Cancer

Cancer
by Heather Granato

The second leading cause of death in the United States, cancer is expected to lead to more than 563,000 deaths this year, according to the American Cancer Society (ACS). However, thanks to aggressive treatment, early detection and control over causal factors, overall observed cancer incidence rates have dropped 0.5 percent per year over the past decade, according to the National Cancer Institute (NCI).

While incidence may be high, consumers can take control of a number of factors contributing to cancer development. NCI reported it is estimated between 50 percent and 75 percent of cancer deaths in the United States are caused by human behaviors such as smoking, physical inactivity and poor dietary choices; in fact, smoking causes about 30 percent of all U.S. deaths from cancer. Consumers can take steps to decrease their risk factors by maintaining a healthy weight, being physically active and eating a low-fat diet rich in fruits and vegetables.

The power of produce can’t be overstated. The American Institute of Cancer Research (AICR) estimated if the only dietary change Americans made was to increase their daily intake of fruits and vegetables to five servings per day, cancer rates could decline as much as 20 percent.¹

They note fruits and vegetables are excellent sources of fiber, vitamins, minerals and specialty components such as sulforaphane, indole-3- carbinol and phenolic compounds.

A review from the Institute of Food Research in Norwich, England, agreed with the assessment.² “Plant foods contain a variety of components including micronutrients, polyunsaturated fatty acids, and secondary metabolites such as glucosinolates and flavonoids, many of which can inhibit cell proliferation and induce apoptosis, and which may well act synergistically when combined in the human diet,” they wrote.

Population studies support these suggestions. A study from the National Cancer Center Research Institute East in Chiba, Japan, compared 264 patients with stomach or colorectal cancer to 517 controls, and found higher intake of cruciferous vegetables such as broccoli decreased the risk of both types of cancer, while mushroom intake was linked with a decreased risk of stomach cancer.³ And a study from Health Canada, Ottawa, Ontario, assessed the role of diet in relation to development of renal cell carcinoma (RCC).⁴ A significant inverse association with RCC was observed with increasing total consumption of vegetables, with females showing particularly high associations between high intake of dark-green and cruciferous vegetables and decreased RCC risk.

In addition to hoping consumers will change their diets to include healthy fats, produce and whole grains, researchers are also turning their attention to the host of nutritional compounds found in these foods.

Categories of phytochemicals, botanicals and specialty compounds are showing promise in scientific studies in mitigating the effects of cancer and preventing its onset.

One of the best known categories in the nutrition field is the antioxidants. Their relation to cancer genesis comes via the free radical theory of aging, which holds that it is important that the body maintain a healthy stasis between desirable and undesirable effects of reactive oxygen species (ROS). It has been noted that unregulated or prolonged production of cellular oxidants has been linked to genetic mutation and modified gene expression, which can lead to carcinogenesis.⁵ A research review from the University of Copenhagen, Denmark, found single dose antioxidant interventions have shown positive effects with relation to DNA oxidation.⁶ However, there is also data reporting antioxidants may interfere with radiotherapy or chemotherapy treatments.⁷

In a research review from the University of Colorado, Denver, the scientists suggest the contrasting data comes in when results from one experiment are extrapolated to another with no distinction on issues such as form, number of antioxidants or dose schedule.⁸ Instead, they suggest a nutritional protocol of high doses of antioxidants as an adjunct to standard therapy, which could increase tumor response and decrease toxicity, followed by a maintenance nutritional protocol containing lower doses of antioxidants to reduce recurrence of the original tumor and development of secondary cancers.

Studies show this may be a positive approach. In a two-phase study of 56 advanced stage cancer patients at the University of Cagliari, Italy, researchers divided the patients into five groups; during the first phase they received a single antioxidant agent, and in the second phase a combination of two of the agents.⁹ Antioxidants included alpha-lipoic acid, vitamin E or vitamin C. The researchers reported all single antioxidants tested were effective in reducing ROS levels and increasing glutathione peroxidase activity. And a case report from the University of Kansas Medical Center in Kansas City reported on two ovarian cancer patients who took adjunctive antioxidants with first-line chemotherapy; the antioxidants improved the efficacy of the chemotherapy, with no recurrent disease after three years.¹⁰

There are many types of antioxidants available. The single nutrient supplement most commonly used by cancer patients is reported to be vitamin C (ascorbic acid), although researchers note it often is used without medical supervision.¹¹ This 2003 research review reported while six uncontrolled studies reported positive results, the release of two controlled studies with no results may have colored physicians’ opinion on vitamin C in cancer therapy.

Unfortunately, recent in vivo and in vitro studies have not shown positive results for vitamin C. A study on the effects of ascorbic acid on apoptosis in human colon carcinoma cells found the nutrient blocked drug-mediated apoptosis induction, allowing the cancer cells to become insensitive to chemotherapy.¹² Data analyzed from the Danish Diet, Cancer and Health Cohort comparing 418 cases of breast cancer to 394 controls found vitamin C intake increased the risk for breast cancer, with the risk increasing with consumption.¹³

When vitamin C is combined with vitamin E, however, it may benefit both compounds. In a study of human prostate cancer cell lines, combinations of vitamins C and E reduced cell growth and enhanced apoptosis; vitamin C was also found to enhance the growth suppressive effect of vitamin E.¹⁴ And researchers from the University of North Carolina, Chapel Hill, found the risks of recurrence and disease-related mortality among postmenopausal women diagnosed with breast cancer were reduced among women using vitamin C and vitamin E supplements for more than three years.¹⁵

Individually, accumulating evidence shows vitamin E has an important role in preventing and treating cancer. A comprehensive literature review of vitamin E and cancer found individuals with higher serum vitamin E levels and people taking vitamin E supplements have a decreased risk of some cancers, including lung, prostate, stomach and gastrointestinal carcinoma.¹⁶ While there was variance in the study results, the researchers noted, “Vitamin E is likely to be important in the prevention of some cancers.”

One specific type of cancer vitamin E may impact is colorectal cancer, where it is suggested to work by decreasing the formation of mutagens in the colon, decreasing oxidative stress and influencing apoptosis.¹⁷

These researchers, from East Tennessee State University in Johnson City, singled out the gamma-tocopherol isomer as particularly beneficial. Researchers at Johns Hopkins in Baltimore also saw a strong association between gamma-tocopherol levels and prostate cancer risk in a case-control study of 10,456 men.¹⁸

The more common type of vitamin E in supplements is alphatocopherol, which was the form used in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, best known for connecting supplemental beta-carotene to an increased risk of lung cancer in current smokers. Follow-up work from the study cohort has shown alpha-tocopherol decreased prostate cancer incidence during the study and up to eight years after, but was not associated with a preventive effect for other cancers.¹⁹ Interestingly, the follow-up study also found the excess risk for beta-carotene was no longer evident after four to six years following the end of intervention.

Additional studies on alpha-tocopherol have shown mixed results.

Vitamin E supplement use was not associated with overall risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort of more than 72,000 men;²⁰ and hepatitis C patients, who are prone to hepatocarcinogenesis, who were treated with alpha-tocopherol showed slightly longer tumor-free survival, but there was no statistical difference.²¹

More positive results were reported by ACS, which found regular vitamin E supplement use for more than 10 years is associated with a reduced risk of bladder cancer mortality;²² and in research from NCI, which found participants in the General Population Trial in Linxian, China, who took alpha-tocopherol had a decreased risk of upper gastrointestinal cancers.²³

Separately, researchers have found more positive results from the use of alpha-tocopheryl succinate (VES), which is reported to be highly selective for malignant cells, inducing them into apoptosis through their mitochondria.²⁴ VES was found in an in vitro study to eliminate the lag time in apoptosis of cancer cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).25 It was also found to itself induce apoptosis by restoring particular signaling pathways that contribute to c- Jun N-terminal kinase (JNK)-mediated apoptosis, working similar to the method of the vitamin E isomer delta-tocotrienol.²⁶

The tocotrienol isomers have also been studied for a preventive effect against cancer growth. Researchers from the University of Louisiana showed malignant mouse mammary epithelial cells preferentially accumulated tocotrienols compared to tocopherols, and that the malignant mammary cells were most sensitive to the antiproliferative and apoptotic effects of tocotrienols.²⁷ Also, researchers from the University of Western Ontario, London, showed tocotrienols (derived from Tocomin® palm tocotrienol complex, supplied by Edison, N.J.-based Carotech Inc.) significantly enhanced the inhibitory effect of tamoxifen (a standard breast cancer drug) against the rate and growth of a breast cancer cell line known as MCF-7.²⁸

Vitamin E has also been studied in connection with selenium, particularly in the realm of prostate cancer. Selenium appears to potentiate vitamin E-induced inhibition of prostate cancer cell growth in vitro, and the combination is being studied in the Selenium and Vitamin E Chemoprevention Trial (SELECT).²⁹ Individually, selenium has been found protective against prostate cancer development. A review of the association between pre-diagnostic plasma selenium level and risk of prostate cancer in men enrolled in the Physicians’ Health Study found an inverse association between baseline plasma selenium levels and risk of advanced prostate cancer, suggesting selenium may slow prostate cancer tumor progression.³⁰ And research from the University of Arizona, Tucson, found supplementation with 200 mcg/d of selenium significantly reduced the overall incidence of prostate cancer, although the effect was restricted to subjects with lower baseline PSA and plasma selenium values.³¹

More generally, it is noted selenium blood and plasma levels are generally lower in patients with cancer, though inconsistent results have been found with toenail selenium values.³² However, this review added the vast majority of human studies have shown a positive benefit of selenium on cancer reduction or biomarkers. The biggest inconsistency has been variance between the sexes; cancer risk in men appears to be more profoundly influenced by selenium status than cancer risk in women, possibly related to sex-based differences in metabolism of selenium or other factors related to tumor biology.³³

Another mineral studied in relation to cancer is zinc. A review from the University of Michigan Medical Center in Ann Arbor stated excess intake of zinc has the potential to encourage the growth of prostate cancer, and suggested most individuals discontinue intake of larger quantities of zinc.³⁴ However, researchers from the University of Maryland, Baltimore, noted malignant prostate cancer cells show a marked decrease in zinc levels, and suggest restoration of high zinc levels in malignant cells could help in treatment of prostate cancer.³⁵ In fact, a study in mice showed in vivo treatment with zinc increased zinc accumulation and citrate production in PC-3 cell induced tumor tissues and inhibited tumor growth.³⁶

In addition to the antioxidant nutrients, other basic nutrients have benefits in the cancer realm. The B vitamins, particularly folate and B12, are important enzymatic cofactors in the body; impairment of folate-mediated metabolic pathways can increase the risk for cancer.³⁷

Folate appears to also modulate DNA methylation, which helps determine gene expression, and maintain DNA integrity, according to a review from the University of Toronto, which singled out colorectal cancer as particularly inversely related to dietary folate intake.³⁸ B12, meanwhile, additionally plays a role in biological methylation and impacts colonic DNA; deficiencies induced in rats resulted in significant methylation of colonic DNA, increasing susceptibility to carcinogenesis.³⁹

Folate has been a focus of breast cancer prevention studies, particularly as alcohol intake in women can both reduce folate levels and increase breast cancer risk.⁴⁰ In a 12-year cohort study of 34,387 postmenopausal women conducted at the Mayo Clinic, Rochester, Minn., researchers identified 1,586 cases of breast cancer.⁴¹ Women in the lowest 10th percentile of folate intake were at modestly increased risk of breast cancer relative to those in the top half of folate intake; the risks were significantly increased among women consuming alcohol.

Similarly, researchers from the University of Hawaii, Honolulu, conducted an investigation into the link between B vitamins and cervical cancer.⁴² Total folate intake from supplements and diet were inversely, dose-responsively associated with incidence of high- and low-grade cervical lesions. Vitamin B12 supplements, riboflavin and thiamin from food were also found to decrease the risk of low-grade lesions. The increased risk of cervical cancer associated with low nutrient intake was most pronounced among smokers and drinkers.

Beyond basic nutrients, consumers get a number of beneficial compounds from their diet—particularly phytochemicals from fruits and vegetables. Consider first the power of carotenoids, the fat-soluble pigments that lend color and antioxidant protection to tomatoes, carrots and more. Their ability to act as antioxidants within the body suggests they can reduce the toxic side effects of ROS, and may also play a role in gene regulation, apoptosis and angiogenesis.⁴³

Population studies have shown a diet high in carotenoids may mitigate the effects of several types of cancers, including those affecting the bladder,⁴⁴ colon⁴⁵ and prostate.⁴⁶ In fact, prostate cancer has been an area of scientific investigation for several carotenoids. A study conducted in southeast China during 2001-2002 compared 130 prostate cancer patients versus 274 controls; prostate cancer risk declined with increasing consumption of lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin.⁴⁷

Perhaps the most promising carotenoid in preventing prostate cancer is lycopene, which is the primary carotenoid found in tomatoes. A meta-analysis from Royal Victoria Hospital and McGill University in Montreal examined 11 case-control studies and 10 cohort studies investigating the use of tomato, tomato products or lycopene and their relation to prostate cancer risk.⁴⁸ The researchers did find a link between increasing intake of tomato products and a decreased risk of prostate cancer; however, they noted the effect was modest. In a 2002 review, researchers from the University of Illinois at Chicago also noted while lycopene may contribute to prevention of prostate cancer, “Numerous other potentially beneficial compounds are present in tomatoes and complex interactions among multiple components may contribute to the anticancer properties of tomatoes.”⁴⁹

Additional research has investigated the effects of tomato oleoresin extract (as Lyc-O-Mato from LycoRed-Biodar, New York), which contains lycopene and the full complex of tomato phytochemicals. A trial of 26 prostate cancer patients conducted at the Barbara Ann Karmanos Cancer Institute demonstrated supplementation with tomato oleoresin extract (as Lyc-O-Mato), which contained 30 mg of lycopene, reduced tumor size and made less involvement of surgical margins and/or extract-prostatic tissues with cancer less than in the control group.⁵⁰ And in a five-year study of patients at high risk of liver cancer, those who were given a natural tomato extract (as Lyc-O-Mato), showed liver cancer was suppressed by 50 percent compared to the control group.⁵¹

Astaxanthin has also shown beneficial results against cancer cells. A study in BALB/c mice found those given astaxanthin (0.02 percent, 40 mcg/kg body wt/d in a beadlet form) before inoculation for tumor growth had significantly lower tumor size and weight than controls.⁵² The antitumor activity was paralleled with higher immune response, characterized by increased cytotoxic T lymphocyte activity and IFNgamma production. Another study on astaxanthin and immune response showed daily oral administration of astaxanthin (1 mg/kg/d) in mice decreased the progression of hepatic metastasis induced by restraint stress.⁵³

A specialized extract of Haematococcus pluvialis containing astaxanthin and saw palmetto berry lipid extract (Alphastat® from Wayne, N.J.-based Triarco Industries) has been patented for the inhibition of 5-alpha reductase, an enzyme linked to prostate cancer. Inhibiting the enzyme prevents the conversion of testosterone to dihydrotestosterone (DHT). A study submitted to the Journal of Herbal Pharmacotherapy in June, 2004, investigated the effects of astaxanthin, saw palmetto berry lipid extract (SPLE) and Alphastat on 5-alpha reductase and the growth of prostatic carcinoma cells in vitro. Astaxanthin showed a 98 percent inhibition of 5-alpha reductase at 300 mg/mL in vitro, and Alphastat showed a 20 percent greater inhibition of 5-alpha reductase than SPLE alone in vitro. In addition, a nine-day treatment of prostatic cancer cells with astaxanthin produced a 24 percent decrease in growth at 0.1 mcg/mL and a 38 percent decrease at 0.01 mcg/mL.

Study results on other carotenoids and cancer have not been as positive. As noted earlier, beta-carotene has been shown in human trials to possibly increase the risk of lung cancer, particularly in smokers.⁵⁴

Studies about beta-carotene’s influence on other types of cancers have been similarly unclear. For example, researchers at Dartmouth Medical School in New Hampshire found beta-carotene markedly decreased colon cancer risk in non-smokers and non-drinkers, but doubled the risk of adenoma recurrence in subjects who smoked and consumed more than one alcoholic beverage per day.55 However, Italian researchers found beta-carotene had growth-inhibitory and pro-apoptotic effects on colon cancer cells.⁵⁶

Carotenoids are not the only class of phytochemicals with cancerprotective properties. The polyphenols—water-soluble plant pigments that are also known as bioflavonoids—encompass more than 4,000 chemically unique flavonoids that can be categorized according to their chemical structure. Subcategories include flavonols (such as quercetin from onions), flavanones (such as narigenin from oranges), anthocyanidins (such as cyanidin from grapes), catechins (such as EGCG from green tea) and isoflavones (such as daidzein from soy and red clover).

While the bioavailability of different types of flavonoids impacts their efficacy in the body, research has clarified the roles of several key polyphenols. Quercetin, for example, can be converted in the body to several metabolites that may inhibit cyclo-oxygenase-2 (COX-2, a proinflammatory enzyme in the body) in human colorectal cells.⁵⁷ Quercetin has also been shown to have a synergistic effect in killing human erythroleukemic cells when combined with the differentiation-inducing agent sodium butyrate (NaB).⁵⁸

The most prevalent citrus flavonones, hesperetin from oranges and naringenin from grapefruit, are largely found as the glycosides hesperidin and naringin; the primary citrus flavones include tangeretin and nobiletin.⁵⁹ They have been studied in vitro and in vivo to identify their potential anticancer effects. One such study investigated the antiproliferative activities of citrus flavonoids against six human cancer cell lines.⁶⁰ The study was conducted at the U.S. Citrus and Subtropical Products Laboratory in Winter Haven, Fla., in conjunction with London, Ontario-based KGK Synergize. The researchers used polymethoxylated flavones without glycosidic linkages and synthetic versions and compared their antiproliferative properties against human cancer cell lines for lung, prostate, colon, melanoma, estrogen receptor positive (ER+) and estrogen receptor negative (ER-) breast cancer. Both the natural and synthetic flavones exhibited strong antiproliferative properties. The findings echoed those from an earlier study by the same researchers, which found the citrus flavonoids induce regulatory enzymes involved in cell activation and receptor binding, without affecting normal cells.⁶¹

Additional investigations into citrus flavonoids have looked at the limonoids, primarily isolated from lemon and lime. In a study from the University of Western Ontario, researchers tested a range of limonoids for their ability to inhibit proliferation of ER+ and ER- breast cancer cells.⁶²

They found deacetylnomilin impacted both types of breast cancer cells, with limonin methoxime, obacunone and methyl nomilinate showing type-specific activity. In addition, the researchers investigated maximum tolerated dose, setting 2 percent of the diet for limonin and 4 percent of the diet for the glucoside mixture.

Other types of fruits are also powerhouses of flavonoids; berries, for example, contain many types of polyphenols with effects that may be magnified in combination. A standardized multiple berry extract (as OptiBerry™ from Benicia, Calif.-based InterHealth Nutraceuticals) was studied in an in vivo model of angiogenesis.⁶³ The researchers found endothelioma cells pretreated with OptiBerry showed a diminished ability to form hemangioma and decreased tumor growth by more than 50 percent. This supports earlier findings that OptiBerry inhibited tumor necrosis factor-alpha (TNF-alpha) induced vascular endothelial growth factor, impairing cell angiogenesis.⁶⁴

Like berries, grapeseed extract (GSE) contains flavonoid-rich compounds, including oligomeric proanthocyanidins (OPCs), which may protect against cancer. Studies in mice implanted with hormone-refractory human prostate carcinoma cells found feeding with 100 mg/kg/d or 200 mg/kg/d of GSE strongly inhibited tumor growth and tumor weight.⁶⁵ It also increased the apoptic index and decreased the proliferation index, possibly by inhibiting VEGF secretion. These findings support an earlier study from the same researcher that found GSE pretreatment induced apoptosis in prostate cancer cells in a dose- and time-dependent manner.⁶⁶

This impact on apoptosis has been the subject of additional studies, which have found GSE impacts TNF-alpha-induced apoptotic death⁶⁷ as well as its ability to activate JNK levels, thus leading to apoptosis.⁶⁸ In addition, GSE appears to inhibit DNA adduction caused by genotoxins such as nicotine.⁶⁹ One study from Creighton University in Omaha, Neb., found a 50 percent level of protection by GSE against tobacco-induced oxidation in normal cells, as well as the ability to modulate tobaccoinduced changes in the p53 gene.⁷⁰

Beyond its polyphenol content, grapes are also the major dietary source of resveratrol, part of a class of natural antibiotic compounds that serve a defensive mechanism in plants. Resveratrol has been shown to inhibit carcinogenesis, induce apoptosis and scavenge cancer cells independently.⁷¹ In a mice study, pre-treatment with resveratrol was found to prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner.⁷² Cellular studies on resveratrol’s impact at the genetic level have shown its ability to induce apoptosis independent of cancer cells’ p53 genetic status,⁷³ and to downregulate the apoptosis-regulated gene Bc1-2.⁷⁴

The polyphenol OPCs are also found in French maritime pine bark extract and may work in cancer prevention. In vitro research conducted at Loma Linda University showed the extract (as Pycnogenol® from Hillside, N.J.-based Natural Health Science) selectively induced death in a human mammary cell line (MCF-7) but did not increase cell death in normal human mammary cells.⁷⁵ Additionally, pretreatment with the extract (as Pycnogenol) was found in a study of endothelial cells to exhibit a concentration-dependent suppression of the inflammatory response associated with NF-kappa B.⁷⁶

While many consumers may not ingest grapeseed or pine bark extract on a regular basis, tea remains the second-most consumed beverage in the world (after water) and the primary source of polyphenols in the diet. Green tea polyphenols include epigallocatechin-3-gallate (EGCG), epigallocatechin and epicatechin-3-gallate (ECG). Population studies have shown the protective effects of green tea consumption against several types of cancer.⁷⁷ Two Chinese population studies found dose-response relationships between green tea consumption and the risk of gastric cancer in men (drinking more than 250 g/month decreased the risk 60 percent),⁷⁸ and the survival rate of women diagnosed with epithelial ovarian cancer.⁷⁹

The polyphenol of greatest interest, EGCG, has been the subject of a host of cellular studies, hoping to elucidate the mechanisms of action. In a study from the University of Washington, researchers found EGCG was able to block induced lipid peroxidation in erythrocyte membranes, showing its ability to protect cells against oxidative stress.⁸⁰ Another study, this one on liver cancer cells, found EGCG combined with ascorbic acid exhibited a 73.2 percent inhibition of cell proliferation, leading the researchers to suggest ascorbic acid enhances the activity of EGCG by decreasing intracellular oxidative stress, permitting the compound to work within the cell.⁸¹

Further, EGCG was found in a study of three different cancer cell lines—laryngeal, colon and cervical carcinomas—to induce apoptosis in a dose-related manner, while exerting only a moderate effect on normal cells.⁸² Specific to cervical cancer, researchers have found EGCG prevents carcinogenesis, induces apoptosis and inhibits telomerase activity in early cervical lesions⁸³ and regulates gene expression.⁸⁴ The impact on telomerase is important in breast carcinoma as well, as levels are elevated in more than 90 percent of breast cancer patients; downregulating telomerase leads to suppressed cancer cell viability and induction of apoptosis.⁸⁵

The benefits of tea may be augmented by consumption of soy and its related isoflavones. In a study from Beth Israel Deaconess Medical Center, researchers looked for synergistic effects between soy and tea components on prostate tumor progression in a mouse model.⁸⁶ They found the combination of soy and black tea synergistically inhibited prostate tumorigenicity, final tumor weight and metastases to lymph nodes, while soy and green tea synergistically inhibited final tumor weight and metastasis and reduced serum concentrations of testosterone and DHT. The same researchers conducted a similar experiment in a MCF-7 breast tumor model, and found similar results, leading them to conclude soy plus green tea could be used as an effective regimen to prevent progression of estrogen-dependent breast cancer.⁸⁷

Population studies have also shown the benefits tea and soy. One study conducted at the University of Southern California, Los Angeles, compared the diet of 501 breast cancer patients and 594 control subjects.⁸⁸ The researchers found green tea drinkers showed a significantly reduced risk of breast cancer, with the most significant benefits observed among women who were low soy consumers.

Similarly, the protective effect of soy was primarily observed among women who didn’t drink green tea.

Soy has been seen in many studies to have beneficial effects in cancer prevention. In fact, the U.S. Food and Drug Administration (FDA) confirmed in April 2004 it is reviewing a petition for a health claim linking consumption of soy protein-based foods with a reduced risk of several types of cancer including breast, prostate and colon cancer. The Solae Co., based in St. Louis, submitted the petition to FDA, and included 58 studies supporting the relationship. Among the studies were two related to breast cancer development. The first, conducted at Creighton University in Omaha, Neb., used an animal model to mimic the situation of breast cancer patients.⁸⁹ Breast cancer cells were injected into the mammary tissue of mice, who were fed either a soy protein- or milk protein-based diet. The researchers found the mice given soy protein had fewer and smaller tumors that metastasized. And an observational study found high soy consumers had an approximate 60 percent reduction of dense mammographic patterns, a indication of increased risk of breast cancer.⁹⁰ They concluded, the association between high soy intake and a reduced risk of mammographic parenchymal patterns associated with high breast cancer risk may have important implications in breast cancer prevention.”

A review from Wayne State University in Detroit noted isoflavones in general and genistein in particular may inhibit carcinogenesis, possibly by inhibiting activation of NF-kappa B signaling pathways.⁹¹ They suggest genistein is a promising reagent for cancer chemoprevention and/or treatment. However, not all researchers have been as positive, noting that while phytoestrogens like genistein have anticarcinogenic potential, they also have estrogenic properties that may impact breast cancer risk.⁹²

However, a recently completed study from Wake Forest University School of Medicine in Winston-Salem, N.C., evaluated the long-term effects of soy isoflavones on intermediate markers of cancer risk in normal postmenopausal monkey breast and uterus.⁹³ The monkeys received one of three diets for 36 months: isoflavone-depleted soy protein isolate (SPI-); soy protein isolate with the equivalent of 129 mg/d isoflavones (SPI+); or isoflavone-depleted soy protein isolate with conjugated equine estrogens at a dose scaled to approximate 0.625 mg/d in women (estrogen). The estrogen group had significantly higher epithelial proliferation and progesterone receptor expression in the breast and uterus, compared to the soy groups. SPI+ treatment resulted in significantly lower serum concentrations of estrone and estradiol versus SPI-. The researchers concluded, “high dietary levels of soy isoflavones do not stimulate breast or uterine proliferation in postmenopausal monkeys and may contribute to an estrogen profile associated with reduced breast cancer risk.”

The concern over isoflavones as phytoestrogens that could impact hormone-dependent cancers has also lead to investigations of isoflavones and prostate cancer. A pilot study at Wayne State University involved 39 patients with rising prostate-specific antigen (PSA) levels,  putting them at risk for prostate cancer.⁹⁴ They found 100 mg twice daily of soy isoflavone (as Novasoy® from Decatur, Ill.-based ADM) stabilized PSA levels in 83 percent of hormone-sensitive patients and 35 percent of hormone-refractory patients. And a clinical trial at the University of South Florida, Tampa, involving 59 prostate cancer patients found those receiving soy isoflavones had reduced or even testosterone levels and reductions in total PSA.⁹⁵ The researchers concluded soy consumption could potentially delay onset of prostate cancer in an at-risk population.

Isoflavones are not only found in soy; one additional source of isoflavones that have been the subject of research in the cancer field is red clover. One Australian study involved 38 patients who received either 106 mg/d of red clover-derived isoflavones or placebo before radical prostatectomy.⁹⁶ Apoptosis in prostate specimens from treated patients was significantly higher than in control subjects, particularly in regions of low- to moderate-grade cancer, suggesting the treatment could halt the progression of prostate cancer. In another study of red clover isoflavones, 205 women randomly received a daily red cloverderived isoflavone tablet or placebo for one year.⁹⁷ Mammographic breast density decreased in both groups, and the treatment did not affect estrogen or lymphocyte levels. In an editorial comment in the same issue, another researcher said the study’s results indicate the isoflavones are unlikely to increase the risk for breast cancer.⁹⁸

While isoflavones are one class of phytoestrogens, they are far from the only one in the human diet. Lignans are metabolized in the gut to produce the phytoestrogens enterolactone and enterodiol; similar concerns have been raised about lignans’ possible ability to increase the risk of hormone-related cancers. Studies, however, have not borne out the concern. A population-based, case-control study of 1,122 women with breast cancer and 2,036 controls was undertaken by the Roswell Park Cancer Institute in Buffalo, N.Y.⁹⁹ The researchers found premenopausal women in the highest quartile of dietary lignan intake in fact had a reduced risk of breast cancer, and there was no association between lignan intake and postmenopausal breast cancer. A German study of 278 premenopausal breast cancer patients compared to 666 age-matched controls showed similarly positive results, with lignan intake inversely related to breast cancer risk.¹⁰⁰ The benefits of lignan intake were seen in another population study to be most pronounced among women with at least one A2 allele in their CYP17 genotype.¹⁰¹

One of the richest sources of dietary lignans is flaxseed. Studies have shown rats exposed to flaxseed during suckling had a significantly lower tumor incidence and tumor load rate when they were later induced with breast cancer compared to rats that did not receive dietary lignans.¹⁰² Flaxseed has proven similarly protective in older individuals. A study from the University of Toronto investigated the effects of flaxseed on mice injected with breast cancer cells.¹⁰³ The researchers found a significant reduction in tumor growth rate and a 45 percent reduction in total incidence of metastasis in the rats that received flaxseed, which researchers attributed in part to flaxseed’s ability to downregulate insulinlike growth factor I and epidermal growth factor receptor expression.

Human studies have also investigated flaxseed’s biological effects on cancer. One double blind, placebo-controlled prospective clinical trial randomized patients newly diagnosed with breast cancer to receive a muffin with 25 g of flaxseed or a control muffin.¹⁰⁴ In postmenopausal women, researchers found flaxseed and its lignans reduced tumor growth comparable to the effects seen with preoperative tamoxifen.

Another human study randomized 116 premenopausal women with severe cyclical mastalgia (a disorder associated with breast cancer risk) to receive a muffin with 25 g of flaxseed or a control muffin; flaxseed was found effective in relieving symptoms including breast pain in the treatment group.¹⁰⁵

Flaxseed supplementation has also been studied in prostate cancer models. A study from Duke University Medical Center in Durham, N.C., involved 135 male mice randomized to a control group or an experimental group (5 percent flaxseed) for 20 or 30 weeks after induction of prostate cancer.¹⁰⁶ All the control mice developed prostate cancer versus 97 percent of the mice in the flaxseed group. However, the flaxseed-treated mice had significantly less aggressive tumors and a significantly lower incidence of metastasis.

In addition to its lignan component, flaxseed is also a good source of essential fatty acids (EFAs). The ratio between pro-inflammatory omega-6 EFAs and the mediating omega-3 EFAs may influence the risk of cancer.¹⁰⁷ In a rat model of non-metastasizing malignancy, researchers divided animals to receive 5 g/kg/d EPA (eicosapentaenoic acid, a long-chain omega-3) plus 10 IU vitamin E/g fat; 5 g/kg/d corn oil plus the vitamin E; or a placebo plus vitamin E.¹⁰⁸ EPA-treated rats showed a significant reduction in tumor volume compared to both the corn oil and control animals.

EPA and DHA (docosahexaenoic acid, another omega-3) are both formed in the body from the alpha linolenic acid provided by flaxseed, and come preformed in fish oil. Population studies have not illustrated a clear relationship between long-chain omega-3 EFAs; however, a recent study in Montreal at the Centre Hospitalier de l’Universite de Montreal-Hotel-Dieu assessed the association between carotenoids and other dietary factors and breast cancer risk.¹⁰⁹ They found no association between carotenoids and the risk of breast cancer individually; however, in postmenopausal women, total carotenoids were positively associated with breast cancer risk in those with high intake of arachidonic acid (a pro-inflammatory fat) and inversely related in those with a high intake of DHA.

Also in the plant-based compound arena are medicinal mushrooms, long used in Traditional Chinese Medicine (TCM) for their health-promoting qualities. A review from the University of Haifa, Israel, noted, “Mushrooms comprise a vast and yet largely untapped source of powerful new pharmaceutical products. In particular, and most importantly for modern medicine, they represent an unlimited source of polysaccharides with antitumor and immunostimulating properties.”¹¹⁰

The majority of the polysaccharides are in the beta-glucan group, including the beta 1,3 glucans and the beta 1,6 glucans. Researchers from the University of California-Davis wrote in a recent review that mushrooms may be able to modulate mononuclear cell activation and cytokine expression, as well as preventing metastasis.¹¹¹ However, they added there are possible toxicity concerns based on contamination with heavy metals and/or radioactivity.

Cellular studies have investigated the effects on cell transformation by different types of mushroom extract. Researchers from Methodist Research Institute in Indianapolis investigated the impact of reishi (Ganoderma lucidum) on cell proliferation, cell cycle and apoptosis in human prostate cancer cells.¹¹² They found reishi inhibited proliferation in a dose- and time-dependent manner by impacting genetic expression; it also induced apoptosis by decreasing expression of NF-kappaBregulated markers and upregulating expression of the proapoptotic Bax protein. The researchers concluded reishi exerts effects on cancer cells by multiple mechanisms.

To address the issue of toxicity, researchers at the Hong Kong Polytechnic University, Kowloon looked at the impact of reishi on 18 healthy adults in a four-week double blind, placebo-controlled, crossover trial.¹¹³ At the end of the investigation, researchers found no significant changes in antioxidant status, DNA damage, immune status or inflammation, although a slight trend was seen toward lower lipids and increased antioxidant capacity.

Another mushroom investigated for its immunostimulatory effects is shiitake (Lentinus edodes). One study in mice inoculated with human colon cancer cells found pretreatment with shiitake extract led to significant regression in tumor formation and size.¹¹⁴ In addition, lymphocytes extracted from the shiitake-treated mice inoculated into different mice that were then inoculated with colon cancer cells proved to provide protection against development of tumors in the second group. The results of human studies have not been as promising. A open-label study of 62 men diagnosed with prostate cancer and elevated prostate-specific antigen (PSA) levels who were given shiitake extract found, after taking the rate of PSA rise into account, there was no response in treating prostate cancer.¹¹⁵

Agaricus blazei Murill (A. blazei), another medicinal mushroom, is also thought to protect against cancer development. Researchers at Tokyo University of Pharmacy and Life Science discovered A. blazei’s 1,6- beta glucan showed anti-tumor activity in mice, and a high branded 1,3- beta glucan segment forms the active center of the anti-tumor activity.¹¹⁶

Animal studies have shown oral administration of 1,6-beta-D-polyglucose from A. blazei results in significant tumor regression in tumor-bearing mice;¹¹⁷ pre-treatment with A. blazei shows stronger effects in mice induced with liver cancer, significantly reducing DNA damage.¹¹⁸

A recent human study from The Catholic University of Korea, Seoul, investigated the effects of A. blazei consumption on immune status and quality of life in cancer patients undergoing chemotherapy.¹¹⁹ A total of 100 patients with cervical, ovarian or endometrial cancer underwent chemotherapy with or without oral consumption of A. blazei. The researchers found NK cell activity was significantly higher in the A. blazei group, though there was no significant difference between the groups’ lymphokine-activated killer and monocyte activities. However, chemotherapy-associated side effects such as appetite, alopecia, emotional stability and weakness were improved by A. blazei treatment.

One of the best-known medicinal mushrooms is maitake (Grifola frondosa), which has been called the “king of mushrooms.” Reviews suggest the D-fraction, MD-fraction and other extracts show particular promise as immunomodulating agents and as an adjunct to cancer therapy.¹²⁰ Several in vitro studies have investigated the effects of different fractions on immune function and cancer development.

Researchers at Kobe Pharmaceutical University in Japan have conducted several studies on effects of the D-fraction (as Maitake DFraction ® from Maitake Products in Paramus, N.J.) on NK activity and immune function. A study in tumor bearing mice that received D-fraction for 19 days found supplementation markedly suppressed tumor growth, corresponding with a significant increase in TNF-alpha expressed in NK cells.¹²¹ In addition, this study found D-fraction increased macrophagederived IL-12, serving to activate NK cells. Another animal study these researchers conducted investigated the effects of D-fraction in splenocytes of mice given D-fraction for 17 days.¹²² Administration of Dfraction increased immunoglobulin E levels, suggesting D-fraction induced a Th-2 dominant response through macrophages, enhancing humoral immunity instead of cell-mediated immunity.

A recent human study at Kobe Pharmaceutical University with Dfraction involved 10 patients who received D-fraction without cancer drugs.¹²³ Maitake D-Fraction was found to hinder metastasis, lessen expression of tumor markers and increase NK cell activities in all patients examined. The researchers concluded D-fraction primarily impacts cancer progression by stimulating NK cell activity.

The MD-fraction has also been studied by these researchers. They reported in a non-random case series how a combination of MD-fraction and whole maitake powder was investigated to determine its effectiveness in stage II, stage III and stage IV cancer patients.¹²⁴ Cancer regression or significant symptom improvement was observed in 58.3 percent of liver cancer patients, 68.8 percent of breast cancer patients and 62.5 percent of lung cancer patients. In addition, immunecompetent cell activities were enhanced 1.2 to 1.4 times when maitake was taken in addition to chemotherapy.

MD-fraction (as MaitakeGold 404® from Brattleboro, Vt.-based The Tradeworks Group) is the subject of an ongoing, multi-phase clinical trial on breast cancer. The first published study associated with this trial investigated the impact of MD-fraction on mouse bone marrow cells in vitro, particularly whether it could enhanced bone marrow colony formation and reduce toxicity of chemotherapy agents.¹²⁵ The researchers, from Memorial Sloan-Kettering Cancer Center in New York, reported MD-fraction acted in a dose-dependent manner to enhance bone marrow growth and reduce the toxic effects of a chemotherapeutic drug on the bone marrow cells.

Another ingredient, AHCC® (Active Hexose Correlated Compound), is a hybridization of several species of medicinal mushrooms that has immune-enhancing properties, particularly in the realm of cancer. [Editor’s note: Amino Up Chemical Co. in Sapporo, Japan, owns the trademark for AHCC; Purchase, N.Y.-based Quality of Life Labs, a division of Maypro Industries, is the U.S. distributor.] AHCC appears to work by increasing NK cell activity, and helping the production of IFN-gamma and IL-12, according to a study of stage IV cancer patients.¹²⁶ However, animal research indicates it may be more effective at enhancing IL-12 levels in Th-1 dominant individuals.¹²⁷

Human studies on AHCC have shown positive results. A prospective cohort study was performed at Kansai Medical University in Osaka, Japan, on 269 patients with liver cancer who underwent surgery to remove the tumor.¹²⁸ Of the total patient base, 113 received AHCC orally after surgery; that group had a significantly longer no recurrence period and an increased overall survival rate, suggesting AHCC can improve the prognosis of postoperative liver cancer patients. Research just presented in July 2004 at the 12th International Symposium of AHCC Research Association in Sapporo, Japan, further investigated the impact of AHCC given to patients undergoing chemotherapy.¹²⁹ During the crossover investigation of 189 patients, researchers found AHCC increased IL-2 activated kill cell activity significantly and enhanced NK cell activity, both of which were significantly decreased in the untreated patients by the third day after chemotherapy.

Another study presented at the symposium involved a combination of AHCC and GCP (Genistein Combined Polysaccharide) on the side effects and quality of life in prostate cancer patients.¹³⁰ Researchers found oral administration of the combination formula (5g/d for six months) decreased DNA damage of blood lymphocytes and decreased serum total cholesterol in hypercholesterolemic prostate cancer patients. They concluded that despite the combination’s lack of effect on serum PSA levels, it may improve quality of life in prostate cancer patients.

GCP® is a fermentation product of soy extract and medicinal mushrooms that is rich in bioactive aglycone isoflavones. [Editor’s note:

Amino Up Chemical Co. in Sapporo, Japan, owns the trademark for GCP; Purchase, N.Y.-based Quality of Life Labs, a division of Maypro Industries, is the U.S. distributor.] A case report of GCP in prostate cancer indicated 44 days of low-dose supplementation induced a significant drop in PSA levels with no side effects.¹³¹ Cell culture studies from Columbia University Medical Center, New York, investigated the impact of GCP on androgen-sensitive and androgen-independent prostate cancer cells, and found GCP significantly suppressed cell growth in both lines.¹³² The reduction was associated with apoptosis in the androgensensitive cell line, but not in the androgen-independent line.

Mushrooms are not the only source of beta glucans; beta 1,3/1,6 glucan, derived from baker’s yeast, has also been investigated for its impact on immune function. In a recently published study from the University of Louisville School of Medicine, Ky., researchers found beta 1,3/1,6 glucan (as WGP® Beta Glucan from Biopolymer Engineering) could bind to receptors on neutrophils, enabling the immune cells to recognize cancer in the body.¹³³ Researchers found mice with liver cancer that were given WGP Beta Glucan three days before the start of monoclonal antibody therapy survived 100 days, compared with 35 days for mice treated with only the drug therapy. In addition, the mice that received beta glucan showed increased tumor regression.

In the mechanism of action portion, researchers used fluorescently labeled WGP Beta Glucan in mice, and found the beta glucan was taken up by gastrointestinal macrophages and taken to the bone marrow and reticuloendothelial tissues. Within the marrow, macrophages degraded the beta glucan and secreted fragments to neutrophils, which could then migrate to tumor cells and help kill them.

Other sources of positive polysaccharides are the green foods, including spirulina, aphanizomenon flos-aquae and chlorella. A study from the University of Mississippi found high molecular weight polysaccharide preparations from these microalgae were able to substantially increase levels of IL-1beta and TNF-alpha.¹³⁴ Chlorella has been investigated for its ability to enhance the body’s ability to suppress cancer cell growth.¹³⁵ Tumor-bearing mice given chlorella extract showed bone marrow and spleen granulocyte-macrophage levels similar to those of control animals without tumors.

The plant kingdom also provides herbs and spices with powerful activities in the body. Garlic (Allium sativum) is one such botanical agent containing active constituents that may make it effective against cancer.

Researchers in Kuwait noted garlic’s sulfur constituents—alliin and allicin—have been credited with the herb’s chemoprotective activity.¹³⁶

Their research review suggested garlic could detoxify chemical carcinogens and prevent carcinogenesis, as well as inhibit the growth of cancer cells. Another review out of India seconded the observations, noting garlic may also be able to prevent binding of carcinogens to DNA and have free radical scavenging properties.¹³⁷

A cellular study on allicin showed it could inhibit the growth of cancer cells of murine and human origin, inducing the formation of apoptotic bodies and a DNA ladder in cancer cells.¹³⁸ And a mouse study conducted in France explored the impact of different quantities of alliin in garlic added to the diet before and during initiation of liver cancer.¹³⁹ The researchers found the garlic diets decreased the appearance and size of tumors, with the highest dose of alliin showing the strongest results.

Additional organosulfur compounds from garlic have been studied for their usefulness in cancer treatment. Ajoene was found to induce apoptosis in a dose- and time-dependent manner in basal cell carcinoma (BCC) cultures, as well as to reduce tumor size in 17 patients with BCC.¹⁴⁰ In a rat study of hepatocarcinogenesis, S-allylcysteine was found to inhibit tumor incidence and lipid peroxidation and simultaneously elevate antioxidant levels.¹⁴¹ And, diallyl disulfide appears to have chemopreventive activity by increasing apoptosis, as shown in a study of T24 human bladder cancer cells in vitro.¹⁴²

The spice turmeric is another source of powerful anti-cancer compounds, including curcumin. A review from the University of Texas M.D. Anderson Cancer Center in Houston noted curcumin appears to serve as a cancer preventive and treatment through a number of mechanisms.¹⁴³ These include suppressing tumor proliferation and initiation, downregulating transcription factors, preventing metastasis and serving as an antioxidant.

A study in 30 smokers and non-smokers found curcumin prevented DNA damage to lymphocytes in a dose-dependent manner.¹⁴⁴ The protection to DNA was further extended to gene expression in a rat study of colon cancer, in which curcumin impacted gene expression changes to prevent colon carcinogenesis.¹⁴⁵ Further cell studies have shown the ability of curcumin to inhibit angiogenesis by preventing proliferation and migration of endothelial cells,¹⁴⁶ and to induce apoptosis by decreasing expression of certain genetic drivers of cancer initiation.¹⁴⁷

Another, more controversial, botanical in the cancer field is mistletoe. While mistletoe extracts are commonly used in Europe, a 2003 literature review of 23 studies conducted by German researchers found generally positive trends in quality of life and survival; however, the researchers noted all the studies suffered from some methodological shortcomings and most were not conclusive.¹⁴⁸ Two human studies published after the review involved the use of mistletoe extract in women with cancer. The first, conducted at Institut fuer Biometrie in Hannover, Germany, involved 689 postoperative breast cancer patients, 219 of whom received mistletoe.¹⁴⁹ The women receiving the extract had a significant reduction in adverse reactions induced by post-operative therapies (i.e., chemotherapy, radiation) and prolonged relapse-free intervals. In the second study, 224 patients with breast, ovarian and nonsmall cell lung cancer received standard tumor-destructive treatment and either mistletoe extract or the immunomodulating pharmaceutical Lentinan.¹⁵⁰ Quality of life was significantly improved for patients taking mistletoe compared to Lentinan, and the occurrence of adverse events was less frequent in the mistletoe patients.

Also from the plant kingdom—though not specific to any one plant— is fiber. Dietary fiber has been shown in many population studies to prevent the incidence of many types of cancer, including rectal,¹⁵¹ prostate¹⁵² and breast.¹⁵³ A dietary intervention trial conducted in California, for example, involved 291 women with a history of breast cancer; those in the intervention group aimed to increase fiber, vegetable and fruit intake while lowering fat intake.¹⁵⁴ After one year, the change in fiber intake was significantly related to reduced serum bioavailable estradiol concentration, possibly decreasing breast cancer risk.

Cancer remains one of America’s top health fears, even as public health officials and scientists search for ways to mitigate the impact of external and internal carcinogens. As researchers expand their reach into human trials, based on strong in vitro findings, it is likely increasing numbers of nutraceutical compounds will be found to exert profound effects on preventing and treating cancer.

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