Breast Cancer Research Summaries

A survey of licensed American and Canadian naturopathic physicians carried out in the winter of 1998-99 indicated that 77% had provided care to women to breast cancer at some point in the past and 67% had provided such care in the past 12 months. The physicians were asked what they thought their patients’ reason(s) was for seeking naturopathic care: 70% thought it was it was because of patients’ belief in a holistic approach to care; 69% thought it was for alleviation of the side effects of standard therapies; and 66% thought it was patients’ interest in trying every possible treatment to cure their cancer. The four most popular sources of information [at the time of the survey] were books on alternative medicine; colleagues in the field of complementary and alternative medicine; alternative medicine journals; and conferences on complementary and alternative medicine. The use of antioxidants during radiation and/or chemotherapy is controversial, so the authors asked the respondents what they recommended to their patients; 64% of them suggested that their patients use them during chemotherapy and 72% recommended their use during radiation therapy. Most reported having some or all of their patients’ conventional medical records; only 16% requested none at all. Many (30%) reported problems in getting records because of a lack of cooperation from conventional medical offices. Some were in regular communication with their patients’ primary care physicians (22%) or medical oncologists (19%); fewer were in regular contact with radiation oncologists (9%) or surgeons (9%).
Standish LJ et al. Complementary and alternative medical treatment of breast cancer: a survey of licensed North American naturopathic physicians. Alt Ther Health Med 2002;8:74-81.

In a recent survey of Latino, Chinese, African-American, and white women with breast cancer, 48% of the respondents said they had used at least one alternative therapy; such treatments included dietary therapies (26.6%), spiritual healing (23.7%), special diets (19.8%), physical treatments such as acupuncture and massage (14.2%), herbal remedies (12.9%), psychological methods (9.2%), and the use of megavitamins (8.2%).
Low Dog T et al. Traditional and alternative therapies for breast cancer. Alt Ther 2001;7:36-47.

Risk factors for breast cancer

Age (risk increases with age)
Use of hormone replacement therapy increases risk by 30-40%
Family history of breast cancer (breast cancer in first-degree relatives increases a woman’s risk more than that in second-degree relatives)
Age at menarche (risk is higher with earlier onset)
Age at menopause (risk is higher with later onset)
Age at first childbirth (risk is higher with later age)
History of atypical hyperplasia on breast biopsy
Armstrong K et al. Assessing the risk of breast cancer. N Engl J Med 2000;342:564-571.

Increased exposure to estrogen increases the risk of breast cancer:
Earlier age of menarche increases risk
Early age of first pregnancy decreases risk (terminal differentiation of breast cancer cells and cell cycle is longer with the first pregnancy, allowing more time for DNA repair)
Early menopause decreases risk
In postmenopausal women, obesity is linked to higher reproductive hormone levels and also to increased risk of breast cancer
Duration of hormone replacement therapy is significantly associated with the risk of breast cancer
Risk is significantly increased in women with high serum levels of estradiol (the risk of breast cancer associated with high serum levels of estradiol is higher than the association between serum cholesterol and heart disease)
Women with higher bone density, a marker of postmenopausal estrogen exposure, are at increased risk of breast cancer
Greater breast tissue density, as is seen in women taking hormone replacement therapy, is also associated with an increased risk of cancer
Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998;90:814-823.

The risk of death due to breast cancer tends to increase with body mass index, as it does for that due to uterine, cervical, and ovarian cancer. Overall, the relationship between excess body weight and increased risk of all cancers accounts for 20% of deaths from cancer in women.
Calle EE et al. N Engl J Med 2003;348:1625-1638.

Estrogen is probably a late promoter of breast cancer, and higher levels of the hormone after breast cancer diagnosis are associated with a decreased rate of survival.
Data from 51 epidemiologic studies, including more than 52,000 women with breast cancer and  more than 100,000 without, were analyzed to determine the increased risk of breast cancer with hormone replacement therapy (HRT); the results suggested that risk increases by 2.3% with every year of using hormones. For every 1000 women who take HRT for 10 years, starting at age 50, there will be an additional six cases of breast cancer; if they take HRT for 15 years, there will be twelve cases above baseline incidence. However, the mortality rate for breast cancer diagnosed in women with a history of taking HRT is lower than that for breast cancer in women who have never taken these hormones. This may be because breast cancer in women on HRT is estrogen-sensitive, and therefore more responsive to antiestrogen therapy, or because of the cessation of exposure to HRT upon diagnosis.
The data indicate that the relationship between HRT and breast cancer is strongest for current HRT use, although increased risk lasts for at least 5 years after cessation of HRT.
Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998;90:814-823.

Women who are nulliparous are at higher risk of breast cancer than parous women. Lobular development starts at puberty and is culminated, with fully differentiated lobular tissue, at the end of pregnancy.
Russo IH, Russo J. Hormonal approach to breast cancer prevention. J Cell Biochem Suppl 2000:34:1-6.

A 30-year-old woman whose sister or mother has been diagnosed as having breast cancer has an 8-18% lifetime risk of developing breast cancer herself by the age of 70. The lifetime risk in women with a first-degree relative who has breast cancer is 1.4 to 2.8 times higher than that in women with no such family history.
Low Dog T et al. Traditional and alternative therapies for breast cancer. Alt Ther 2001;7:36-47.

The longer a woman lives without developing breast cancer, the lower is her risk of developing it eventually: a 50-year-old woman has an 11% chance of having breast cancer during her lifetime, but a 70-year-old woman with no personal history of breast cancer has a 7% risk.
Armstrong K et al. Assessing the risk of breast cancer. N Engl J Med 2000;342:564-571.

There is a positive correlation between alcohol consumption and risk of breast cancer in premenopausal women but not in postmenopausal women.
Premenopausal obesity seems to decrease the risk of breast cancer, probably because it causes a decrease in the number of ovulatory cycles and thus reduces exposure to estrogen. However, postmenopausal obesity increases breast cancer risk.
Bradlow HL, Sepkovic D. Diet and breast cancer. Ann NY Acad Sci 2002;963:247-267.

The risk of breast cancer increases by about 50% with postmenopausal obesity and is weakly associated with tall adult height. An average intake of one alcoholic drink a day increases risk by about 7%.
Key TJ et al. The effect of diet on risk of cancer. Lancet 2002;360:861-868.

Two major genes, BRCA1 and BRCA2, that increase the risk of breast cancer have been identified: women with either of these genes have an increased lifetime risk.
Armstrong K et al. Assessing the risk of breast cancer. N Engl J Med 2000;342:564-571.

Women with mutations in BRCA1 or BRCA2 genes have a 50% chance of developing breast cancer by age 50 and an 80% chance of developing it by age 65.
Patients with a family history of breast cancer [not necessarily due to these mutations] who were awaiting mammography have reported having high levels of stress; in one study, 27% had scores on the Brief Symptom Inventory that indicated a need for counseling.
Baum A et al. Stress and genetic testing for disease risk. Health Psychol 1997;16:8-19.

Women with positive hormone receptors have significantly better outcomes (longer disease-free times and better overall survival rates) when they have surgery during the follicular phase of the menstrual cycle.
Low Dog T et al. Traditional and alternative therapies for breast cancer. Alt Ther 2001;7:36-47.

Women who develop ductal carcinoma in situ (DCIS) are typically older at the time of their first full-term pregnancy, have fewer full-term pregnancies, and are older at menopause than are women who do not develop it. In one study, there was no association between DCIS and hormone replacement therapy or oral contraceptive use, or between DCIS and alcohol or smoking.  However, many of the risk factors for DCIS are similar to those for invasive breast cancer.
Claus EB et al. Breast carcinoma in situ: risk factors and screening patterns. J Natl Cancer Inst 2001;93:1811-1817.

Although most cases of breast carcinoma in situ (BCIS) do not become invasive, BCIS is generally considered the penultimate step in the development of invasive cancer. Family history, reproductive factors such as increased age at first birth and decreased parity, recent alcohol consumption, and postmenopausal hormone use are all risks associated with breast cancer of both forms; the links between risk of BCIS and postmenopausal hormone use, history of benign  breast disease, and family history of breast cancer are all stronger than are the corresponding risks for invasive cancer. 
Trentham-Dietz A et al. Risk factors for carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 2000;9:697-703.

Toxins and breast cancer risk

Even though DDT is not currently being used in the United States, other organochlorides may be used, and DDT is still being used in other countries. Many kinds of cancer (breast and others) are associated with pesticide exposure.
Safi JM. Association between chronic exposure to pesticides and recorded cases of human malignancy in Gaza Governorates (1990-1999). Sci Total Environ 2002;284:75-84.

Pesticide residues of the halogenated hydrocarbon family have estrogenic activity, suppress immune function, and are carcinogenic in animals.
Concentrations of PBCs (polychlorinated biphenyls) and DDE (dichlorodiphenyldichloro-ethylene) were 50-60% higher in the tissues of patients with breast cancer than in those of controls. 
Falck F Jr et al. Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer. Arch Environ Health 1992;47:143-146.

Women with 10-year occupational exposure to pesticides had an increased risk of breast lesions (e.g., fibroadenoma, ductal hyperplasia, and others) that may be risk markers for subsequent development of malignant tumors.
Triazine herbicides may be linked to increased breast cancer risk, and pyrethroid insecticides (widely used for indoor pest control) have estrogenic activity that may also increase risk.
Dolapsakis G et al. Mammographic findings and occupational exposure to pesticides currently in use on Crete. Eur J Cancer 2001;37:1531-1536.

In a Danish study, average serum DDT and PCB congener concentrations were positively associated with the risk of eventually developing breast cancer. DDT has been shown to have an estrogenic effect.
Høyer AP et al. Repeated measurements of organochlorine exposure and breast cancer risk (Denmark). Cancer Causes Control 2000;11:177-184

Not only do synthetic estrogens, which accumulate in body fat, have long biological half-lives compared with natural estrogen, pesticides with estrogenic activity seem to have synergistic effects, multiplying their potency when present in combination. Foods are not the only sources of pesticides; DCBE, now banned, is still present in aquifers and drinking-water wells, which were the source of contamination in a Hawaiian population. The authors cite research indicating that women with the highest levels of the organochloride DDE (a metabolite of DDT) in their blood had a risk of breast cancer four times that of women with low levels.
Allen RH, Gottlieb M. Breast cancer and pesticides in Hawaii: the need for further study. Environ Health Persp Suppl 1997;105:679-683.

DDT exposure in developing countries is sometimes more than 100 times the accepted level listed by the World Health Organization. DDT accumulates in fatty tissue and therefore is present in higher concentrations in fat-containing foods such as meat, fish, cheese, milk, and oil. Foods containing chemopreventive agents, such as phytoestrogens that compete with DDT for estrogen receptor sites, could inhibit the estrogenic effects of DDT and therefore reduce the risk of breast cancer.
Jaga K, Duvvi H. Risk reduction for DDT toxicity and carcinogenesis through dietary modification. J Royal Soc Promot Health 2001;121:107-113.

Influence of nutrition on risk and prevention of breast cancer

Vegetables, fruits, and diet

Risk factors affecting survival after diagnosis:
Increased body mass index or body weight, including post-diagnosis weight gain
Total dietary fat intake, especially intake of saturated fat
Low intake of vegetables and fruits, especially of Brassica foods like broccoli
The association between alcohol intake and recurrence of breast cancer is not significant, as it is for primary breast cancer
Most women diagnosed with breast cancer state that they are interested in changing their diets, but do not always receive the information they want from their physicians. The authors recommend that physicians take advantage of this high level of interest to suggest healthy changes; those demonstrated to have positive effects on survival after a cancer diagnosis include maintenance of a healthy weight through diet and exercise; decreased total intake of fats, particularly saturated fats; increased intake of fruits and vegetables (especially Brassica vegetables) and high-fiber grains; and decreased intake of alcohol, especially beer.
Rock CL, Demark-Wahnefried W. Nutrition and survival after the diagnosis of breast cancer: A review of the evidence. J Clin Oncol 2002;20:3302-3316.

Carrots and raw vegetables reduce breast cancer risk; in an Italian study, these foods were nearly always consumed with olive oil, which may have influenced the absorption of certain micronutrients such as vitamin E; also, other studies have demonstrated an inverse association with olive oil and breast cancer.
Although fruit consumption is associated with a decreased risk of certain cancers, for breast cancer prevention a diet high in vegetables is apparently more beneficial than one high in both fruits and vegetables. The study authors recommend a high-vegetable, low-sugar, and low-fat diet for the prevention of breast cancer.
Franceschi S et al. Role of different types of vegetables and fruit in the prevention of cancer of the colon, rectum, and breast. Epidemiology 1998;9:338-341.

Results of one study suggested that high intake of vegetables, rather than the absence of meat from the diet, was associated with the decreased risk in breast cancer in vegetarians.
dos Santos Silva I et al. Lifelong vegetarianism and risk of breast cancer: a population-based case-control study among south Asian migrant women living in England. Int J Cancer 2002;99:238-244

Fruit and vegetable intake is inversely associated with breast cancer risk; this effect is probably not just due to a lower fat intake in people consuming these foods.
Block G et al. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992;18:1-29.

The isothiocyanates sulforaphane and phenethylisothiocyanate, present in particularly high amounts in broccoli and watercress respectively, have been seen to be potent antitumor agents in laboratory and animal studies. They are phase II detoxification inducers, increasing conjugation of carcinogens with a variety of agents to render the carcinogens inactive and increase their clearance from the body. The level of these compounds in cruciferous vegetables varies considerably depending on growing conditions.
Bradlow HL, Sepkovic D. Diet and breast cancer. Ann NY Acad Sci 2002;963:247-267.

Lycopene consumption is linked to a low amount of heart disease and cancer in Mediterranean populations. Lycopene’s bioavailability is increased when cooked with olive oil.
Polyphenolic compounds in green and black tea inhibit oxidation reactions.
Weisburger JH. Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea. Food Chem Toxicol 1999;37:943-948.

Several studies have demonstrated a reduced risk of breast cancer with increased intake of vegetables in premenopausal women.
Cooper D et al. Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration: a review of recent research. Nutr Rev 1999;57:201-214.

Intakes of ß-carotene, vitamin E, calcium, olive oil, and lycopene have inverse relationships with risk of breast cancer. 
La Vecchia C et al. Vegetables, fruit, antioxidants and cancer: a review of Italian studies. Eur J Nutr 2001;40:261-267.

In an Italian study an increased breast cancer risk was seen in women who had an increased intake of bread and cereals, pork and processed meats, and sugar and candies. Risk decreased with an increased intake of milk, coffee and tea, poultry, fish, raw vegetables, and potatoes.
Risk of breast cancer was inversely related to intake of foods high in ß-carotene, vitamin E, and calcium.
Favero A et al. Diet and risk of breast cancer: major findings from an Italian case-control study. Biomed Pharmacother 1998;52:109-115.

In a study of premenopausal women, a decreased risk of breast cancer was seen with higher intakes of vegetables and of several nutrients: vitamin C, a-tocopherol, folic acid, a-carotene, ß-carotene, lutein plus zeaxanthin, and dietary fiber from vegetables and fruits. That the effect of these nutrients is linked to vegetable intake was suggested by the finding that the protective effect of fiber was not seen from grain fiber, and the decreased risk of cancer associated with vitamin C, a-tocopherol, and folic acid was not associated with their intake in supplement form. Components found together in vegetables may have a synergistic effect on breast cancer risk.
Freudenheim JL et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88:340-348.

D-Glucaro-1,4-lactone, a derivative of D-glucaric acid, inhibits ß-glucuronidase, reducing the rate of deglucuronidation and thereby increasing the detoxification of carcinogens and tumor promoters.  D-Glucaric acid is found in some fruits and vegetables, including apples, grapefruit, bean sprouts, and cruciferous vegetables. In addition to its positive effects on detoxification, it also seems to regulate the synthesis of cholesterol and steroid hormones.
Walaszek Z et al. Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential use in cancer prevention. Cancer Detect Prev 1997;21:178-190.

In one study, women who eventually developed breast cancer had, before their diagnosis, serum levels of lutein, ß-cryptoxanthin, a-carotene, ß-carotene, and total carotenoids lower than those in control subjects. The authors note that levels of carotenoids may simply be markers for fruit and vegetable intake, and that the reduction in risk may be due to other nutrients in these foods.
Toniolo P. Serum carotenoids and breast cancer. Am J Epidemiol 2001;153:1142-1147.
Lycopene, a carotenoid found mostly in tomatoes, inhibits the growth of mammary cancer cells in vitro by reducing the effects of insulin-like growth factor.
Karas M et al. Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer 2000;36:101-111.

In a meta-analysis of 12 studies, intake of fruits and vegetables was seen to be consistently and significantly negatively associated with breast cancer risk. Although this relationship was approximately equal in strength to the positive association with saturated fat, the risk-reducing effects of fruit and vegetable intake were not simply attributable to a lower-fat diet. Other studies cited indicate increased risk of breast cancer with decreased intake of vitamin A in women over 55; decreased risk of breast cancer in women ingesting the largest amounts of carotene, vitamin C, and dietary fiber; and a threefold risk of breast cancer in women eating less than seven portions of green vegetables per week, compared with those eating eight or more servings per week. 
Block G et al. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992;18:1-29.

Information from more than 42,000 women indicated that consumption of a diet that most closely approached current dietary guidelines reduced all-cause mortality as well as the risk of breast cancer. Women who reported the highest frequency of consumption of 23 foods such as apples, oranges, broccoli, tomatoes, greens, carrots, baked or stewed poultry, dark breads, high-fiber cereals, and low-fat milk had a risk of all-cause mortality 30% less than that of women who consumed these foods the least frequently. Diversity of diet (consuming five food groups daily compared with two or fewer) also significantly decreased mortality; those with low diversity had a 40% greater risk of death within the study time period.
Kant AK et al. A prospective study of diet quality and mortality in women. JAMA 2000;283:2109-2115.

Two groups of rats were treated with a carcinogen: in the group consuming a 9.6% fiber diet, compared with the group on a control diet, there were fewer animals with mammary tumors, a smaller total number of mammary tumors, and fewer tumors per rat. This effect was not due only to alteration of estrogen activity; there was also a decrease in mammary tumors in ovariectomized rats that consumed this level of fiber compared with ovariectomized rats that did not. The authors’ conclusion was that dietary fiber at 9.6% food weight was effective at decreasing the incidence of breast tumors in a variety of animal models.
Zile MH et al. Effect of wheat bran fiber on the development of mammary tumors in female intact and ovariectomized rats treated with 7,12-dimethylbenz(a)anthracene and in mice with spontaneously developing mammary tumors. Int J Cancer 1998;75:439-443.

In an epidemiological study of 22 countries, the correlation between sugar consumption and breast cancer mortality increases with every decade of age after age 35; prior to that age, sugar plays little influence. The authors suggest that the actual cause of the relationship may be insulin levels rather than glucose or sucrose.
Seely S, Horrobin DF. Diet and breast cancer: the possible connection with sugar consumption. Med Hypoth 1983;11:319-327.

Soy

Soy decreases levels of 17ß-estradiol (over the entire menstrual cycle) and progesterone (during the luteal phase) in premenopausal women, which may explain the reduced risk of breast cancer in women who consume diets high in soy.
Lu L-JW et al. Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. Cancer Res 2000;60:4112-4121.

Not only is genistein a strong inhibitor of DDT-induced proliferation, it also inhibits protein tyrosine kinase, thereby preventing the entry of tumor cells into the cell cycle.
Phytoestrogens have a stronger affinity for estrogen receptor sites than do molecules of DDT, increasing the likelihood that, if phytoestrogens are present, they rather than DDT will occupy receptor sites. The level of phytoestrogen intake necessary to exert a protective effect against DDT has not yet been established.
Jaga K, Duvvi H. Risk reduction for DDT toxicity and carcinogenesis through dietary modification. J Royal Soc Promot Health 2001;121:107-113.

In vitro studies of the effects of genistein and daidzen on breast tumor cells demonstrated that these two phytoestrogens stimulated the proliferation of the cells in a dose-dependent manner. They also counteracted the tamoxifen, which normally inhibits the proliferation of breast tumor cells. Although soy has been seen to be chemopreventive, in existing estrogen-dependent tumors it does seem to have a cancer-stimulating effect, at least in low concentrations. Concentrations that are probably too high to be achieved in the human body do have an inhibitory effect on tumor cells; however, levels that are normally seen in human subjects consuming large amounts of soy are those that seem to stimulate tumor growth. Because safe amounts of soy have not been established for women with a history of breast cancer, the authors recommend that these women avoid consuming large amounts of soy or taking soy supplements.
De Lemos ML. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann Pharmacol 2001;35:1118-1121.

Soy does not appear to be protective against breast cancer in adult women; animal research suggests that soy in the diet is most protective when consumed before puberty. However, in women consuming 12 ounces of soy milk three times a day (a total of 100 mg genistein per day) for one month, serum estrogen levels dropped 31-89% and serum progesterone dropped 35%. Similarly, in women consuming 400 milliliters of soy milk (109 mg isoflavones) a day, a 23-27% drop in estrogen was noted.
However, daily consumption of 38 g soy protein (38 mg genistein) produced estrogenic effects on the breast tissue in both pre- and postmenopausal women, leading to increased proliferation of breast tissue. Similar results were seen in women consuming 60 g soy protein (45 mg isoflavones) a day for two weeks. These latter studies indicate that short-term supplementation with soy phytochemicals leads to changes in breast tissue that are linked to increased risk of breast cancer. The author notes that these studies did not address the effects of whole soy, which contains other compounds associated with decreased cancer risk, and which can be substituted for meat, a food that may be linked to an increased risk of breast cancer.
Brignall M. Soy’s benefits for breast cancer: the jury is still out. Healthnotes Newswire: June 1, 2000.

The decreases in 17ß-estradiol and progesterone in women on a soy-containing diet are not due entirely to soy’s isoflavones.
Lu L-JW et al. Effects of an isoflavone-free soy diet on ovarian hormones in premenopausal women. J Clin Endocrinol Metabl 2001;86:3045-3052.

In an animal study, supplementation of the diet with isolated soy protein for three weeks before injection with carcinoma cells reduced the number of pulmonary metastases from primary mammary tumors.
Yan L et al. Dietary supplementation with isolated soy protein reduces metastasis of mammary carcinoma cells in mice. Clin Exp Metastasis 2002;19:535-540.

Although hormone replacement therapy increases risk of breast cancer, soy consumption by healthy women is unlikely to do so; current evidence is that the combination of estrogen and progestin, not estrogen alone, increases breast cancer risk, and soy has no progestin activity. The author suggests that long-term intervention studies be done to confirm this hypothesis.
Messina MJ. Soy foods and soybean isoflavones and menopausal health. Nutr Clin Care 2002;5:272-282.

Genistein can also shift estrogen metabolism towards increased 2-hydroxylation and decreased 16a-hydroxylation, although the degree to which it is seen to do this varies between studies. It has also been seen to block proliferation in vitro. In at least one study, however, consumption of soy products by women with breast cancer increased the rate of recurrence compared with that seen in women on a non-soy diet. The same concern may apply to compounds such as daidzen and lignan derivatives.
Bradlow HL, Sepkovic D. Diet and breast cancer. Ann NY Acad Sci 2002;963:247-267.

At low concentrations, genistein and quercetin from soybeans are full agonists for estrogen receptor-a and estrogen receptor-ß, as well as for proliferation of estrogen receptor-dependent breast cancer cells.  At concentrations seen in humans on a soy-rich diet, they are cytotoxic in an ER-independent fashion. Because low concentrations promote breast cancer and high concentrations are mainly antitumorigenic, the authors suggest that perhaps women should consume either a lot of phytoestrogen-rich foods or none at all, and discourage the intake of large amounts of phytoestrogen-rich food or phytoestrogen supplements without medical follow-up. [Note: This is an in vitro study; no mention is made of whether this recommendation is for premenopausal women, postmenopausal women, or both.]
Maggiolini M et al. Estrogen receptor a mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Molec Pharmacol 2001;60:595-602.

Flaxseed and flax oil

Higher serum levels of enterolactone, a lignan and phytoestrogen, were associated with decreased risk of breast cancer in Finnish women. Some women seemed less able than others to convert plant lignans to enterolactone; the authors hypothesize that this may be due to differences in intestinal microflora, citing previous studies in which antibiotics decreased urinary enterolactone excretion.
Pietinen P et al. Serum enterolactone and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2001;10:339-344.
 
Consumption of either flaxseed or flaxseed oil decreases mammary tumor initiation and growth. Lignans in flax inhibit estrogen synthetase activity, decrease mammary tumor initiation and growth, and stimulate the synthesis of sex hormone binding globulins.
The estrogen metabolites 16a-hydroxyesterone and 2-hydroxyestrogen (2-hydroxyesterone and 2-hydroxyestradiol) have different activities. 16a-Hydroxyestrone has significant estrogenic activity and increases the risk of breast cancer; 2-hydroxyestrogens are protective against breast cancer. Five to ten grams of ground flaxseed per day increased 2-hydroxyestrogen excretion and the ratio of 2-hydroxyestrogens to 16a-hydroxyesterone, suggesting that flaxseed is protective against breast cancer in postmenopausal women. The authors cite other studies in which high-protein and low-fat diets, as well as broccoli and other cruciferous vegetables containing indole-3-carbinol, also increased this ratio.
Haggans CJ et al. Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 1999;33:188-195.

High levels of insulin-like growth factor (IGF) have been associated with an increased risk of breast and other cancers. Like tamoxifen, flaxseed has been seen to reduce IGF-1 levels, although its mechanisms of action are probably different.
Rats that were either fed a 5% flaxseed (ie, high-lignan) diet or given 1.5 mg/day of solariciresinol diglycoside (a plant lignan precursor of mammalian lignans) had IGF-1 levels significantly lower than those in rats fed a control diet. In rats given a carcinogen and fed the 5% flaxseed diet, IGF-1 levels were lower than those in rats also exposed to the carcinogen but fed a control diet. Urinary lignan levels, an indicator of lignan bioavailability, were inversely associated with plasma IGF-1 levels.
Rickard SE et al. Plasma insulin-like growth factor I levels in rats are reduced by dietary supplementation of flaxseed or its lignan secoisolariciresinol diglycoside. Cancer Lett 2000;161:47-55.

Antioxidants

In both pre- and postmenopausal women, increased concentrations of serum antioxidants (a-tocopherol, ß-carotene, zeaxanthin + lutein, retinol, and lycopene) were associated with a decreased risk of breast cancer.
Kim MK et al. Relationship of serum a-tocopherol, carotenoids and retinol with the risk of breast cancer. Nutr Res 2001;21:797-809.

Heterocyclic amines are carcinogens formed during the broiling or frying of creatine-containing foods, including fish and meats. Antioxidants such as those in soy foods, those in tea, and vitamin C can inhibit their formation and their action. Other reactions inhibited by antioxidants include oxidation reactions that would otherwise lead to cell proliferation and development of abnormal pre-neoplastic and neoplastic cells.
Weisburger JH. Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea. Food Chem Toxicol 1999;37:943-948.

Women in the highest quintile for ß-carotene, lycopene, or total carotenoids had approximately half the breast cancer risk of women in the lowest quintile. The authors note that these compounds may simply reflect high fruit and vegetable intake and that there are other beneficial compounds in these foods that accounted for the decreased risk.
Sato R et al. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2002;11:451-457.

In a study of premenopausal women, serum concentrations of a-tocopherol, ß-carotene, cryptoxanthin, lutein plus zeaxanthin, and lycopene were inversely associated with breast cancer risk. In postmenopausal women, risk of breast cancer was inversely associated with a-tocopherol, cryptoxanthin, and lutein plus zeaxanthin. Other studies have also found that low serum concentrations of these antioxidants are strongly associated with a higher risk of cancer.  Carotenoid concentrations in serum are readily increased by dietary intake.
Kim MK et al. Relationship of serum a-tocopherol, carotenoids and retinol with the risk of breast cancer. Nutr Res 2001;21:797-809.

It may be that the antiproliferative effect of retinoids is due to their inhibition of insulin-like growth factor–stimulated growth.
Decensi A et al. Chemoprevention of breast cancer: the Italian experience. J Cell Biochem Suppl 2000;34:84-96.

Reduced CoQ10 protects unsaturated lipids in the mitochondrial membrane from free radical damage and reduces oxidative damage to DNA and proteins. In one study, CoQ10 levels in tumor tissues of the breast were lower than in the surrounding noncancerous tissues.  Levels of malonyldialdehyde, an indicator of lipid peroxidation and oxidative cell damage, were higher in cancerous tissues of the breast than in noncancerous tissue. 
Portakal O et al. Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Clin Biochem 2000;3:279-284.

Compounds that neutralize free radicals include the enzymes superoxide dismutase, catalase, and glutathione peroxidase; vitamins E and C; carotenes; flavonoids; glutathione; alpha-lipoic acid, and N-acetyl cysteine.
Mantovani G et al. Restoration of functional defects in peripheral blood mononuclear cells isolated from cancer patients by thiol antioxidants alpha-lipoic acid and N-acetyl cysteine. Int J Cancer 2000;86:842-847.

Women who had breast cancer with axillary lymph node involvement were given a combination of antioxidants in addition to their standard surgical and therapeutic treatment. The supplements given daily were 2850 mg vitamin C; 2500 IU vitamin E; 32.5 IU beta-carotene; 387 mcg selenium; secondary vitamins and minerals; 1.2 g gamma linolenic acid; 3.5 g omega-3 fatty acids; and 90 mg coenzyme Q10. None of the 36 patients died during the 18 months of the study (four deaths would have been expected over this period); there were no signs of further distant metastases; quality of life was improved (there was no weight loss and use of pain killers was reduced); and in six patients there was apparent partial remission.
Lockwood K et al. Apparent partial remission of breast cancer in “high risk” patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Aspects Med 1994;15 Suppl:s231-s240.

Tocopherols and tocopheryls

Many chemopreventive and therapeutic agents work by inducing differentiation. Vitamin E succinate (RRR-a-tocopheryl succinate) is a differentiating agent in some breast cancer cell lines, but not all. It also induces apoptosis, stops DNA synthesis, and acts as a cell cycle blocker in some cancer cell lines. Its ability to induce differentiation in breast cancer cells is not estrogen dependent, as differentiation was induced in both estrogen-responsive and non-estrogen-responsive cells.
You H et al. RRR-a-Tocopheryl succinate induces MDA-MD-435 and MCF-7 human breast cancer cells to undergo differentiation. Cell Growth Differ 2001;12:471-480.

Vitamin E succinate (RRR-a-tocopheryl succinate) induces cell cycle blockage, cellular differentiation, increased expression of TGF-ß, expression of TGF-ß type II receptors, and apoptosis. It exerts its antiproliferative and apoptotic effects in tumor cells but has low toxicity in normal cells.
Yu W et al. Activation of extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-a-tocopheryl succinate-induced apoptosis of human breast cancer cells. Cancer Res 2001;61:6569-6576.

Tocopherols and tocotrienols inhibit several mitogenic signaling pathways, inhibiting protein kinase C, adenylate cyclase, and cyclic AMP-dependent protein activation in various cell lines. Although tocopherols and tocotrienols are antioxidants, their antitumor effect does not depend on their exerting this activity. In vitro experiments on different mouse mammary epithelial cell lines demonstrated that the more malignant cells were the most susceptible to tocopherol- and tocotrienol-induced growth inhibition and apoptosis, and the preneoplastic (nonmalignant) cells were the least susceptible. Tocotrienols are more potent in these actions than are tocopherols; relative biopotency in these experiments was determined to be d-tocotrienol ? ?-tocotrienol > a-tocotrienol > d-tocopherol > ?- and a-tocopherol. The authors hypothesize that tocotrienols were more potent than tocopherols because they are more readily taken up by preneoplastic and neoplastic breast epithelial cells.
McIntyre B et al. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exper Biol Med 2000;224:292-301.

Calcium

Studies of the link between milk consumption and breast cancer incidence have conflicting results; in some a strong positive correlation was seen, and in others milk consumption seemed to be associated with decreased breast cancer risk. Researchers have suggested that the calcium and vitamin D in milk are responsible at least in part for any protective effect.
Bradlow HL, Sepkovic D. Diet and breast cancer. Ann NY Acad Sci 2002;963:247-267.

Breast cancer rates in white women are higher in areas with less sunlight and longer winters.
In premenopausal women there is a significant inverse relationship between intake of low-fat dairy foods and breast cancer risk. The decreased risk of premenopausal breast cancer seen with increased calcium and vitamin D intake is due mostly to dietary sources and not to supplements.
Shin M-H et al. Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 2002;94:1301-1311.

Fatty acids

High-fat diets rich in omega-6 polyunsaturated fatty acids (PUFAs) stimulate mammary tumor cell development; diets high in omega-3 PUFAs inhibit tumor growth and metastasis. 
The authors of this study observed a reduction in breast cancer risk with increased alpha-linolenic acid intake, although they note that other studies have had different results.
Klein V et al. Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer. Eur J Cancer 2000;36:335-340

Risk of breast cancer decreases with monounsaturated fat intake and increases with polyunsaturated fat intake. No relationship between saturated fat intake and breast cancer risk was reported in this study. The authors note that linoleic acid was associated in other studies with increased incidence and metastasis of mammary tumors.
Wolk A et al. A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer. Arch Intern Med 1998;158:41-45.

Botanicals

Curcumin inhibits oxidative damage to DNA and increases the activity of glutathione-S-transferase, an enzyme that binds toxins with glutathione and thereby helps remove them from the body.
Luper S. A review of plants used in the treatment of liver diseases: part 2. Altern Med Rev 1999;4:178-189.

Curcumin has antioxidant, anticarcinogenic, and anti-inflammatory properties, acts synergistically with phytoestrogens, and inhibits the estrogenic effects of DDT.
Jaga K, Duvvi H. Risk reduction for DDT toxicity and carcinogenesis through dietary modification. J Royal Soc Promot Health 2001;121:107-113.

Pregnant rats were separated into two groups, one consuming a diet containing 1% curcumin and the other consuming a control diet. After being fed the diets for 9 days, the rats were exposed to gamma radiation, and at 1 month after weaning, a DES (diethylstilbestrol, a tumor promoter) pellet was implanted in each study animal. The pellets were replaced every 8 weeks. Levels of luteinizing hormone were higher in rats fed the curcumin diet, but there were no significant differences in prolactin, estrogen, or progesterone levels between the two groups, By the end of 1 year, 70.3% of the control rats had tumors, but only 18.5% of the rats fed curcumin did; in addition, the tumors in the curcumin-fed rats appeared significantly later than did those in the control rats.
Inano H et al. Potent preventive action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats. Carcinogenesis 2000;21:1855-1841.

High doses of PSK can decrease estrogen receptor and progesterone receptor levels in breast cancer cells in vitro. PSK also dose-dependently inhibits DNA synthesis in these cells.
Aoyagi H et al. Effects of OK-432 (Picibanil) on the estrogen receptors of MCF-7 cells and potentiation of antiproliferative effects of tamoxifen in combination with OK-432. Oncology 1997;54:414-423.

Components of green tea that fight cancer are epigallocatechin gallate (EGCG) and epicatechin (EC), which enhances the effects of EGCG.  EC also stimulates apoptosis induced by other constituents of green tea, and co-treatment with EGCG and EC stops cancer cells from secreting tumor necrosis factor-a.  Green tea is therefore more effective at preventing cancer than is EGCG alone.
The authors cite a study in which patients with a history of Stage I or II breast cancer had a recurrence  rate of 24.3% if they consumed four or fewer cups of green tea a day and a rate of 16.7% if they consumed five or more cups.
Suganuma M et al. Green tea and cancer chemoprevention. Mutat Res 1999;428:339-344.

Epigallocatechin gallate has antioxidant activity; it can also shift estrogen metabolism towards a more protective ratio of estrogen metabolites.
Bradlow HL, Sepkovic D. Diet and breast cancer. Ann NY Acad Sci 2002;963:247-267.

Folate and alcohol

Alcohol consumption increases the risk of breast cancer; in several studies, folate has been seen to reduce this effect. Subjects in the Nurses’ Health Study who were in the highest quintile of plasma folate had a multivariable relative breast cancer risk of 0.73 compared with women in the lowest quintile; findings were similar (relative risk = 0.70) for women in the highest quintile of plasma vitamin B6 compared with those in the lowest. The effect of folate was particularly strong in women who consumed at least 15 grams of alcohol per day; in this group, women in the highest quintile of plasma folate had a relative risk of 0.11 compared with women in the lowest quintile. In women consuming less than 15 g/day, the benefits conferred by folate were less pronounced (relative risk of 0.72 for women in the highest quintile compared with those in the lowest).
Zhang SM et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 2003;95:373-380.

Postmenopausal women consuming 15 or more grams of ethanol per day had a risk of breast cancer 1.26 times that of postmenopausal women who consumed no alcohol. The authors of this study found no relationship between breast cancer and folate intake, multivitamin use, or methionine intake.
Feigelson HS et al. Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2003;12:161-164.
 
Postmenopausal women who had folate intakes below the 50th percentile and who had a high intake of alcohol were at a risk of breast cancer 1.46 times that of nondrinking postmenopausal women with folate intakes above the 50th percentile. Most of the difference in risk was seen for estrogen-receptor-positive tumors, leading the authors to suggest that alcohol’s influence on breast cancer risk may be through its metabolite acealdehyde rather than through changes in estrogen levels or receptor-mediated pathways.
Sellers TA et al. Interaction of dietary folate intake, alcohol, and risk of hormone receptor-defined breast cancer in a prospective study of postmenopausal women. Cancer Epidemiol Biomarkers Preve 2002;11:1104-1107.

Indole-3-carbinol

Indole-3-carbinol, a compound in cruciferous vegetables, induces phase II enzymes, to increase carcinogen conjugation and elimination; inhibits cell growth and proliferation; blocks both tumor initiation and, in most cases, tumor promotion; and has many antiestrogenic effects.
Bradlow HL, Sepkovic D. Diet and breast cancer. Ann NY Acad Sci 2002;963:247-267.

Dietary indole-3-carbinol, a compound found in cruciferous vegetables, reduces the incidence of spontaneous and carcinogen-induced mammary tumors in animals. A study of in vitro treatment with I3C suppressed the growth of two human breast cancer cell lines, in part by induction of apoptosis.  The authors suggest that consumption of large amounts of cruciferous vegetables (cabbage, Brussels sprouts, turnips, broccoli, and cauliflower) may decrease the risk of various cancers in humans.   
Ge X et al. Induction of apoptosis in MCF-7 cells by indole-3-carbinol is independent of p53 and bax. Anticancer Res 1999;19:3199-3204.

Indole-3-carbinol from cruciferous vegetables tilts estrogen metabolism towards the formation of 2-hydroxyestrone, which reduces estrogenic response in a breast tumor cell line.
Jaga K, Duvvi H. Risk reduction for DDT toxicity and carcinogenesis through dietary modification. J Royal Soc Promot Health 2001;121:107-113.

The inhibition of indole-3-carbinol of breast cancer cell growth is seen only in estrogen-responsive cell lines; the compound has little effect on estrogen-nonresponsive cells. Both induction of cytochrome P4501A1 and enhancement of C-2 hydroxylation of estrogen were seen in MCF-7 (estrogen-responsive) cells but not in MDA-MB-231 cells.
Tiwari RK et al. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. J Natl Cancer Inst 1994;86:126-131.

Indole-3-carbinol increases C-2 hydroxylation but minimally affects C-16 alpha hydroxylation of estradiol in MCF-7 cells in vitro, shifting estrogen metabolism in a way that decreases breast cancer risk.
Niwa T et al. Alterations in estradiol metabolism in MCF-7 cells induced by treatment with indole-3-carbinol and related compounds. Steroids 1994;59:523-527.
 
Reduced glutathione

In vitro evidence suggests that reduced glutathione, as well as S-acetylglutathione, can induce apoptosis in several tumor cell lines without influencing growth and viability of normal cells.
Donnerstag B et al. Reduced glutathione and S-acetylglutathione as selective apoptosis-inducing agents in cancer therapy. Cancer Lett 1996;110:61-70.

Calcium D-glucarate

Animal studies have demonstrated that increasing the net glucoronidation of carcinogens reduces the likelihood of chemically induced carcinogenesis. Inhibition of the enzyme ß-glucuronidase, which catalyzes deglucoronidation, should therefore be protective against carcinogen-mediated tumorigenesis. Supplementation of the diet with calcium D-glucarate decreases ß-galactosidase activity in the liver, lung, and GI microsomes of rodents, and has been shown in other studies to inhibit carcinogen-induced carcinogenesis in animals. Many drugs and toxins, or their metabolites, are substrates for glucoronidation, so this is a potentially powerful method of chemoprevention. The probable mechanism of action of calcium D-glucarate is the conversion of about a third of it to glucaro-1,4-lactone, which is a specific inhibitor of the enzyme.
Dwivedi C et al. Effect of calcium glucarate on ß-glucuronidase activity and glucarate content of certain vegetables and fruits. Biochem Med Metabol Biol 1990;43:83-92.

One method of decreasing the level of estrogen in the body is to increase its excretion, and one method of increasing its excretion is through the glucoronidation pathway. Fortification of the diet with calcium glucarate has been shown in animal studies to result in a decrease in serum estradiol levels and an increase in 17-ketosteroid excretion.
The authors cite a study in which calcium glucarate, given to rats after they were exposed to a mammary carcinogen, decreased tumor formation; when it was given after tumor induction had already taken place, tumor volume was decreased. The results of another animal study demonstrated a pronounced effect of calcium glucarate on mammary tissue, where it decreased beta-glucoronidase activity and reduced proliferation in terminal ducts and terminal end buds.
Heerdt AS et al. Calcium glucarate as a chemopreventive agent in breast cancer. Isr J Med Sci 1995;31:101-105.

Glutamine

The cardiopathy induced  by doxorubicin can be reduced by dietary supplementation with glutamine in rats; administration of glutamine upregulates cardiac glutathione levels, limiting oxidative damage from the drug.
Cao Y et al. J Surg Res 1999;85:178-182

Thirty grams of glutamine, administered intravenously, did not alter the response rate of breast tumors to chemotherapy (doxifluridine), the median time to response, or the median duration of response. However, it also did not prevent doxifluridine-induced diarrhea.
Bozzetti F et al. Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study. Nutrition 1997;13:748-751.

Tamoxifen

Tamoxifen is a selective estrogen receptor modulator used as a palliative treatment in advanced breast cancer and as a preventive agent against recurrence in women who have a history of estrogen-receptor positive breast cancer; in at least one study it increased the 10-year survival rate for women with breast cancer of unknown estrogen receptor status as well. A decreased rate of invasive breast cancer in the affected breast, and to a lesser extent a decreased rate of invasive and noninvasive cancer in the opposite breast, was seen in women who had a history of DCIS treated with lumpectomy, radiation, and subsequent tamoxifen administration than in those treated with lumpectomy and radiation only. Higher mammographic density is associated with an increased risk of breast cancer; tamoxifen may decrease breast density as measured by mammography, and hormone replacement therapy may increase it.
Decensi A et al. Chemoprevention of breast cancer: the Italian experience. J Cell Biochem Suppl 2000;34:84-96.

Melatonin blocks the estradiol-induced growth of breast cancer cells in vitro, is a strong scavenger of free radicals, enhances the immune system, influences the development and involution of tissues that are dependent on sex hormones for their growth, and potentiates the sensitivity of cells to tamoxifen. It has been proposed that melatonin acts as an antiestrogen in breast cancer cells. A combination of tamoxifen and melatonin may be helpful in the treatment of tamoxifen-resistent breast cancer.
García Rato A et al. Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J 1999:13:857-868.

The antiproliferative effect of melatonin on breast cancer cells may be reversible.
Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 1988;48:6121-6126.

A combination of curcumin and isoflavonoids inhibits pesticide-induced growth in both estrogen receptor-positive and estrogen receptor-negative breast cancer cell lines. Curcumin also enhances the ability of tamoxifen to inhibit growth in an estrogen receptor-positive cell line exposed to an estrogenic environmental compound.
Verma SP et al. The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids. Environ Health Perspect 1998;106:807-812.

Treatments (support during cancer therapy)

Survival in patients diagnosed with cancer is significantly shorter in patients with weight loss than in those without; even a loss of <5% body weight is associated with a poorer prognosis. Complications such as infection also occur more frequently, and are more severe, in malnourished patients.
Conversely, women receiving chemotherapy for breast cancer frequently gain weight; the authors hypothesize that, because excess body weight increases a woman’s risk of cancer, weight gain could increase the risk of recurrence.
The authors cite Shils’ principles of nutritional support for cancer patients, 20 years old but still considered relevant:
Malnutrition induced by cancer and its treatment affects the patient and complicates further treatment of the disease.
Malnutrition is not an obligatory response of the host to cancer.
A rational therapeutic program for a patient requires an analysis of the factors inducing depletion in the patient.
Every patient should have an early and periodic assessment of nutritional status.
Nutritional therapy, when indicated, should be initiated early.
The application and effectiveness of therapeutic programs must become part of the medical audit and general clinical procedure for inpatients and outpatients.
The objectives of nutritional therapy are (1) supportive, (2) adjunctive, and (3) definitive.
Nutritional status, tumor growth, and antitumor treatment are intimately related.
Nutritional therapy has the potential for difficulties as well as benefits.
The provision of optimal nutritional care requires a multidisciplinary approach with physicians, nurses, dietitians, and pharmacists working as a team with adequate laboratory facilities and administrative and financial support.
Shils ME. Principles of nutritional therapy. Cancer 1979;43:2093-2102; cited in Cunningham RS, Bell R. Nutrition and cancer: An overview. Semin Oncol Nurs 2000;16:90-98.

People are most easily persuaded to make dietary changes when they are in programs that involve small groups and/or goal setting. Behavioral interventions are more effective among people who are at risk of or who have been diagnosed with disease than among control subjects.
Ammerman AS et al. The efficacy of behavioral interventions to modify dietary fat and fruit and vegetable intake: a review of the evidence. Prev Med 2002;35:25-41.

Liver support

Cytochrome P450 enzymes activate certain carcinogens; phase II detoxification enzymes increase detoxification. Dandelion tea, administered to rats over four weeks, significantly decreased certain cytochrome P450 isoforms, decreasing the bioactivation of several precarcinogens, and increased the activity of a phase II enzyme, which may increase the detoxification of carcinogens.
Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic drug metabolizing enzymes in rats. J Pharm Pharmacol 2001;53:1323-1329.

Silymarin, a compound in milk thistle (Silybum marianum), reduces the cellular absorption of xenobiotics; inhibits leukotriene B4 formation, thus acting as an hepatoprotective agent; has antioxidant and free radical–scavenging properties; increases the expression of superoxide dismutase by lymphocytes; exerts anticarcinogenic and anti-inflammatory effects by inhibiting the activation of nuclear factor kappa B; and reduces the injury to kidney cells induced by paracetamol, cisplatin, or vincristine in vitro. At high concentrations it also reduces the cytotoxicity of methotrexate that is enhanced by concomitant ethanol or acetaminophen administration. In patients with alcohol-induced liver disease, silymarin decreased levels of the hepatic enzymes alanine amino transferase and aspartate amino transferase.
Saller R et al. The use of silymarin in the treatment of liver diseases. Drugs 2001;61:2035-2063.

Curcuma longa, or turmeric, has been shown to be hepatoprotective in animal and in vitro studies. It contains several antioxidant compounds, the most potent of which is curcumin. Turmeric increases levels of superoxide dismutase, catalase, and glutathione peroxidase; it also increases the activity of glutathione S-transferase, promoting detoxification. By inhibiting production of arachidonic acid, it has anti-inflammatory activity; it has been found to be as effective when taken orally as cortisone or phenylbutazone in acute inflammation. Despite this finding, absorption of curcumin when taken by mouth is poor, but is improved when curcumin is taken with piperine, a substance in black pepper.
Camellia sinensis, or green tea, contains hepatoprotective polyphenols, the bioflavonoids classified as catechins, which are powerful antioxidants that inhibit lipid peroxidation induced by various toxins, including singlet oxygen. They also help maintain intracellular protein thiol levels, which in turn maintain intracellular reduction-oxidation balance. Green tea enhances phase 2 liver detoxification, increasing glucuronidation by 100% in one animal study. The most active compound in green tea is epigallocatechin gallate.
Glycyrrhiza glabra, or licorice, exerts its hepatoprotective effect by decreasing lipid peroxidation. It increases both cytochrome P450 activity and glucuronidation, promoting detoxification.
Luper S. A review of plants used in the treatment of liver diseases: part 2. Altern Med Rev 1999;4:178-189.

Licorice protects the liver by decreasing inflammation and by normalizing levels of aspartate transaminase and alanine transaminase.
Silymarin, from milk thistle, inhibits lipid peroxidation and protects cell membranes from free radical damage. It decreases liver enzymes that are elevated due to alcohol-related liver disease.  In people with liver disease, milk thistle has an antifibrotic effect in the liver, reducing the proliferation of the cells that produce excess collagen in profibrotic conditions.
Schuppan D et al. Herbal products for liver diseases: a therapeutic challenge for the new millenium. Hepatology 1999;30:1099-1104.

Silymarin is an antioxidant and free-radical scavenger that helps prevent free-radical formation and glutathione depletion. Another of its protective effects in the liver may include action as an antifibrotic agent.
Glycyrrhizin, an aqueous extract of licorice root, also has several hepatoprotective actions: it is an antioxidant, it inhibits prostaglandin E2 production, modifies the metabolism of arachidonic acid, induces glutathione-S-transferase and catalase activity, and decreases the degree of fibrosis and ALT elevation seen in liver disease. One drawback to its use is that its mineralocorticoid activity can lead to fluid retention and hypokalemia; because these symptoms are associated with cirrhosis, patients with this condition should avoid using licorice root.
Seeff LB et al. Complementary and Alternative Medicine in Chronic Liver Disease. Hepatology 2001;34:595-603.

Silymarin inhibits phase I detoxification, decreasing the bioactivation of some toxins, and increases the effectiveness of phase II detoxification by inhibiting ß-glucoronidase, an enzyme that breaks the bond between glucoronic acid and the toxin bound to it. It has a number of other effects on liver: it protects hepatic cells from radiation, iron toxicity, and ischemic injury; it lowers liver enzymes, high levels of which are indicators of poor liver health; it has antioxidant properties; it modulates immune function; it prevents depletion of glutathione; and it inhibits lipoxygenase, thereby decreasing production of harmful leukotrienes. Milk thistle components other than silymarin that have protective effects are betaine and anti-inflammatory essential fatty acids.
Picrorhiza kurroa, an Ayurvedic herb, has been shown to be as effective as or more effective than silymarin at protecting liver cells from various toxins. It also has antioxidant actions, reducing lipid peroxidation and free radical damage, as well as anti-inflammatory effects.
Luper S. A review of plants used in the treatment of liver diseases: part 1. Altern Med Rev 1998;3:410-421.

Monoterpenes like limonene, perillyl alcohol, and perillic acid have chemopreventive and chemotherapeutic actions on breast cancer cells in animal models. Studies have shown increased tumor latency, decreased numbers of tumors, and even tumor regression in rats. One mechanism of action is to change carcinogen-metabolizing liver enzymes; another is to alter cell cycles in such a way that cellular proliferation is inhibited.
Bardon S et al. Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer cell lines. Nutr Cancer 1998;32:1-7.

Immune support

Study subjects who took weekly or twice-weekly sauna baths had significantly fewer common colds over a 6-month period compared with subjects who did not. When they did get a cold, its intensity and duration was not significantly different; however, it should be noted that sauna bathing was not done while subjects were sick or for a week afterwards. The authors suggest that the mechanism of hyperthermia’s effects on the immune system might be to induce DNA synthesis and increase levels of immunoglobulins.
Ernst E et al. Regular sauna bathing and the incidence of common colds. Ann Med 1990;22:225-227

The antioxidant coenzyme Q10 may protect normal cells from the free radical damage caused by conventional cancer therapies; however, there is evidence that its use during radiation therapy reduces the effectiveness of the treatment. Cancer patients may also benefit from its positive effects on the immune system.
Low Dog T et al. Traditional and alternative therapies for breast cancer. Alt Ther 2001;7:36-47.

Low levels of CoQ10 have been reported in patients with various types of cancer, and there is a significant positive relationship between plasma CoQ10 level and good prognosis in patients with breast cancer. Its protective effect against cancer may be due not only to its antioxidant effects but also to its ability to stimulate the immune system. It increases the ratio of CD4 to CD6 T-cells, a ratio that tends to be decreased in people with cancer. It may also increase the synthesis of antibodies in B cells.
CoQ10 reduces the cardiotoxicity of anthracycline chemotherapy drugs such as doxorubicin.
Cancer.gov. Coenzyme Q10. National Cancer Institute.

       Subcutaneous and intraperitoneal adminstration of standardized aqueous mistletoe extract, three times a week for two weeks, dose-dependently increased thymus weight and peripheral leukocytes, lymphocytes, and monocytes in mice with liver or lung sarcomas. Administration of the extract by either method significantly reduced lung and liver metastases, also in a dose-dependent manner. Mistletoe extract has several modes of action: it promotes apoptosis and necrosis in vitro, activates granulocyte activity in mice and humans, and affects lymphocyte and monocyte activity in vitro and in vivo.
Braun JM et al. Application of standardized mistletoe extracts augment immune response and down regulates metastatic organ colonization in murine models. Cancer Lett 2001;170:25-31.

One of the reasons a high intake of fruits and vegetables is associated with decreased cancer risk may be the positive effect of antioxidants, present in large amounts in these foods, on the immune system.
Kim MK et al. Relationship of serum a-tocopherol, carotenoids and retinol with the risk of breast cancer. Nutr Res 2001;21:797-809.

After patients with alcoholic liver disease and abnormal immune status took silymarin for 6 months, there was a normalization of all immune-system parameters measured.
Luper S. A review of plants used in the treatment of liver diseases: part 1. Altern Med Rev 1998;3:410-421.

A polyphenol in green tea, (+)-catechin, dose-dependently promotes the activation of macrophages, cytotoxic T-lymphocytes, and natural killer cells in mice.
Luper S. A review of plants used in the treatment of liver diseases: part 2. Altern Med Rev 1999;4:178-189.

Hydrotherapy

Hyperthermia treatments, in which body temperature is raised to 105-107º for many hours, have been observed to delay tumor growth and sometimes bring about a temporary regression of a tumor.
Thrash A, Thrash C. Diseases and their home remedies. In: Home Remedies [no other information available]

Hydrotherapy is one of the modalities used in naturopathic medicine that may help reduce cancer pain: others include transcutaneous electrical nerve stimulation, cutaneous stimulation, ultrasound, massage therapy, exercise, and acupuncture.
Chang HM. Chronic pain: cancer pain management. Med Clin North Am 1999;83:711-736.

There is little precedent for the use of hydrotherapy in the debridement of necrotic tissue in patients with cancer; although whirlpool immersion has been used to debride other wounds for decades, there is a concern that disrupting cancerous tissue might cause metastasis. However, in one case, a highly dilute povidone-iodine solution was used in a whirlpool bath to safely debride a large wound caused by eruption of a carcinoma through the skin of the breast. She was treated with chemotherapy and the wound was debrided, and two years after starting treatment she was free of cancer.
Nash MS et al. Nonselective debridement and antimicrobial cleansing of a venting ductal breast carcinoma. Arch Phys Med Rehabil 1999;80:118-121.

Hormonal regulation

A phytoestrogen is a compound that either closely resembles 17ß-estradiol or promotes actions considered to be estrogenic. Plant estrogens—isoflavones, lignans, and coumestans—can bind with estrogen receptors and exert weak estrogenic effects. When bound to an estrogen receptor, a phytoestrogen blocks estrogen from attaching to that same receptor; in women with high levels of endogenous estrogen (premenopausal women), the net result is a decreased estrogenic effect, and in women with low levels (postmenopausal women), the net result is an increased effect.
Soybeans, red clover, black cohosh, licorice, alfalfa, dong quai, and hops contain phytoestrogens. It has not yet been established whether it is safe for women with a history or risk of breast cancer to use these herbs medicinally without medical supervision.
Wade C et al. Hormone-modulating herbs: implications for women’s health. JAMWA 1999;54:181-183.

Among the foods, spices, and herbs tested, those with the greatest estrogen receptor-binding potential were (in descending order) soy milk, licorice, red clover, mandrake, bloodroot, thyme, yucca, turmeric, hops, verbena, yellow dock, and sheep sorrel. Botanicals with high progesterone receptor-binding potential were bloodroot, ocotillo, mandrake, oregano, damiana, pennyroyal, verbena, nutmeg, turmeric, yucca, thyme, calamus root, red clover, goldenseal, licorice, mistletoe, cumin, fennel, chamomile, and cloves.
Note that receptor-binding activity does not necessarily translate into hormone-like activity. For example, estrogen receptor-binding herbs tend to be agonists, but progesterone receptor-binding herbs tend to be neutral or antagonists. 
Zava DT et al. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med 1998;217:369-378.

Increased levels of testosterone are thought to increase the risk of breast cancer. It is possible to alter decrease serum testosterone levels and increase levels of sex hormone binding globulin by making dietary changes: increasing consumption of phytoestrogen-rich foods such as soy, flaxseed, whole grains, and cruciferous vegetables, which may stimulate production of sex-hormone binding globulins; consumption of foods with a low glycemic index, to decrease insulin level and thereby maintain a higher level of sex-hormone binding globulins; increasing consumption of nutrients that promote insulin sensitivity, such as omega-3 fatty acids, fiber, vitamin B6, and chromium; and decreasing intake of less animal fat.
Berrino F et al. A randomized trial to prevent hormonal patterns at high risk for breast cancer: the DIANA (Diet and Androgens) project. Abstract presented at Second International Symposium on the role of soy in preventing and treating chronic disease, September 15-18, 1996, Brussels, Belgium.

Lignans in flaxseed are thought to exert their protective effects by increasing the synthesis of sex hormone binding globulin, inhibiting the growth of breast cancer cells, and inhibiting estrogen synthase activity. The a-linolenic acid in flaxseed has been seen in animal studies to reduce growth of mammary tumors. Increased consumption of dietary fiber is also thought to reduce the risk of breast cancer because it decreases sex hormone levels and increases estrogen excretion.
The ratio of 2-hydroxyestrogen to 16a-hydroxyestrogen increased, indicating a protective effect against breast cancer, during the luteal phase in premenopausal women consuming 10 g ground flaxseed a day. This increase was seen whether or not the study subjects were simultaneously consuming 28 g wheat bran a day, suggesting that substances other than the fiber in flaxseed were responsible, and that wheat bran did not reduce the effect of flaxseed. (In contrast, one study has indicated that dietary fiber decreases absorption of genistein from tofu and textured vegetable protein.)
Haggans CJ et al. The effect of flaxseed and wheat bran consumption on urinary estrogen metabolites in premenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9:719-725.

Mammalian lignans, enterolactone and enterodiol, are similar in structure to estradiol and diethylstilbesterol, and it is thought that this similarity is how they affect the course of hormone-related cancers. Flaxseed has 75-800 times more mammalian lignan precursors than do other plant foods. After exposure to a mammary cancer-causing carcininogen, rats were fed a diet that consisted of a 5-10% inclusion of secoisolariciresinol diglycoside (SD), a mammalian lignan precursor isolated from flaxseed. Compared with control animals, these rats had significantly smaller tumors when the SD was given at the promotional stage of tumorigenesis and a significantly decreased incidence of tumors when it was given at the initiation stage. The possible mechanisms for these effects are as follows: 1) lignans bind to estrogen receptors and reduce estrogen-induced tumor growth; 2) in both rats and humans, enterolactone and enterodiol can bind to a-fetoprotein, a protein that affects tumor growth; 3) mammalian lignans inhibit aromatase (an enzyme involved in the formation of estrone from androgens) as well as other enzymes that are involved in cell proliferation; 4) these lignans inhibit vascular endothelial cell proliferation and angiogenesis; and 5) some have antioxidative properties.
Thompson LU et al. Antitumorigenic effect of a mammalian lignan precursor from flaxseed. Nutr Cancer 1996;26:159-165.

Mammalian lignans, enterolactone and enterodiol, are similar in structure to estradiol and diethylstilbesterol, and it is thought that this similarity is how they affect the course of hormone-related cancers. Flaxseed has 75-800 times more mammalian lignan precursors than do other plant foods. After exposure to a mammary cancer-causing carcininogen, rats were fed a diet that consisted of a 5-10% inclusion of secoisolariciresinol diglycoside (SD), a mammalian lignan precursor isolated from flaxseed. Compared with control animals, these rats had significantly smaller tumors when the SD was given at the promotional stage of tumorigenesis and a significantly decreased incidence of tumors when it was given at the initiation stage. The possible mechanisms for these effects are as follows: 1) lignans bind to estrogen receptors and reduce estrogen-induced tumor growth; 2) in both rats and humans, enterolactone and enterodiol can bind to a-fetoprotein, a protein that affects tumor growth; 3) mammalian lignans inhibit aromatase (an enzyme involved in the formation of estrone from androgens) as well as other enzymes that are involved in cell proliferation; 4) these lignans inhibit vascular endothelial cell proliferation and angiogenesis; and 5) some have antioxidative properties.
Thompson LU et al. Antitumorigenic effect of a mammalian lignan precursor from flaxseed. Nutr Cancer 1996;26:159-165.

Premenopausal women with comparatively high levels of insulin-like growth factor (IGF) are likelier than other premenopausal women to develop breast cancer. IGF mediates the actions of estrogen in breast cancer cell lines, and can stimulate the estrogen signaling pathway in the absence of estrogen. Insulin-like growth factor (IGF) increases cell proliferation by protecting tumor and normal cells from apoptosis; it is also highly mitogenic, and is required for several cell types for tumorigenesis. Retinoids inhibit proliferation of breast cancer cells by inhibiting IGF-stimulated growth, and tamoxifen and a synthetic retinoid, fenretinide, used together had a synergistic effect in animals.
Decensi A et al. Chemoprevention of breast cancer: the Italian experience. J Cell Biochem Suppl 2000;34:84-96.

High levels of insulin-like growth factor-1 (IGF-1) were associated with an increased risk of breast cancer in Chinese women, as had been seen in previous studies involving Caucasian women. In laboratory studies, IGF-1 has demonstrated strong mitogenic and antiapoptotic effects on breast cancer cells and acts synergistically with estrogen to stimulate breast cancer growth. High intakes of protein or calories have been shown to increase IGF-1, although the relationship has not been seen in epidemiological studies.
Yu H et al. Insulin-like growth factors and breast cancer risk in Chinese women. Cancer Epidemiol Biomarkers Prev 2002;11:705-712.

There are several metabolites of estrogen, some carcinogenic and others not. One, 16a-hydroxyestrone promotes breast tumor growth, whereas 2-hydroxyestrogen seems not to. Women with a low 2-hydroxyestrogen:16a-hydroxyestrone (2/16a) ratio have a higher risk of breast cancer. Vegetarians have an increased 2/16a ratio, as do other women with a low-fat, high-fiber diet. Vegetarians also have lower ß-glucoronidase activity than omnivores, and a diet high in soluble fiber may also decrease levels of this enzyme. When soluble fiber ferments in the gut, the number of bacteria present increases and the metabolism of fats to short-chain fatty acids is facilitated, resulting in a lower pH and decreased activity of ß-glucoronidase.
Fowke JH et al. Macronutrient intake and estrogen metabolism in healthy postmenopausal women. Breast Cancer Res Treat 2001;65:1-10.

Melatonin is a strong antioxidant; it also directly inhibits an estrogen-responsive breast cancer cell line by a mechanism that is reversed when estradiol is added to the culture. Melatonin augments sensitivity to tamoxifen in one breast cancer cell line, making tamoxifen up to 100 times more effective at inhibiting the cells’ proliferation.
Low Dog T et al. Traditional and alternative therapies for breast cancer. Alt Ther 2001;7:36-47.
 
Soy decreases levels of ovarian hormones in premenopausal women, which may explain the reduced risk of breast cancer in women who consume diets high in soy.
Lu L-JW et al. Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. Cancer Res 2000;60:4112-4121.

In postmenopausal women, a high-fat, low-fiber diet combined with aerobic exercise produced significant increases in levels of sex hormone binding globulin and significant decreases in insulin levels, regardless of whether the women were taking hormone replacement therapy. The authors hypothesize that a low-fat, high-fiber diet plus an exercise program may reduce breast cancer risk because increasing sex hormone binding globulin reduces the amount of estradiol that is available to act on breast tissue.
Tymchuk CN et al. Changes in sex hormone-binding globulin, insulin, and serum lipids in postmenopausal women on a low-fat, high-fiber diet combined with exercise. Nutr Cancer 2000;38:158-162.

A combination of curcumin and isoflavonoids inhibits pesticide-induced growth in both estrogen receptor-positive and estrogen receptor-negative breast cancer cell lines. Curcumin also enhances the ability of tamoxifen to inhibit growth in an estrogen receptor-positive cell line exposed to an estrogenic environmental compound.
Verma SP et al. The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids. Environ Health Perspect 1998;106:807-812.

Anti-tumor therapies

Chalcones, precursors of flavonoids, are abundant in plant foods. They have antimitotic activity in vitro against tumor cells, and some are better able to inhibit growth and induce apoptosis in cancer cell lines than is the flavonol quercitin. Studies have indicated that some chalcone analogues are toxic to tumor cells but not to normal cells.
Quercitin may act synergistically with chemotherapy agents both in vitro and in vivo.
De Vincenzo R et al. In vitro evaluation of newly developed chalcone analogues in human cancer cells. Cancer Chemother Pharmacol 2000;46:305-312.

Heat shock proteins, which are involved in protein synthesis, folding, assembly, and degradation, protect normal cells from protein damage; in breast cancer cells they are linked to drug resistance, invasion, and metastasis. Quercetin has been studied as a possible sensitizing agent in chemotherapy because it inhibits expression of heat shock protein. In breast cancer cells its action is apparently to regulate the initiation of heat shock protein transcription; in other cells, it works by other mechanisms.
Hansen RK et al. Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Biochem Biophys Res Commun 1997;239:851-856.

Some compounds can affect carcinogenesis in its late stages. These include retinoids (in the skin), monoterpenes (in carcinogen-induced breast tumors), and inhibitors of the arachidonic acid cascade (including nonsteroidal anti-inflammatory agents).
Wattenberg LW. What are the critical attributes for cancer chemopreventive agents? Ann NY Acad Sci [no other data given]73-81.

Berberine downregulates expression of an oncogene, c-ki-ras 2, possibly indicating that it can inhibit proliferation of human cancer cells caused by carcinogens; potentiates the activity of cyclophosphamide and radiation in animals; and has been shown to induce apoptosis. In mice, oral administration of berberine hydrochloride for 5 days before and three times a week for 8 weeks after injection with a carcinogen decreased liver tumor incidence in a dose dependent manner.
Anis KV et al. Inhibition of chemical carcinogenesis by berberine in rats and mice. J Pharm Pharmacol 2001;53:763-768.
 
Green tea extract inhibits breast cancer cell and endothelial cell proliferation and breast cancer angiogenesis in vitro. Epigallocatechin-3 gallate (EGCG), a component of green tea, inhibits secretion of vascular endothelial growth factor and other angiogenic compounds, as well as tumor necrosis factor-a gene expression and production of interleukin-8, in vitro.
Sartippour MR et al. Green tea inhibits vascular endothelial growth factor (VEGF) induction in human breast cancer cells. J Nutr 2002;132:2307-2311.

European mistletoe (Viscum album loranthaceae) is an effective immunoadjuvant and has antitumor effects. These actions are mediated by natural killer cells, lymphokine-activated killer cells, and macrophages. European mistletoe preparations have direct cytotoxic activity against tumor cells in culture, and Korean mistletoe (Viscum album coloratum) is more cytotoxic to at least one line of tumor cells than is European mistletoe. Natural immunity, involving the immune cells listed above, is critical to immunosurveillance and helps reduce primary tumor metastasis.
The authors hypothesize that because European mistletoe’s effects have already been demonstrated to increase natural killer cell activity and help suppress tumors, Korean mistletoe might have similar effects. In their study, intravenous administration of Korean mistletoe extract to mice before they received injections of lung or colon tumor cells prolonged lifespan, increased the effectiveness of the animals’ defense system against tumors, and had an inhibitory effect on tumor metastasis.
Yoon TJ et al. Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity. Int J Immunopharmacol 1998;20:163-172.

Silymarin has strong anticarcinogenic effects in epithelial cell cancer lines. Its inhibition of cell growth and proliferation, demonstrated in a breast cancer cell line, may be due to increased expression of a cyclin-dependent kinase inhibitor, which in turn arrests cell cycle progression.
Zi X et al. Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. Clin Cancer Res 1998;4:1055-1064.

In vitro treatment of prostate and breast cancer cell lines with silymarin led to decreased intracellular growth and survival signaling, inducing apoptosis dose dependently. It also produced a dose-dependent decrease in secretion of vascular endothelial growth factor, a primary angiogenic cytokine. By these two mechanisms, silymarin has an antiangiogenic effect on cancer cells in vitro.
Jiang C et al. Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun 2000;276:371-378.

Many natural and synthetic compounds prevent cancer by suppressing, slowing, or reversing carcinogenesis, and are therefore referred to as chemopreventive agents. They act in two main ways: as blocking agents and as suppressing agents. Blocking agents inhibit the formation of carcinogens from procarcinogens or reactive metabolites, or prevent the interaction of carcinogens with RNA, DNA, or target proteins. Suppressing agents inhibit the expression of cells in which initiation has already taken place. Use of these latter compounds is probably a more effective and more practical strategy for cancer prevention, because of the number of initiators in the environment; blocking the formation of every possible carcinogen is not feasible. However, some chemopreventive compounds are both blocking and suppressing agents. Among these are several phenolic substances, including the following:
Capsaicin, from chili pepper, affects cytochrome P450 activity and thus modulates the metabolism of carcinogens and xenobiotics. It also has anti-inflammatory effects and inhibits platelet aggregation by interfering with phospholipase A2. In one study, capsaicin stopped the growth of different human cancer cells, including mammary adenocarcinoma cells. This was associated with the induction of apoptosis.
Ginger contains [6]-gingerol, which has antioxidant activity. This compound also inhibits arachidonic acid-induced platelet aggregation and formation of thromboxane B2 and prostaglandin D2. Tumor promotion is strongly associated with inflammation and oxidative stress; [6]-gingerol’s antitumor effects may well be due to its inhibition of these two processes.
Curcumin is also an anti-inflammatory and an antioxidant. It inhibits the mutagenicity of some carcinogens as well as their binding to DNA, inhibits tumor promotion, and has been shown to suppress mucosal cyclooxygenase and lipoxygenase activity in the colon. Curcumin interferes with enzymes involved in signal transduction pathways that are critical for cell growth and proliferation, has antiproliferative activity, and has been seen to induce apoptosis in cancer cells.
Resveratrol, a compound found in grapes, is a potent antioxidant and anti-inflammatory agent; inhibits processes associated with tumor initiation, promotion, and progression; induces phase 2 detoxification enzymes; and has been shown to inhibit the proliferation of human breast epithelial cells in culture. Resveratrol may inhibit the cyclooxygenase enzyme, thus suppressing prostaglandin synthesis.
Consumption of epigallocatechin gallate (EGCG), an antioxidant compound in green tea that has both antimutagenic and anticarcinogenic effects, is associated with a decreased occurrence of several cancers. It scavenges hydroxyl radicals, blocks production of reactive oxygen species, and prevents oxidation of LDL. EGCG induces apoptosis and is reported to have potent antimetastatic ability. It also has chemopreventive effects at the promotion phase of carcinogenesis.
Surh Y-J. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 1999;428:305-327.

Soybeans and soybean buds (hypocotyls) inhibit tumor promotion, an effect apparently due to their isoflavone content. Rats who had been consuming a diet containing soy and/or roast hypocotyls, and who continued to consume this diet after administration of two doses of a mammary carcinogen, developed fewer tumors than did controls. The tumors that did develop in these rats developed later than in the control group.
Zaizen Y et al. Antitumor effects of soybean hypocotyls and soybeans on the mammary tumor induction by N-methyl-n-nitrosurea in F344 rats. Anticancer Res 2000;20:1439-1444.

Mandrake, bloodroot, juniper, and mistletoe strongly inhibited cell proliferation in both estrogen receptor-positive and -negative breast cancer cell lines.
Zava DT et al. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med 1998;217:369-378.

Silymarin has strong anticarcinogenic effects in epithelial cell cancer lines. Its inhibition of cell growth and proliferation, demonstrated in a breast cancer cell line, may be due to increased expression of a cyclin-dependent kinase inhibitor, which in turn arrests cell cycle progression.
Zi X et al. Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. Clin Cancer Res 1998;4:1055-1064.

D-Limonene, a monoterpene found in some foods and volatile oils, especially in citrus oils, has chemopreventive and therapeutic actions in animals, and very low toxicity. The authors cite a study in which rats with mammary tumors were fed a 10% D-limonene diet; 80% of tumors regressed, most completely, and there was very low toxicity. Oral administration of D-limonene to 32 patients with advanced nonhematologic tumors, at dosages ranging from 0.5 g/m2 to 12 g/m2, caused gastrointestinal side effects in some patients taking more than 8 g/m2 per day, but toxicity was reversible. One patient (taking 8 g/m2 per day) experienced a partial response, which lasted for 11 months; tumor progression was halted in several other patients for several months. A major finding of the study was that D-limonene has very low toxicity.
Vigushin DM et al. Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Chemother Pharmacol 1998;42:111-117.

The polyphenols in red wine—mostly catechin, epicatechin, quercitin, and resveratrol but including many others—are synthesized through a common pathway through phenylalanine. Catechin, quercitin, and resveratrol in particular have effects in addition to their antioxidant activity: they promote the vascular endothelium’s production of nitric oxide, inhibit thromboxane synthesis in platelets and leukotriene synthesis in neutrophils, stop tumor growth, and inhibit carcinogenesis. Resveratrol, and perhaps others of these wine polyphenols, may have antiestrogenic activity; in addition, studies have indicated that reveratrol has antiproliferative and chemopreventive effects in both estrogen receptor–positive and –negative cells.
Damianaki A et al. Potent inhibitory action of red wine polyphenols on human breast cancer cells. J Cell Biochem 2000;78:429-441.

In one study, increasing doses of melatonin were associated with decreasing numbers of tumors in mice bred to develop breast cancer. Melatonin and flaxseed oil in combination significantly decreased levels of IGF-1, but did not delay tumor development or reduce tumor size any more than did melatonin alone. Melatonin may slow down tumor growth by inhibiting prolactin production, linoleic acid uptake (thus decreasing its availability for synthesis of a mitogenic signaling molecule, 13-hydroxyoctadecadienoic acid), and enhances the activity of other antioxidants.
Rao NR et al. Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene. Breast Cancer Res Treat 2000;64:287-296.

Intestinal integrity and reduction of side effects during conventional treatment

Cachexia

Of cancer patients given supportive care plus melatonin (20 mg/day in the evening), only 4% had an incidence of >10% weight loss over 3 months; of those given supportive care only, 32% had this degree of weight loss. The authors of this study suggest that these results may be due to the decrease in tumor necrosis factor-alpha levels that was associated with melatonin supplementation. No toxicity of melatonin was observed; in fact, in patients taking melatonin, signs and symptoms of cancer-related respiratory distress improved over the course of the study.
Lissoni P et al. Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer 1996;32A:1340-1343.

A mixture of beta-hydroxy-beta-methylbutyrate (3 g/day), L-arginine (14 g/day), and L-glutamine (14 g/day) was administered to patients with solid tumors and a weight loss of at least 5%; control patients received an isonitrogenous mixture of nonessential amino acids. Over 4 weeks, patients receiving the HMB/arginine/glutamine supplement gained weight (an average of 0.95 kg) and fat-free body mass (1.12 kg) and patients receiving the nonessential amino acid mixture lost weight (0.26 kg) and fat-free body mass (1.34 kg). The gain in fat-free body mass in the study group was sustained over time, being 1.60 kg over 24 weeks.
May PE et al. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg 2002;183:471-479.