Natural Agents in the Prevention of Cancer,

Part Two: Preclinical Data and

Chemoprevention for Common Cancers
Davis W. Lamson, MS, ND
and Matthew S. Brignall, ND

Abstract
This paper is the second of a series examining the use of nutritional supplements as
chemopreventive agents. The animal and in vitro data are reviewed in support of their
use. Human safety data and mechanisms of action are described as well. Many over-
the-counter dietary supplements have been shown to have significant chemopreventive
activity in preclinical studies. Few side effects are associated with even long-term use
of these agents. Along with dietary and lifestyle risk-reducing strategies, nutritional
supplementation appears to be a viable intervention for those considered to be at high
risk of developing cancer.
(Altern Med Rev 2001;6(2):167-187)

Introduction
This paper is the second of a series examining the use of nutritional supplements as
chemopreventive agents. The first paper in the series examined the data from human
chemoprevention trials.1 In the present paper the mechanisms of action of promising treatments
will be discussed. In vitro and animal data are presented in support of the agents as appropriate.
The subject of chemoprevention with nutritional agents has been the subject of voluminous
research, and this review should not be considered exhaustive. In cases where review articles
already exist regarding a particular agent (e.g., vitamin A, beta-carotene), these papers should
be consulted for a more complete summary.
The data presented in this review will focus on three common tumor types: breast, pros-
tate, and colon cancers. While data are available regarding prevention of other tumor types, it is
not as extensive as the data covered in this paper. It is the opinion of the authors that agents with
a clear record of safety in human studies, evidence of chemoprevention in animal studies, and
well-understood mechanisms of action, should be considered for clinical use pending results of
large human trials.

Davis W. Lamson, MS, ND – Coordinator of Oncology, Bastyr University, Kenmore, WA. Private practice, Tahoma Clinic,
Kent, WA. Product consultant, Thorne Research. Correspondence address: 9803 17th Ave NE, Seattle, WA 98115.
E-mail: davisl@seanet.com

Matthew S. Brignall, ND – Practicing with Seattle Cancer Treatment and Wellness Center; Evergreen Integrative Medicine,
Kirkland, WA; Cascade Cancer Center, Kirkland, WA. Product consultant, Thorne Research.
E-mail: mattandmolly@home.com

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 Vitamin A Although the preclinical data have
Vitamin A is obtained from the diet in been promising, human studies using vitamin
the form of retinyl esters, which are subse- A or retinoids as chemopreventive agents have
quently de-esterified to retinol. Retinol is then been largely disappointing.1 It appears likely
irreversibly oxidized to become retinoic acid. from the epidemiological data that the protec-
Retinoic acid is the form of vitamin A that tive effect of retinoids is limited to those who
binds with nuclear receptor sites and is neces- are deficient in dietary vitamin A. It is also
sary for the normal growth and differentiation possible that the effect is limited to particular
of epithelial tissue.2 The effects of vitamin A clinical situations (e.g., bladder cancer, pre-
on cellular differentiation are mediated by two menopausal breast cancer).
separate classes of nuclear receptors, which
in turn modify the effects of many compounds, Carotenoids
including prostaglandins, vitamin D, and ste- Carotenoids are a family of conjugated
roid and thyroid hormones.3 Many studies have polyene molecules found largely in fruits and
examined the effects of isomers of vitamin A, vegetables. Carotenoids are antioxidant, and
including all-trans retinoic acid, 9-cis retinoic certain carotenoids can serve as precursors to
acid, and 13-cis retinoic acid. These isomers retinol in humans. Of the more than 600 caro-
are all considered to be interconverted in hu- tenoids, beta carotene and lycopene have gen-
mans, and may be less hepatotoxic than ret- erated the most attention in the
inol. chemoprevention field.
Animal research has demonstrated a As discussed in the first paper in this
chemopreventive effect of retinoids in many series,1 beta carotene has been extensively
types of cancer, including mammary cancer studied in human trials as a chemopreventive
and colon cancer models.4,5 In vitro research agent. In contrast to the human data, which
has identified a number of promising mecha- have largely found beta carotene supplemen-
nisms of action, including decreasing serum tation to be associated with either no change
insulin-like growth factor-1, inhibition of 5- or an increase in cancer risk, epidemiological
alpha-reductase (the enzyme that catalyzes evidence has very strongly associated beta
formation of dihydrotestosterone), and up- carotene intake with reduction in the risk of
regulation of transforming growth factor-beta.4 cancer of many different types. 8 Several
Epidemiological studies on the cancer schools of thought exist regarding the discrep-
preventive activity of dietary vitamin A have ancy between epidemiology and human ex-
been inconclusive, perhaps because of perimental data.
confounding factors. Vitamin A is only present The first is that the human studies that
in animal foods, and thus dietary vitamin A used synthetic beta carotene may not have used
intake may be a marker for a high meat diet, a the right nutrient mixture for
risk factor for many cancers. Prospective trials chemoprevention.9 Animal10 and preliminary
have shown a very modest reduction in breast human research11 have shown mixed carotenes
cancer risk in women with the highest intakes have a better chemopreventive action than syn-
of dietary vitamin A. 6 One prospective thetic beta carotene. Secondly, it has been theo-
epidemiological trial concluded that people rized that beta carotene may have a pro-oxi-
taking supplemental vitamin A had a reduced dant effect in vivo,12 an effect that could po-
risk of developing breast cancer only if they tentially be carcinogenic. These two theories
were in the lowest third of dietary vitamin A are not mutually exclusive, and it is possible
intake.7 both are true to some extent.

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 Cancer
In vitro and animal studies have dem- greatest in those with significant deficiencies,
onstrated a number of mechanisms by which such as in patients taking sulfasalazine (a drug
beta carotene can inhibit carcinogenesis, in- that depletes folate) for ulcerative colitis.26
cluding antioxidant activity, vitamin A precur- Data from the Nurses’ Health Study indicate
sor status, enhancement of gap junction com- folic acid may at least partially offset the
munication, an immunological effect, and in- increased breast cancer risk associated with
duction of hepatic detoxification of carcino- consumption of alcohol. 27 Human
gens.13 chemoprevention trials using folic acid have
Epidemiological studies have corre- been performed and were discussed in the first
lated both high intake14 and high serum con- paper in this series.1
centrations15 of lycopene with reduced risk of
prostate cancer. High adipose concentrations Vitamin B6
of lycopene have been associated with a re- Increased likelihood of recurrence of
duced risk of breast cancer.16 Lycopene has breast cancer after mastectomy has been cor-
been shown to inhibit cancer cell growth in related in preliminary studies with both poor
vitro, including prostate,17 breast,18 and lung18 metabolism of a loading dose of L-tryptophan
cancer cell lines. Animal studies have shown (indicating a functional deficiency of vitamin
lycopene inhibited development of mammary19 B6),28 and low urinary concentration of 4-py-
and colon20 tumors. ridoxic acid, a major metabolite of vitamin
Lycopene’s mechanisms of action are B6.29 Dietary intake of vitamin B6 was found
somewhat obscure. A human crossover trial not to correlate at all with the risk of breast
found that consumption of tomatoes contain- cancer in a prospective study, however.30
ing 16.5 mg of lycopene for 21 days led to a Elevated levels of prolactin have been
33-percent reduction in the amount of lympho- implicated in the pathophysiology of both
cyte DNA damage sustained after exposure to breast31 and prostate32 cancers. Although B6
hydrogen peroxide ex vivo.21 Lycopene has has been reported to suppress production of
been shown to reduce the growth-stimulating prolactin,33 some studies have failed to find this
effect of insulin-like growth factor on human effect.34,35
breast cancer cells.22
Vitamin B12
Folic Acid Like folic acid, deficiency of vitamin
Expression of genes is controlled in B12 can lead to hypomethylation of DNA.24
part by DNA methylation. Hypomethylation A role for vitamin B12 in the process of car-
in the presence of folic acid deficiency has cinogenesis has been theorized since 1954,
been theorized to be one of the mechanisms when abnormal cell types were found in the
by which cancer development can be encour- stomach lining of patients with pernicious ane-
aged. 23 Both low folate status and DNA mia.36 Women in the lowest quartile of serum
hypomethylation have been directly observed vitamin B12 have been found to be at increased
in squamous cell lung cancer tissue compared risk of developing breast cancer in a prospec-
to uninvolved bronchial mucosa from the same tive, epidemiological study.30 High mean cor-
patients.24 puscular volume (MCV), which is often a sign
Epidemiological studies have shown of either vitamin B12 or folate deficiency, has
low folate status to correlate with increased been found to be predictive for a risk of
risk of cancers of the cervix, lung, esophagus, colorectal polyps in men.37 Vitamin B12 treat-
brain, pancreas, breast, and especially the ment, together with folic acid, has been shown
colon.25 The benefits of folic acid may be to reverse a precancerous condition of the lung

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 called squamous metaplasia1,38 but has not been months led to a significant reduction in polyp
used in primary prevention trials to date. area in patients with polyposis coli compared
to placebo.46 In a later trial, supplementation
Vitamin C with 30,000 IU vitamin A palmitate, 70 mg
Since vitamin C is a potent water- d,l-alpha-tocopherol, and 1 g vitamin C per
soluble antioxidant, it has generated interest day for six months led to a statistically
as a potential cancer preventive compound. significant reduction in abnormal cell
Vitamin C is necessary for the recycling of proliferation in patients with colorectal
glutathione, another endogenous antioxidant.39 adenomas.47 Also, supplementation with 4 g/
It has been theorized to protect against the day vitamin C for four years, in addition to
ability of cancer cells to invade tissue, in part vitamin E (400 IU) and a fiber supplement (22
by strengthening the cellular matrix.40 Vitamin g/day) was associated with a reduction in
C is directly cytotoxic to certain cancer cell polyps in patients with familial polyposis.48 In
lines in vitro. This toxicity can be reversed by the negative trial, supplementation with 1 g/
the addition of the enzyme catalase into the day vitamin C with 400 mg vitamin E for four
medium, suggesting that the cell-killing effect years was not associated with reduced risk of
of vitamin C is due to a production of hydro- recurrent colonic adenoma.49 While the data
gen peroxide within the cell.41 For most can- are not unanimous, evidence exists to support
cers, however, the only information available the possibility that oral vitamin C can help
regarding the chemopreventive activity of vi- reduce the area, proliferation, and recurrence
tamin C is epidemiological research. of precancerous colon lesions.
Retrospective dietary data show that
each 300 mg of dietary vitamin C intake is Vitamin D
associated with a roughly 30-percent decrease Vitamin D is a molecule with hormonal
in breast cancer risk.42 But when the same re- activity that is best known for its effects on
search group analyzed prospective dietary calcium metabolism. The metabolism and
studies (those that did dietary analysis before safety of vitamin D has been recently re-
the breast cancer diagnosis), no association viewed,50 with the conclusion that supplemen-
between dietary vitamin C and breast cancer tation with vitamin D is likely to be safe up to
risk was noted. Another prospective trial found levels approaching 10,000 IU/day. In addition
no relationship between plasma levels of ascor- to its role in calcium metabolism, vitamin D
bate and risk of breast cancer in the subsequent appears to be important in regulation of cellu-
five years.43 lar growth and differentiation. Vitamin D has
Similar to breast cancer, no consistent been shown to cause G1 cell cycle arrest in
relationship has emerged from epidemiologi- prostate cancer cells, mediated through direct
cal studies between dietary vitamin C intake effects on p21, p27, and E-cadherin.51 Cells
and prostate cancer risk.44 In one study, sub- expressing vitamin D receptors have been
jects taking vitamin C supplements of any dose found in human tumor lines, including breast,52
were found to have a 23-percent decreased risk prostate,53 and colon.54 Vitamin D has been
of developing prostate cancer (p > 0.05).45 shown to reduce tumor secretion of type IV
Three of four intervention trials have collagenases,55 and thus to reduce the number
found a significant benefit from vitamin C of metastases in an animal study.56
supplementation, often along with other Epidemiology has long suggested a
interventions, in the treatment of colon polyp role for suboptimal vitamin D levels in the risk
patients. In the first of these trials, of common tumor types. Exposure to low
administration of 3 g/day of vitamin C for nine levels of UV light from the sun is thought to

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 Cancer
account for about six percent of the U. S. Health Study63 and the Physician’s Health
variation in prostate cancer mortality.57 Low Study II64 are ongoing clinical trials with large
prediagnostic serum levels of vitamin D have patient populations following up on the prom-
been correlated with increased risk of poorly ising results of the preliminary vitamin E
differentiated prostate tumors.58 Women with chemoprevention trials.
breast tumors that express vitamin D receptors The subject of vitamin E in cancer pre-
(over 80 percent of tumors) were found to have vention has been reviewed previously.65,66
a significantly longer disease-free survival than These reviews discuss the extensive animal and
women whose cancers did not express this in vitro research in support of vitamin E in
receptor.52 cancer prevention. Several mechanisms of vi-
Vitamin D has been shown to reduce tamin E are considered important in this re-
the proliferation of many tumor cell lines in gard, including stimulation of wild-type p53
vitro, including breast,52 prostate,53 and colon.54 tumor suppressor gene, down-regulation of
Treatment of animals with synthetic vitamin mutant p53, activation of heat shock proteins,
D analogues has been shown to inhibit me- and an antiangiogenic effect mediated by
tastasis and prolong survival time in breast blockage of transforming growth factor-alpha
cancer models.59 Vitamin D has been shown (TGF-α).65
to inhibit the development of colon tumors in
animals, an effect the authors attributed par- Selenium
tially to angiogenesis inhibition.60 Treatment Administration of 200 mcg selenium
of men having recurrent prostate cancer with from yeast has been shown to reduce the inci-
between 0.5 and 2.5 mcg of oral calcitriol at dence of several types of cancers in a human
bedtime (hypercalcemia was the dose-limit- trial.1,67 These data from the intervention trial
ing side effect) caused a significant slowing confirm prior epidemiological studies that have
of the rate of prostate specific antigen (PSA) often shown low selenium status to be associ-
increase compared to pretreatment levels in six ated with increased total cancer incidence.68,69
of seven patients.61 In the seventh patient, a In these studies, the inverse association be-
non-significant trend toward reduction in the tween selenium and gastrointestinal, prostate,
rate of PSA elevation was noted. In another and lung cancers appears to be particularly
preliminary study, 44 percent of patients with strong. The relationship between selenium sta-
hormone-refractory advanced prostate cancer tus and breast cancer risk is less well-defined,
and bone metastases were found to have low with a large geographical study showing clear
serum concentrations of vitamin D.62 In this inverse correlation in risk,70 but a prospective
trial, supplementation with 2000 IU vitamin trial showing no significant relationship be-
D2 was associated with reduced bone pain and tween toenail selenium levels and breast can-
improved quality of life from baseline. cer risk.71 Animal studies using a variety of
different tumorigenesis models have largely
Vitamin E found selenium to have significant
Several human intervention trials have chemopreventive activity.72
examined the ability of vitamin E to prevent Although there are several proposed
carcinogenesis. Vitamin E, often as part of a mechanisms of action for selenium, including
larger nutritional protocol, has been found to induction of glutathione peroxidase, modula-
significantly reduce incidence of prostate, tion of cytochrome p450 systems, and immune
bladder, and stomach cancers, as well as to modulation, 73 the most important
prevent recurrence of colonic adenomas in mechanism(s) probably remain elusive. Simi-
some, but not all studies.1 Both the Women’s larly, the most effective form of selenium

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 Table 1: Nutrients in the Chemoprevention of Cancer

Nutrient Proposed Mechanisms

Vitamin A Inhibition of insulin-like growth factor-1;

inhibition of 5-alpha-reductase;
upregulation of transforming growth
factor-beta.

Antioxidant; vitamin A precursor;

Carotenoids: enhanced gap junction communication;
Beta Carotene induction of hepatic detoxification of
carcinogens

Carotenoids: Protect DNA from H2O2-induced

Lycopene damage; decrease growth-stimulating
effect of insulin-like growth factor

Folic Acid DNA methylation for normal gene

expression

Vitamin B12 DNA methylation for normal gene

expression

Antioxidant necessary for the recycling

Vitamin C of glutathione; strengthening the
cellular matrix preventing metastases;
directly cytotoxic to certain cell lines in
vitro, possibly due to production of
hydrogen peroxide within the cell.

Important in cellular growth and

Vitamin D differentiation; G1 cell cycle arrest;
reduce tumor secretion of type IV
collagenases (reducing metastases)

Stimulation of wild-type p53 tumor

Vitamin E suppressor gene; antiangiogenesis;
down regulation of mutant p53

supplementation has not been definitively acid conjugates (e.g., selenocysteine,

demonstrated. While the majority of the ani- methylselenocysteine), and 40-percent uniden-
mal chemoprevention studies have used inor- tified selenopeptides.74 In one animal study,
ganic selenium, the most successful human co-administration of vitamin C nullified the
trial used organic selenium from yeast. Yeast- chemopreventive effect of inorganic selenium
based selenium is approximately 40-percent (selenite), but not that of selenomethionine.75
selenomethionine, 20-percent other amino

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 Cancer
Calcium mammary cancers in an animal study.86 Serum
A human intervention trial found that zinc concentrations have been found to be
supplementation with 1200 mg calcium car- mildly reduced in patients with breast cancer
bonate per day led to a significant reduction and slightly elevated in patients with colon
in colonic adenoma recurrence risk.76 Both cancer compared with healthy controls.87 An-
men and women with high dietary intakes of other study found a strong positive correlation
calcium have been found to have a lower risk between high serum zinc concentrations and
of developing colon cancer.77 Calcium has been breast cancer.88
found to protect against colon carcinogenesis
in animal models as well. 78 Although the Table 1 summarizes the cancer preven-
mechanism by which calcium appears to pro- tive potential of vitamins and minerals.
tect against colon cancer formation is not en-
tirely clear, it appears calcium may precipi- Coenzyme Q10
tate toxic bile acids in the colonic lumen, thus Coenzyme Q10 (CoQ10) is a lipid-
reducing the rate of proliferation of colonic soluble antioxidant involved in the production
epithelium.79 of ATP via the electron transport chain. Tu-
High calcium concentrations in drink- mor tissue levels of this nutrient have been
ing water have been correlated with a signifi- found to be significantly lower in breast can-
cantly reduced risk of developing breast can- cers than in surrounding normal tissue.89 A
cer,80 but not prostate cancer81 in Taiwan. Ani- series of preliminary reports suggest a potent
mal studies have not yet clarified a role for treatment effect of CoQ10 in advanced breast
calcium in breast and prostate cancer preven- cancer.90,91 These reports have methodological
tion. flaws that make them difficult to interpret,
however. An unpublished human trial found
Zinc CoQ10 treatment to cause regression of pros-
The zinc concentration of cancerous tate tumors, as well.92 Colon cancer tissue con-
prostate tissue (146 mcg/g) has been found to tains significantly higher levels of CoQ10 than
be significantly lower than that of normal pros- surrounding tissues, for reasons that are un-
tate tissue (1018 mcg/g) and BPH prostate tis- clear.93 Future animal and human studies will
sue (1142 mcg/g).82 Whether this finding is a need to elucidate the role of CoQ10 in pre-
cause or an effect of neoplastic transforma- vention and treatment of cancers.
tion is still debated. Zinc has been found to
inhibit the growth of prostate cancer cell lines Quercetin
in vitro.83 Cell cycle arrest (G2/M) was noted Quercetin is a flavonoid present in
in lines that had mutated or wild-type (nor- many foods of plant origin. The anticancer
mal) p53 tumor suppressor gene. Men who mechanisms of quercetin have been reviewed
take supplemental zinc were found to have a in a recent issue of this journal.94 Quercetin
borderline-significant 45-percent reduction in has been shown to have a preventive effect in
prostate cancer risk in a case-control study.84 a number of different animal tumor models,
Zinc inhibits the activity of prostatic 5-alpha- including oral cancer,95 fibrosarcoma,96 skin,97
reductase and may inhibit prostatic uptake of mammary,98 and multi-organ tumorigenesis.99
the potential carcinogen cadmium.85 Colon cancer models have yielded conflicting
Diets containing high concentrations results, with studies that show decreased
of zinc, with or without high levels of copper, risk,100 no change,101 or even increased risk.102
were found to be ineffective in preventing Quercetin was found to be superior to

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 tamoxifen in vitro as a growth inhibitor of the cell culture study found a synergism in effect
estrogen-receptor negative MCF-7 breast can- on cellular differentiation between curcumin
cer cell line.103 and either the active form of vitamin D or all-
Although early research on quercetin trans retinoic acid, although curcumin alone
showed a minimal absorption of the com- had no significant effect.109 Curcumin also
pound, newer research has refuted these find- shows synergy with genistein in its ability to
ings.94 Quercetin chalcone has been proposed reduce the proliferative effect of estrogenic
as a more absorbable form of quercetin due to pesticides on estrogen-receptor positive breast
its increased water solubility, but has not un- cancer cells.110
dergone human trials to demonstrate this abil- Rats eating a diet containing 2000 ppm
ity. Quercetin chalcone administration has curcumin developed colon tumors at a signifi-
been shown to slow the growth of human co- cantly reduced rate compared to controls.111
lon tumors transplanted into mice.104 Curcumin’s tumor inhibiting effect is similar

Figure 1: Curcumin

CH3O OCH3

HO CH CHCOCH2COCH CH OH

to many of the NSAIDs, including aspirin,

Curcumin ibuprofen, and indomethacin.112 A diet contain-
Curcumin (Figure 1), a compound ing two-percent curcumin by weight reduced
found in turmeric (Curcuma longa), has a num- the percentage of animals developing colon
ber of potential cancer-preventing mechanisms cancers from 40 percent to zero.109 Adminis-
of action. The first is its inhibitory effect on tration of curcumin blocked the induction of
the proinflammatory enzymes cyclooxygenase mammary carcinogenesis by radiation.113
and lipoxygenase.105 A study found the anti- Curcumin has also been found to inhibit
inflammatory efficacy of curcumin to be su- chemically-induced mammary cancers in
perior to indomethacin. Curcumin has also some,114 but not all115 studies. The effect of
been found to induce G2/M phase cell cycle curcumin on prostate carcinogenesis has not
arrest in human colon cancer cells indepen- been evaluated in animal studies.
dently of its control of prostaglandin synthe-
sis.106 Preliminary animal evidence suggests Green Tea
curcumin may have effects on the ability of The catechins contained in green tea,
carcinogens to form DNA adducts107 and on which make up about 30 percent of the dry
cytochrome p450 metabolism,108 but the im- weight of tea leaves, have several anticancer
portance of these mechanisms is not clear. One activities. The catechins are oxidized in the

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 Cancer
manufacture of black tea, and thus black tea than women drinking four cups or less.127 No
would not be expected to have similar actions. influence on prognosis was noted in women
One of the main catechins in tea is with stage III breast cancer, however. A study
epigallocatechin gallate (EGCG), and many of 8,000 Japanese adults found those with the
studies have focused specifically on its actions. highest consumption of green tea had a re-
EGCG has been shown to induce G2/M cell duced total cancer risk, particularly in
cycle arrest and to block the tumor-promoting women.128
activities of epidermal growth factor and NF-
kappaB in vitro.116 In a human study, 10 of 14 N-Acetylcysteine
subjects drinking up to 1.8 grams of dissolved N-acetylcysteine (NAC), a thiol-con-
green tea solids had a greater than 50-percent taining amino acid derivative, is a precursor
reduction in rectal concentrations of PGE2, a to glutathione synthesis. Due to its relative lack
prostaglandin associated with tumor promo- of toxicity and impressive results in preclini-
tion.117 The in vitro antimutagenic activity of cal studies, NAC has generated interest as a
green tea catechins has been demonstrated to chemopreventive agent. Human trials have
be greater than that of many antioxidants, in- shown that NAC administration is associated
cluding curcumin, vitamins C and E, querce- with reduced proliferative index of colonic
tin, glutathione, and N-acetylcysteine.118 Green mucosa in patients with a history of colon pol-
tea has been shown to inhibit release of TNF- yps,129 but not with prevention of lung cancer
α, a suspected tumor promotor and a cytokine recurrence. 130 NAC has several theorized
suspected to be involved in the pathogenesis mechanisms by which it could prevent cancer
of cachexia.119,120 Green tea polyphenols have occurrence and spread, including replenishing
been shown to inhibit glucuronidation of es- of glutathione stores,131 prevention of DNA
trogens in vitro, but to mildly stimulate this damage due to environmental exposures,132 and
metabolic pathway in vivo.121 Glucuronidation inhibition of type IV collagenase stimulation
is a major hepatic conjugation pathway by of invasion and metastasis.133
which estrogens are removed from circulation. NAC has been shown to prevent colon
Green tea catechins have been shown to in- carcinogenesis in animal studies,134 but did not
hibit the actions of 5-alpha-reductase and or- prevent mammary cancer occurrence in a rat
nithine decarboxylase, two enzymes consid- model.135 NAC has not been studied as a pre-
ered important in the development of prostate ventive agent for prostate cancers. It is sug-
cancer.122 Human studies suggest that serum gested NAC be used with caution in patients
concentrations of green tea compounds mim- undergoing chemotherapy, as some evidence
icking those used in animal cancer prevention suggests it can reduce the effectiveness of cer-
studies can be achieved by drinking approxi- tain cytotoxic drugs, including alkylating
mately five cups of green tea per day.123 agents.136
Green tea compounds have been found
to inhibit chemically-induced carcinogenesis Indole-3-Carbinol
of several sites, including mammary124 and
Indole-3-carbinol (I-3-C) is a compo-
colon125 cancer models. Injection with EGCG
nent of foods of the Brassica family (i.e., broc-
was shown to significantly inhibit the growth
coli, kale, brussels sprouts, cauliflower). Hu-
of human prostate tumors transplanted into
man studies have shown that addition of ei-
athymic mice.126 After resection of stage I or
ther 500 grams per day of broccoli or 400 mg
stage II breast tumors, Japanese women drink-
per day I-3-C to the human diet is associated
ing five cups or more of green tea per day were
with a significant increase in the urinary ratio
44-percent less likely to have tumor recurrence

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 of 2-hydroxyestrogens (2-OH):16- Inositol Hexaphosphate
hydroxyestrogens (16-OH).137 Low urinary 2- Inositol hexaphosphate (IP6) (Figure
OH:16-OH ratios have been associated with 2), also known as phytate or phytic acid, is
increased risk of breast cancer.138 I-3-C has ubiquitous in plant foods. It is present in par-
been shown to arrest the cell cycle in the G1 ticularly high concentrations in cereals and
phase and to increase expression of the p21 legumes. IP6 was first identified as an “anti-
and p27 genes.139 A major metabolite of I-3-C nutrient”— a compound able to block absorp-
has been shown to be an antagonist of estro- tion of many minerals. Once inside the cell,
gen binding in vitro.140 IP6 is dephosphorylated to a number of lower
A human dose-ranging study con- inositol phosphates (e.g., IP1-5) that play im-
cluded that 300 mg I-3-C per day is the mini- portant roles in signal transduction.154 Cell
mum dose necessary for chemoprevention.141 culture studies found IP6 to have several ben-
In this and other human studies adverse events eficial genetic effects, including down-regu-
were rare and mild. In addition to breast can- lation of mutant p53 and up-regulation of wild-
cer prevention, I-3-C has generated interest
in the prevention of cervical cancer.142 A pre-
liminary study showed indole-3-carbinol re-
versed some cases of cervical dysplasia.143
Animal studies have shown a chemopreventive Figure 2: Inositol Hexaphosphate
effect in both cervical144 and breast cancer145
models. An in vitro study showed I-3-C and
tamoxifen work by different signaling path-
ways, and thus represent a potential combi-
OPO3H2
nation treatment in estrogen receptor-positive
OPO3H2 OPO3H2
breast cancers.146
Animal studies have shown significant
chemoprevention in chemically induced tu-
mors of the colon,147 lung,148 and stomach.149
I-3-C has been shown to both inhibit150 and OPO3H2
enhance151 hepatic carcinogenesis, depending
OPO3H2
on the model used. A phase I human trial OPO3H2
showed I-3-C administration arrested or
slowed growth of respiratory papillomas (a
pre-cancerous condition) in 12 of 18 sub-
jects.152
I-3-C is an unstable molecule, and un- type p53 and p21.155 These two genes are both
dergoes oligomerization in the gut to a num- thought to be very important in the expression
ber of different compounds, including of the malignant phenotype. Ex vivo studies
diindolylmethane. Diindolylmethane itself has with human neutrophils have shown IP6 en-
been shown to be chemopreventive in animal hanced the immune response to specific stimuli
breast cancer models.153 Dose-ranging studies without direct activation of non-specific in-
have not been performed in humans with flammatory pathways.156 None of these mecha-
diindolylmethane, however. It is also not clear nisms have been confirmed by clinical trials.
whether all of the effects seen with I-3-C are
mediated by conversion to diindolylmethane.

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Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
 Cancer
In animal models IP6 prevented chemi- ratios.167 Urinary excretion of 2-OH estrone
cally-induced colon carcinogenesis.154 In these was increased by consumption of 158 mg/day
studies, doses as low as 0.1-percent IP6 in soy isoflavones for an entire menstrual cycle
drinking water had significant effect.157 Addi- in premenopausal women.168 Consumption of
tion of 15 mM IP6 and 15 mM inositol to the 154 mg/day soy isoflavones for one menstrual
drinking water of rats led to significant inhi- cycle was associated with a 25-percent
bition of chemically-induced mammary car- reduction in circulating 17-beta-estradiol
cinogenesis.158 The tumors that formed in the concentrations in premenopausal women.169
treated rats were also smaller than those in the Some research has shown, however,
control group. IP6 has been theorized to be at that soy isoflavones have an estrogenic effect
least in part responsible for the observed rela- on the normal breast. Clinical trials found con-
tionship between a high-fiber diet and reduced sumption of 45 mg isoflavones increased the
risk of breast cancer in humans.159 proliferation of normal breast tissue.170,171
Animal and in vitro studies have also Supplementation with 38 mg per day of the
shown antitumor effects of IP6 in leukemia, isoflavone genistein was found to increase the
hepatocellular carcinoma, lung cancer, pros- secretion of breast fluid in healthy pre- and
tate cancer, papilloma, and fibrosarcoma.160 postmenopausal women, a finding suggestive
Human data regarding the safety and efficacy of an estrogenic effect.172
of IP6 are scarce, and are largely limited to Preliminary in vitro studies suggest soy
epidemiology. The mineral-binding activity of may attenuate the estrogen-receptor antago-
IP6 suggests it should be given either away nist activity of tamoxifen.173 Soy has been
from meals or in a program including a multi- found to be ineffective in preventing hot
vitamin/mineral supplement. flashes in breast cancer survivors.174
Men who drank soy milk more than
Soy once per day had a 70-percent reduction in
Soybeans, and particularly the prostate cancer risk compared to non-soy milk
isoflavones contained in soy, have generated drinkers.175 Soy isoflavones have been found
interest as chemopreventive agents. Although to inhibit the growth of prostate cancer cells
no clinical trials have been completed to date, in vitro,176 and in some,177,178 but not all animal
several preclinical studies have examined the studies.179 Studies have not been performed to
effects of soy in different tumor types. Mul- demonstrate the effect of soy on the normal
tiple mechanisms of action have been demon- human prostate. Although in vitro studies show
strated, including protease inhibition,161 anti- soy isoflavones inhibited colonic cancer cell
mitotic effect,162 antiangiogenesis,163 inhibition growth, very little experimental or epidemio-
of protein tyrosine kinase activity,164 and 5-al- logical data point to a significant preventive
pha-reductase inhibition.165 The most cel- effect of soy on colon cancer.180
ebrated mechanism of action of soy, however,
is its binding at the estrogen receptor site. Soy Glucaric Acid
exhibits a biphasic effect on estrogen recep- D-glucaric acid is a chemical found in
tors, acting as an agonist at low concentrations many fruits and vegetables in amounts rang-
and an antagonist at higher levels.166 ing from 100 mg to 3 grams per kilogram.181
Soy has been found to alter estrogen After ingestion, some D-glucaric acid is con-
metabolism in both pre- and postmenopausal verted to D-glucaro-1,4-lactone (1,4-GL),
women. Consumption of 65 mg isoflavones which appears to be the active compound (Fig-
per day by postmenopausal women was found ure 3). D-glucaro-1,4-lactone inhibits beta-glu-
to increase serum 2-OH:16-OH estrone curonidase in the colonic microflora.181 This

Alternative Medicine Review ◆ Volume 6, Number 2 ◆ 2001 Page 177

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
 Figure 3: Gut Metabolism of
Glucaric Acid mechanism of action and preclinical data re-
garding glucaric acid derivatives are promis-
ing, until human safety and efficacy data are
available these compounds should be used with
Calcium D-Glucarate caution.
(Stomach)
Serenoa Repens (Saw Palmetto)
Saw palmetto is an herb that has been
Glucaric acid used to treat symptoms of benign prostatic
hyperplasia (BPH). Its efficacy has been shown
to be similar to that of finasteride, a 5-alpha-
reductase inhibitor.185 Although saw palmetto
D-glucaro-6,3-lactone extracts have 5-alpha-reductase inhibitory ac-
tivity in vitro, studies conflict regarding the in
vivo effect of the herb on dihydrotestosterone
levels.186,187 Saw palmetto has also been shown
*D-glucaro-1,4-lactone to reduce prostatic concentrations of epider-
mal growth factor181 and to inhibit the growth
* inhibits beta-glucuronidase stimulating effect of prolactin in the prostate.188
Although the mechanisms of action of
saw palmetto could plausibly reduce the risk
of prostate cancer, this effect has not been stud-
ied in clinical trials. Saw palmetto is a key
action theoretically reduces the amount of con- component of the herbal formulation PC-
jugated estrogens and other steroid hormones SPES, a Chinese herbal formula that has been
that are deconjugated in the gut and returned shown in preliminary human research to have
to circulation. It has been theorized that 1,4- activity against androgen-independent prostate
GL also has systemic activity, possibly regu- cancer.189
lating cholesterol and steroid synthesis.182
Oral administration of calcium D- Rosemary
glucarate (a calcium salt of D-glucaric acid)
Dietary treatment with one-percent
led to an inhibition of chemically induced
rosemary methanol extract inhibited mammary
mammary carcinogenesis in rats.183 Serum es-
tumor formation in rats.190 Treatment of ani-
trogen levels were 23-percent lower in rats
mals with rosemary increased 2-OH estrone,
receiving the calcium D-glucarate. The 4.5
reduced 16-OH estrone, and stimulated
mM/kg doses of calcium D-glucarate used in
glucuronidation of estrogen in the liver.191 It is
this trial were very large, however. To approxi-
not currently known, however, whether these
mate this dose in a 70 kg human, 78 grams
effects are possible to duplicate in humans
would be required.
using tolerable doses of rosemary extract.
Other animal trials found D-glucaric
acid had chemopreventive activity in colon,
lung, liver, and skin cancer models.184 The Conclusion
doses used in these studies were either 70 or Many promising preclinical studies
140 mM/kg of diet. Assuming a 2 kg per day have been performed on the efficacy of
diet in a human, this would imply an active nutritional interventions for cancer prevention.
dose of roughly 35 to 70 grams. While the Some of these studies are currently being

Page 178 Alternative Medicine Review ◆ Volume 6, Number 2 ◆ 2001

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
 Cancer
followed up with clinical trials. Others 3. Singh DK, Lippman SM. Cancer
hopefully will follow. chemoprevention part 1: retinoids and caro-
tenoids and other classic antioxidants. Oncol-
It is the opinion of the authors that ogy (Huntingt) 1998;12:1643-1653, 1657-
agents with a good record of safety may be 1658; discussion 1659-1660.
considered for use before results of large-scale 4. Whelan P. Retinoids in chemoprevention. Eur
clinical trials are available. An agent with evi- Urol 1999;35:424-428.
dence of safe use in humans can be consid- 5. Maziere S, Meflah K, Tavan E, et al. Effect of
ered for therapeutic use if it has epidemiologi- resistant starch and/or fat-soluble vitamins A
cal, animal, and in vitro data in support of ef- and E on the initiation stage of aberrant crypts
in rat colon. Nutr Cancer 1998;31:168-177.
ficacy. Many of the agents discussed above
6. Willett WC, Hunter DJ. Vitamin A and cancers
meet these criteria. of the breast, large bowel, and prostate:
As discussed in the first paper in this epidemiologic evidence. Nutr Rev
series, preliminary human data show nutri- 1994;52:S53-S59.
tional interventions can have cancer preven- 7. Hunter DJ, Manson JE, Colditz GA, et al. A
tive efficacy similar to pharmaceutical options prospective study of the intake of vitamins C,
E, and A and the risk of breast cancer. N Engl J
in some cases. Toxicity from these agents tends Med 1993;329:234-240.
to be much lower than drug therapies, and
8. Cooper DA, Eldridge AL, Peters JC. Dietary
health benefits in other areas (e.g., decreased carotenoids and certain cancers, heart disease,
cardiovascular disease risks) may occur. and age-related macular degeneration: a review
Nutritional supplementation is no sub- of recent research. Nutr Rev 1999;57:201-214.
stitute for dietary and lifestyle risk reductions. 9. Brignall MS, Lamson DW. Re: Beta-carotene:
Physicians interested in cancer prevention a miss for epidemiology? J Natl Cancer Inst
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should look into the risk factors for the com-
10. Narisawa T, Fukaura Y, Hasebe M, et al.
mon tumor types and counsel their patients Inhibitory effects of natural carotenoids, alpha-
accordingly. For the patient known to be at carotene, beta-carotene, lycopene and lutein,
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on the data presented should be considered. rats. Cancer Lett 1996;107:137-142.
11. Yeum KJ, Zhu S, Xiau S, et al. Beta-carotene
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Acknowledgements lesions. J Am Coll Nutr 1995;14:536. [abstract
The authors wish to thank Richard and 48]
Jileen Russell and the Smiling Dog Founda- 12. Omaye ST, Krinsky NI, Kagan VE, et al. Beta-
tion for a grant supporting this project and carotene: friend or foe? Fundam Appl Toxicol
Bastyr University for its administration. 1997;40:163-174.
13. Wang XD, Russell RM. Procarcinogenic and
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