Colorectal Cancer-3

Modified citrus pectin (MCP) is a polysaccharide found in the peel and pulp of citrus fruits. MCP is rich in galactoside residues that bind galectin-3 on tumor cells, which in turn interferes with tumor cells binding to healthy cells as they circulate (Glinskii OV et al. 2005).

Cancer spread (via metastasis) is one of the most life-threatening aspects of cancer. The lack of effective anti-metastatic therapies has prompted research on modified citrus pectin's effectiveness in blocking colorectal cancer spread. MCP slows cancer growth by 70 percent and spontaneous liver/lung metastasis in mice injected with human colon cancer cells, presumably via its interfering effects on galectin-3 (Nangia-Makker P et al 2002; Hayashi A et al 2000; (Pienta KJ et al. 1995).

MCP produces a healthy bile acid profile (Ide T et al. 1990) and protects against chemically induced colon cancer via carcinogen binding in the colon (Smith-Barbaro P et al. 1981). Furthermore, as a fermentable, soluble fiber, MCP produces high butyrate levels, which in turn inhibit colon cancer development (vivi-Green C et al. 2000).

Curcumin (Curcuma longa Linn or diferuloylmethane) is extracted from the spice turmeric. Curcuma extract at doses of up to 2.2 grams daily (equivalent to 180 mg of curcumin) was given for up to four months to 15 advanced colorectal cancer patients who did not respond to standard chemotherapy treatment. Five patients had disease stabilization for two to four months of treatment (Sharma WP et al 2001) without any dose-limiting toxicity. Results from another study of colorectal cancer patients suggest that a daily dose of 3.6 grams of curcumin achieves pharmacologically effective levels in the colorectum (Garcea G et al. 2005).

Curcumin’s anti-cancer mechanism of action is complex and multifactorial. It includes preventing colorectal cancer cell division (Leyon PV et al 2003) and the growth of new tumor blood vessels (Gao C et al 2003; Gururaj AE et al 2002), killing cancer cells via apoptosis (Chauhan DP 2002; Moragoda L et al 2001), reducing levels of enzymes involved in cancer progression, migration, and invasion, such as cyclooxgenase 1 and 2, lipoxygenase, and nitric oxide synthase (Su CC et al. 2006) Skrzypczak-Jankun E et al 2003; Cuendet M et al 2003; Brouet I et al 1995), and exerting antioxidant, anti-inflammatory, and anti-metastatic activities (Aggarwal BB et al 2003; Kos M et al 2002).

Green tea has been shown to prevent cancer in preclinical studies (Fujiki H et al. 1998). Its primary anti-cancer component is epigallocatechin gallate (EGCG). Seven patients with familial polyposis who underwent surgical removal of the colon were treated with green tea extract and chemotherapy suppositories (5-fluorouracil) after surgery. No rectal cancer developed in any of the patients and some polyps degenerated in the remaining rectum (Ichikawa et al 1998).

Green tea prevents cancer growth and spread through several different mechanisms, including reducing levels of pro-inflammatory mediators such as prostaglandin E2 (PGE2), COX-2, and lipoxygenase (Peng G et al. 2006); Salucci M et al 2002; Hong J et al 2001; August DA et al 1999), causing mitochondrial damage and direct tumor cell death (Chen C et al 2003), interfering with interactions between tumor cells and normal cells (Mueller-Klieser W et al 2002), and preventing cancer spread by blocking new tumor blood vessel development (Jung YD et al 2001a,b).

A phase I trial of oral green tea extract in patients with solid tumors determined that a dose equivalent to seven to eight cups (120 ml) of Japanese green tea three times daily can be taken safely for at least six months. Side effects of green tea are mild and related to the stimulating effect of caffeine (Pisters KM et al 2001).

Omega-3 fatty acids. EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) supplementation prior to colorectal cancer surgery improves the immune response and decreases the infection rate, improving patients’ outcome (Braga M et al 2002). In advanced cancer patients, EPA at doses of 18 grams is well tolerated and improves survival (Barber MD et al 2001; Burns CP et al 1999). Diets rich in omega-3 fatty acids decrease both the initiation and promotion of colon cancer (Kontogiannea M et al 2000). EPA prevents tumor cells from binding to healthy cells, as in blood vessels (Kontogiannea M et al 2000), and thus inhibits the development of liver metastasis (in animals) (Iwamoto S et al 1998). An omega-6 to omega-3 ratio of 2.5:1 reduced rectal cell proliferation in patients with colorectal cancer (Simopoulos AP 2002).

Omega-3 fatty acids (EPA and DHA) are found in oily, cold-water fish such as salmon, mackerel, herring, bluefin tuna, sardines, and trout. Vegan sources of omega-3 fatty acids come from dietary alpha-linoleic acid conversion and include ground flaxseed, soybeans, pumpkin seeds, and walnuts (Davis BC et al 2003; Vegan Society 2003; Mantzioris E et al 1994)

The EPIC study performed in 23 centers in 10 European countries found that high fish consumption had a protective effect against colorectal cancer (Gonzalez CA 2006a). Dietary fish oil supplementation in patients with adenomatous polyps reduces rectal cell proliferation, a marker of cancer risk (Bartram HP et al 1995). In a double-blind study of 60 patients with sporadic adenomas, low-dose fish oil supplementation (2.5 grams, 5.1 grams, or 7.7 grams per day for 30 days) had normalizing effects on the abnormal rectal proliferation patterns associated with increased colon cancer risk (Anti M et al 1994).

Large doses of fish oil prevent tumor growth through a free radical-mediated mechanism, while more moderate doses hinder inflammation, angiogenesis, and Ras protein activity (Grimm H et al 2002; Collett ED et al 2001; McCarty MF 1996). Mild gastrointestinal symptoms such as belching, bloating, gas, diarrhea, and a fish-oil aftertaste occur in some patients (Bruera E et al 2003; Gogos CA et al 1998).

Selenium is an essential trace element found in vegetables, cereals, grains, and nuts. Selenium reduces the incidence of colorectal cancer (Finley JW 2006), at least in part by increasing antioxidant levels that protect against cancer initiation (Peters U et al. 2006b); Wallace K et al 2003; Fleet JC 1997).

High selenium levels are associated with restoration of glutathione peroxidase levels (Ip C et al 1991), proper functioning of immune system cells, and a reduced occurrence of colorectal adenomas (Connelly-Frost A et al. 2006; Peters U et al. 2006a); Ferencik M et al 2003). By contrast, selenium deficiency increases susceptibility to colorectal cancer (Davis CD et al 2003; Kowal M et al 2003) and is associated with high levels of the tumor marker CA 19-9 (Lasch K et al 1999). Patients prone to colon adenomas and those with colon cancer have significantly lower selenium levels (less than 70 micrograms per liter (µg/L) (Fernandez-Banares F et al 2002; Milde D et al 2001; Psathakis D et al 1998).

In a double-blind, placebo-controlled trial, patients with colon adenomas presented with low serum levels of selenium before treatment, but supplemental selenium normalized their selenium levels (Al-Taie OH et al 2003). Reduced activity of this selenium-dependent enzyme is associated with increased risk and poor prognosis in colorectal cancer patients (Milde D et al 2001). In a double-blind, three-year intervention study of polyp-bearing patients, selenium (101 mcg) protected against the formation of new adenomas (Hofstad B et al 1998). A phase III clinical trial is investigating selenium to see how well it works in preventing the recurrence of polyps in patients with adenomatous colorectal polyps (for more information, visitwww.clinicaltrials.gov).

Brazil nuts, plant foods, tuna, cod, and eggs contain high levels of selenium.

Folic acid and folate are forms of a B vitamin and are naturally found in dark green, leafy vegetables such as spinach, blackeye and Great Northern beans, brewer’s yeast, and liver. Bacteria in the human colon are also capable of producing folate, and certain dietary fibers such as citrus pectin enhance this effect (in rats) (Thoma C et al 2003). Low folate status is associated with colorectal cancer (Pufulete M et al 2003; Cravo M et al 1994).

Clinical studies show that the higher the level of blood folate and dietary folate intake (Zhang SM et al. 2006), the lower the risk of developing colorectal cancer (Martinez ME et al. 2006); Giovannucci E 2002).

In a study of patients with recurrent adenomatous polyps at high risk for colon cancer development, folate supplementation (2 mg of folic acid per day for three months) decreased colon cell division, thus reducing colon cancer development (Khosraviani K et al 2002). Supplementation with folic acid (5 mg/day for three months) led to a 35 percent decrease in ornithine decarboxylase activity, a key enzyme enhanced in cancer growth (Bukin YUV et al 2001).

In one study, healthy women taking folic acid supplements for at least 15 years showed an astounding 75 percent reduction in colon cancer occurrence (Giovannucci E et al 1998). In another study examining the effect of folate supplementation on cancer risk in ulcerative colitis patients, folate supplementation was associated with a 62 percent lower incidence of cancer compared to individuals who did not receive folate supplementation (Lashner BA et al 1989,1997).

Folate’s cancer-preventive mechanisms include improving DNA methylation status (Cravo ML et al 1998), stabilizing tumor suppressor gene(s) such as DCC, adenomatous polyposis coli (APC), and p53, and preventing further increases in cell growth (Nagothu KK et al 2003).

The chemotherapy drugs pemetrexed (Alimta®) and oxaliplatin (Eloxatin®), in combination with folic acid and vitamin B12 supplementation, have anti-cancer activity in advanced colorectal cancer patients (Atkins JN et al. 2005). Folic acid and vitamin B12 markedly decrease the frequency of bone marrow toxicities of pemetrexed (Louvet C et al. 2004).

Cancer prevention with folic acid is currently under investigation at the National Institutes of Health (for more information, visit www.clinicaltrials.gov).

Calcium. In a randomized, controlled trial of 15 patients who had the right side of their colons removed, 1000 mg of elemental calcium per day for two months had a protective effect against colorectal cancer development (van Gorkom BA et al 2002). In adenoma patients, daily calcium carbonate supplementation (1.5 grams of elemental calcium) for one year significantly curbed abnormal rectal cell growth (Rozen P et al 2001).

In individuals at high risk for colon cancer, calcium supplementation (2.0 to 3.6 grams/day for three to four months) reduces the abnormal growth of colon cells, partly by decreasing the level of diacylglycerol, or DAG (Steinbach G et al 1994; Wargovich MJ et al 1992), and partly by producing a healthier bile acid profile (Terry P et al 2002; Lupton JR et al 1996).

Calcium impedes colon cancer development (Lamprecht SA et al 2001) and reduces the risk of colorectal adenoma recurrence by 45 percent (Grau MV et al 2003).

Vitamin A. The risk of developing colorectal adenomas is reduced in those with high vitamin A levels (Breuer-Katschinski B et al 2001; Rumi G et al 1999). By contrast, patients with polyps exhibit significantly lower serum levels of vitamin A. Retinol, retinoic acid, and beta-carotene block protein kinase C (PKC) activity, which when active increases tumor activity in the colon (Kahl-Rainer P et al 1994). When combined, vitamins A and D3 prevent new tumor blood vessel growth, or angiogenesis (Majewski S et al 1996).

Vitamin A comes from green and yellow leafy vegetables, fish liver oils, liver, eggs, and milk.

Caution: Monthly blood tests are necessary to ensure vitamin A toxicity does not occur.

Vitamin D. Increased vitamin D intake reduces colon cancer risk (Garland CF et al 1999). Vitamin D3 brings about normalization (differentiation) of colon cancer cells (Martinez ME et al 1996) and slows liver cancer growth (Martinez ME et al 2002; Alvarez-Dolado M et al 1999; Majewski S et al 1996).

Exposure to sunlight provides most people with their vitamin D requirement; however, elderly people with cancer have a reduced ability to produce vitamin D in their skin and should consider vitamin D supplementation. Foods that contain vitamin D include fish liver oil, fatty fish, and milk; vegan sources include foods fortified with vitamin D derived from torula yeast.

Caution: When taking doses of vitamin D3 in excess of 2000 IU a day, kidney and liver function and serum calcium metabolism should be monitored via a complete blood count (CBC) test.

Vitamin E. Men with a high vitamin E intake are 65 percent less likely to develop colorectal adenomas compared to men with low vitamin E intake (Tseng M et al 1996). For those with advanced-stage colorectal cancer (Dukes' C and D), a daily dose of 750 mg of vitamin E (beginning two weeks prior to chemotherapy or radiation treatment) increases immune function—specifically, increased CD4:CD8 ratios and enhanced capacity of T-cells to produce the T helper-1 cytokines, interleukin 2, and interferon-gamma (Malmberg KJ et al 2002).

Vitamin E succinate (d-alpha tocopheryl succinate) is a potent, highly specific anti-cancer agent of considerable therapeutic potential (Neuzil J 2003; Weber T et al 2002). It reduces colon cancer growth in mice by 80 percent (Neuzil J et al 2001).

Vitamin E is found in wheat germ, avocado, corn, soybeans, sunflower seeds, cod liver, and nuts. It helps prevent colorectal cancer, probably by decreasing the formation of mutagens arising from the oxidation of fecal lipids, as well as by decreasing oxidative stress in the colorectal epithelial cells (Campbell S et al 2003).

Resveratrol, a natural polyphenol found in peanuts, seeds, mulberries, grape skin, and red wine (Latruffe N et al 2002), has colon cancer-preventive activity in experimental studies (Aziz MH et al 2003; Stierum R et al 2001). Resveratrol directly interferes with colon cancer cell growth and causes cancer death by damaging the mitochondria (Liang YC et al 2003; Delmas D et al 2002; Mahyar-Roemer M et al 2002; Schneider Y et al 2000) of cells in vitro. Phase I and II clinical trials are studying the effects of resveratrol treatment in colorectal cancer patients (for more information, visit www.clinicaltrials.gov).

For More Information…
Colorectal cancer patients may wish to read the following chapters and design a program addressing the full range of their cancer concerns:

1)Cancer Surgery

2)Cancer Chemotherapy

3)Cancer Radiation Therapy

4)Cancer Vaccines and Immunotherapy

5)Complementary Alternative Cancer Therapies

6)Anemia, Leukopenia, and Thrombocytopenia.


Life Extension Foundation Recommendations
Colorectal cancer patients should consult their physician before supplementing with any nutrient while under conventional medical treatment. In addition, patients should enlist the assistance of their physician to ensure the implementation of blood tests and diagnostic procedures that are essential for monitoring the effectiveness of any adjuvant therapy for colorectal cancer.

The following summary of an adjuvant/supportive approach to conventional colorectal cancer treatment should be discussed with your physician prior to consideration of implementation:

The Life Extension Foundation suggests:

1)Aged garlic extract (Kyolic®)—1800 milligrams (mg) daily

2)Alpha tocopherol—400 to 1200 mg of d-alpha tocopheryl succinate daily

3)Gamma tocopherol—minimum of 200 mg daily

4)Avemar®—9 grams (g) daily

5)Calcium—1000 to 3600 mg daily

6)Curcumin—Up to 3.2 g daily

7)d-Limonene—7.3 to 14.4 g daily

8)Fiber—4 to 12 g daily before meals

9)Fish oils—2800 mg of EPA and 2000 mg of DHEA daily

10)Folic acid—800 micrograms (mcg) daily

11)Green tea—725 mg three times daily, or 10 cups of Japanese green tea

12)Modified citrus pectin—15 g daily in three divided doses

13)Silymarin—900 mg daily

14)Multivitamin—containing bioflavonoids daily

15)Perillyl alcohol—250 mg, four times daily

16)PSK (polysaccharide K)—3 g daily

17)Resveratrol—20 to 60 mg daily (Walle T et al. 2004)

18)Selenium—200 to 400 mcg daily

19)Vitamin A—10,000 to 30,000 international units (IU) daily; reduce dosage at six months

20)Vitamin C—500 to 5000 mg daily

21)Vitamin D3—2000 IU daily

22)Wheat grass juice extract—100 cubic centimeter (cc) or 1 scoop daily


Innovative Drug Strategies

Cimetidine—800 mg nightly for 12 continuous months.
Celebrex®—100 to 200 mg every 12 hours.

PSK (Polysaccharide K) can be purchased by visiting: http://www.jhsnp.com/store/vpscoriolusversicolor.html.

Product Availability
All the nutrients and supplements discussed in this section are available through the Life Extension Foundation Buyers Club, Inc.
The blood tests discussed in this section are available through Life Extension National Diagnostics, Inc.
Colorectal Cancer Safety Caveats
An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:

Calcium

a)Do not take calcium if you have hypercalcemia.

b)Do not take calcium if you form calcium-containing kidney stones.

c)Ingesting calcium without food can increase the risk of kidney stones in women and possibly men.

d)Calcium can cause gastrointestinal symptoms such as constipation, bloating, gas, and flatulence.

e)Large doses of calcium carbonate (12 grams or more daily or 5 grams or more of elemental calcium daily) can cause milk-alkali syndrome, nephrocalcinosis, or renal insufficiency.

Curcumin

a)Do not take curcumin if you have a bile duct obstruction or a history of gallstones. Taking curcumin can stimulate bile production.

b)Consult your doctor before taking curcumin if you have gastroesophageal reflux disease (GERD) or a history of peptic ulcer disease.

c)Consult your doctor before taking curcumin if you take warfarin or antiplatelet drugs. Curcumin can have antithrombotic activity.

d)Always take curcumin with food. Curcumin may cause gastric irritation, ulceration, gastritis, and peptic ulcer disease if taken on an empty stomach.

e)Curcumin can cause gastrointestinal symptoms such as nausea and diarrhea.

EPA/DHA

a)Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.

b)Discontinue using EPA/DHA 2 weeks before any surgical procedure.

Fiber

a)Take fiber supplements with a full 8-ounce glass of water.

b)Drink eight 8-ounce glasses of water daily while taking fiber.

Folic acid

a)Consult your doctor before taking folic acid if you have a vitamin B12 deficiency.

b)Daily doses of more than 1 milligram of folic acid can precipitate or exacerbate the neurological damage caused by a vitamin B12 deficiency.

Garlic

a)Garlic has blood-thinning, anticlotting properties.

b)Discontinue using garlic before any surgical procedure.

c)Garlic can cause headache, muscle pain, fatigue, vertigo, watery eyes, asthma, and gastrointestinal symptoms such as nausea and diarrhea.

c)Ingesting large amounts of garlic can cause bad breath and body odor.
Green Tea

Consult your doctor before taking green tea extract if you take aspirin or warfarin (Coumadin). Taking green tea extract and aspirin or warfarin can increase the risk of bleeding.
Discontinue using green tea extract 2 weeks before any surgical procedure. Green tea extract may decrease platelet aggregation.
Green tea extract contains caffeine, which may produce a variety of symptoms including restlessness, nausea, headache, muscle tension, sleep disturbances, and rapid heartbeat.

Milk Thistle

a)Consult your doctor before taking milk thistle with tranquilizers such as Haldol, Serentil, Stelazine, and Thorazine. Milk thistle combats the effect of tranquilizers.

b)Do not combine milk thistle with the blood pressure medication Regitine. Milk thistle combats the effect of Regitine.

Pectin

a)Do not take pectin if you have a gastrointestinal obstruction.

b)Pectin can cause gastrointestinal symptoms such as flatulence, cramps, gas, and diarrhea.

Selenium
a)High doses of selenium (1000 micrograms or more daily) for prolonged periods may cause adverse reactions.

b)High doses of selenium taken for prolonged periods may cause chronic selenium poisoning. Symptoms include loss of hair and nails or brittle hair and nails.

c)Selenium can cause rash, breath that smells like garlic, fatigue, irritability, and nausea and vomiting.

Vitamin A
a)Do not take vitamin A if you have hypervitaminosis A.

b)Do not take vitamin A if you take retinoids or retinoid analogues (such as acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin). Vitamin A can add to the toxicity of these drugs.

c)Do not take large amounts of vitamin A. Taking large amounts of vitamin A may cause acute or chronic toxicity. Early signs and symptoms of chronic toxicity include dry, rough skin; cracked lips; sparse, coarse hair; and loss of hair from the eyebrows. Later signs and symptoms of toxicity include irritability, headache, pseudotumor cerebri (benign intracranial hypertension), elevated serum liver enzymes, reversible noncirrhotic portal high blood pressure, fibrosis and cirrhosis of the liver, and death from liver failure.

Vitamin C

a)Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.

b)Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.

Vitamin D

a)Do not take vitamin D if you have hypercalcemia.

b)Consult your doctor before taking vitamin D if you are taking digoxin or any cardiac glycoside.

c)Only take large doses of vitamin D (2000 international units or 50 micrograms or more daily) if prescribed by your doctor.

d)See your doctor frequently if you take vitamin D and thiazides or if you take large doses of vitamin D. You may develop hypercalcemia.

e)Chronic large doses (95 micrograms or 3800 international units or more daily) of vitamin D can cause hypercalcemia.

Vitamin E
a)Consult your doctor before taking vitamin E if you take warfarin (Coumadin).

b)Consult your doctor before taking high doses of vitamin E if you have a vitamin K

c)deficiency or a history of liver failure.

d)Consult your doctor before taking vitamin E if you have a history of any bleeding disorder such as peptic ulcers, hemorrhagic stroke, or hemophilia.

e)Discontinue using vitamin E 1 month before any surgical procedure.