prostate cancer (63%). A selenium deficiency appears to increase the risk of prostate cancer four- to five-fold. It was determined that as the male population ages selenium levels decrease, paralleling an increase in prostate cancer (Brooks et al. 2001).
Data is compelling regarding the usefulness of selenium’s protective effects against cancer:
- Selenium-enriched broccoli is protective against chemically induced mammary and colon cancer in rats (Davis et al. 2002).
Note: While selenium is contributing to the lower incidence of malignancy, the anticancer affects of broccoli should also be factored into the defense. Please read the section What Should the Cancer Patient Eat (appearing in this protocol) for valuable information regarding dietary factors affecting patient outcome.
- The relationship between serum levels of selenium and the development of upper digestive tract cancer was examined (Mark et al. 2000). The relative risk of esophageal cancer was 0.56 in individuals in the highest quartile of selenium level compared with those in the lowest quartile. The corresponding relative risk of gastric cardia cancer was 0.47. Based on the data, it was concluded that 26.4% of esophageal and gastric cardia cancers are attributable to low selenium levels.
- Adding selenium to salt resulted in a significant reduction in the incidence of cancer (Whanger 1998).
- A significant increase in apoptosis and a decrease in DNA synthesis in breast cancers cells (MCF-7 and SKBR-3) occurred with selenium supplementation. The selenium benefit was just as impressive in cancers of the lung (RH2), small intestine (HCF8), colon (Caco-2), and liver (HepG2). Prostate cancers (PC-3 and LNCaP) as well as colon cancer (T-84), although initially less affected by supplementation, became responsive when selenium was coadministered with Adriamycin or Taxol (Vadgama et al. 2000). This study suggests that selenium potentiates the anti-cancer effects of chemotherapy. Selenium supplementation in patients undergoing radiation therapy for rectal cancer improved quality of life and reduced the appearance of secondary cancers (Hehr et al. 1997).
- It appears that selenium acts as an immunologic response modifier, normalizing every component of the immune system (Ferencik et al. 2003; Arthur et al. 2003)
An important form of selenium is Se-methylselenocysteine. This is the form of selenium found naturally in plants such as broccoli and garlic. A suggested selenium dosage is 200 mcg a day. The optimal dose for cancer patients is unknown at this time, but suggestions have ranged from 200-400 mcg a day depending upon the selenium content of the soil. Foods considered good sources of selenium include Brazil nuts, grains, onions, tomatoes, broccoli, chicken, eggs, garlic, liver, seafood, and wheat germ. Americans typically consume 60-100 mcg of selenium a day from dietary sources.
Silibinin (from milk thistle)--has antioxidant activity, increases sensitivity to chemotherapy while reducing its side effects, assists in arresting the growth of cancer, promotes differentiation, inhibits COX-2 enzyme, and suppresses NF-kB
Fourteen years ago, the Life Extension Foundation introduced silymarin, a hepato-protective herb, to members. The major active constituent of silymarin is silibinin; a long-recognized antioxidant with more recently ascribed anticarcinogenic traits. Silibinin inhibits the growth of various cancer cell lines. The silibinin acts synergistically with cisplatin and doxorubicin, common chemotherapeutic drugs, improving their efficacy. By arresting tumor cell division at a strategic stage, silibinin appears to make tumor cells more sensitive to chemotherapy. Also, the harsh side effects associated with cytotoxic chemicals are less damaging when silibinin is utilized (Bokemeyer et al. 1996).
Milk thistle is described as an adaptogenic herb. For example, it encourages new cell growth where repair is needed but arrests cell division in tumor tissue; it increases the activity of certain enzymes but inhibits others. Milk thistle inhibits COX-2 (Zhao et al. 1999). Note: Go to Cyclooxygenase (COX-2) Inhibitors (Naturally Occurring) appearing in this protocol for other nutraceuticals capable of inhibiting the COX-2 enzyme. Also, consult Cyclooxygenase Inhibitors in the protocol entitled Cancer Treatment: The Critical Factors to learn more about the COX-2-cancer connection.
Silibinin arrests cell growth in the early phase of the cycle known as G1, a period of growth before DNA replication. Silibinin discourages cell growth by inhibiting various kinase enzymes (those playing a pivotal role in regulatory mechanisms), enabling a critical stage in cellular development referred to as differentiation. Differentiated cells abandon their primitive façade and assume the physical likeness and behavioral patterns of healthy cells. In fact, silibinin caused differentiation of a significant number of malignant prostate cells to more normal cells, while simultaneously decreasing PSA levels (Zi et al. 1999).
Silibinin inhibits growth of drug-resistant breast and ovarian cancer lines. It binds to type II estrogen binding sites, an action that turns off the proliferative effects of the cell (Scambia et al. 1996). In addition, silymarin inhibited the secretion of VEGF (an angiogenic factor) by malignant cells, thwarting the formation of cancer's vascular network (Jiang et al. 2000). |