OF VITAMINS, MINERALS AND SUPPLEMENTS IN THE PREVENTION AND MANAGEMENT
OF PROSTATE CANCER
Download pdf )
VINCENT M. SANTILLO,
FRANKLIN C. LOWE
of Urology, St. Luke’s-Roosevelt Hospital, and Department of Urology,
Columbia University, College of Physicians and Surgeons, New York, NY,
authors review the current literature on the complementary and alternative
medicines most frequently utilized by prostate cancer patients and those
at risk for the disease. Products covered are vitamin E, vitamin A, selenium,
zinc, soy, lycopene, pomegranate juice, green tea and omega-3 fatty acids.
There is no definitive proof that any of the nutritional supplements discussed
can impact the course of prostate cancer or its development. The authors
believe that simply taking a standard daily multivitamin should be sufficient
to ensure that patients have the appropriate levels of vitamins and minerals
without risking the over utilization of vitamins, minerals, and supplements
which can lead to numerous negative side effects.
words: prostatic neoplasms; chemoprevention; complementary medicine;
dietary supplements; lycopene; omega-3 fatty acids
Int Braz J Urol. 2006; 32: 3-14
the last decade there has been an increase in the awareness and utilization
of complementary and alternative medicines (CAM). Population surveys indicate
that the increase is due to people’s desire to be pro-active in
their health management as well as their sense that anything “natural”
is inherently safe (1,2). In terms of prostate cancer, the highest utilization
of CAM is amongst those who have already been diagnosed and treated for
prostate cancer, and patients with progressive prostate cancer were more
likely to use CAM than those with stable disease (3). However, the data
supporting this over exuberance of usage is contradictory at best. This
article will review the current available data of the most frequently
utilized CAM products.
E (actually a group of 4 tocopherols and 4 tocotrienols) is the most popular
supplement used by men. It is estimated that 15% to 17% of men are taking
this supplement (4,5). As it is a fat-soluble vitamin, good dietary sources
tend to be foods rich in plant-derived oils: avocadoes, nuts, eggs, peanut
butter, soybeans, and ready-to-eat whole-grain breakfast cereals. Cooking
oils tend to be the largest source of vitamin E in the diet (6). The recommended
daily allowance (RDA) is 15 mg (22.5 IU). Plasma levels of vitamin E are
saturable at approximately 800 IU.
Vitamin E is generally thought to be safe
and has not shown mutagenic properties despite years of megadosing. However,
high-dosage (≥400 IU/day) vitamin E supplements have recently been
shown to increase the risk of cardiovascular events (7). Alpha-tocopherols
(the most abundant natural form of vitamin E) also decrease platelet aggregation
and thereby increase the risk for bleeding. Patients should be advised
to withhold vitamin E intake 10 to 14 days before prostate biopsy, radical
prostatectomy, radioactive seeding or any other surgical procedure (6).
Many in vitro studies across a variety of
human cancer cell lines have shown that vitamin E can have a beneficial
impact on carcinogenesis. The most well known function of vitamin E is
as an antioxidant, detoxifying oxidizing radicals that arise as unwanted
by-products during normal metabolism. These oxidizing radicals can interfere
with many cellular mechanisms important in cell growth and regulation
including those mechanisms involved with prostate carcinogenesis (6).
Others roles for vitamin E include as an antiprostaglandin; prostaglandins
are believed to have some role in prostate carcinogenesis (9).
In vitro studies of prostate cancer cell
lines have also shown that vitamin E induces cell cycle arrest in prostate
cancer cells at physiological levels as well as up-regulating the expression
of p27, a cell cycle regulator (9).
The potential impact of vitamin E usage
on the development of prostate cancer was first demonstrated in the findings
of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study)
(10). This was a randomized, double-blind study of 29,133 male smokers
who were given vitamin E (50 mg), beta-carotene (20 mg), both substances,
or a placebo daily for 5 to 8 years in order to evaluate the impact of
these 2 nutrients on preventing lung cancer. While lung cancer incidence
was not diminished, the male smokers taking vitamin E had a dramatic 32%
reduction in prostate cancer and a 41% reduction in prostate cancer deaths
at 7 years (10). The fact that the ATBC Study was not conceived as a prostate
cancer prevention trial, leaves open the possibility that the results
represent a statistical fluke.
The answer to the question of whether or
not the result was a coincidence is now being tested in the Selenium and
Vitamin E Cancer Prevention Trial (SELECT). The SELECT trial is testing
vitamin E (400 mg of racemic alpha-tocopheryl acetate) and selenium (200
mcg from L-selenomethionine) in 32,400 American men. Randomization will
be equally distributed among 4 study arms (selenium, vitamin E, selenium
and vitamin E, and placebo). The study is designed to allow detection
of a 25% reduction in the incidence of prostate cancer from the combination
of selenium and vitamin E compared to either nutrient alone. The combination
effect of the selenium and vitamin E could be synergistic, as was demonstrated
in in vitro experiments where the 2 supplements together achieved greater
cell growth inhibition than either alone (11). The SELECT trial reached
their full complement of men in April 2004. Initial data is anticipated
in 2006 with final results in 2013 (12).
A is a very versatile fat-soluble vitamin that has roles in several body
processes. The recommended dietary allowance (RDA) for men is 900 mcg
and it is estimated that approximately 3% of men are taking this vitamin
as a supplement(s).
According to epidemiological and clinical
research, vitamin A is not associated with prostate cancer risk (13).
The relationship was hypothesized based on the role retinoids play in
regulating the growth differentiation and apoptosis of normal and malignant
cells. In the Beta-Carotene and Retinol Efficacy Trial (CARET), a 7-year,
randomized, double-blinded, placebo-controlled chemoprevention trial that
tested the combination of beta-carotene (30 mg) and retinyl palmitate
(vitamin A) (25,000 IU) taken daily against placebo in 12,025 men and
6,289 women at high risk of developing lung cancer, there was no difference
in prostate cancer incidence among those men receiving vitamin A and a
placebo (14). While that study’s primary endpoint was the reduction
of lung cancer incidence in a population at high risk of that disease,
the data is compelling that vitamin A is most probably not going to be
a chemopreventive agent for prostate cancer.
is a trace element that occurs in both organic and inorganic forms. The
organic form enters through the food chain via the consumption of plants
grown in soil containing the inorganic form. It is found in seafood, meat
and grains and the amount varies depending on the amount present in the
soil. It is estimated that 9% to 10% of men are taking this supplement
(4,5).The RDA is 55 mcg and the Tolerable Upper Intake Level (UL) for
adults is 400 mcg. An excess of selenium can impair natural killer cell
activity, impact the synthesis of thyroid hormones and the metabolism
of growth hormone and insulin-like growth factor-1, and also has dermatologic
effects, such as nail and hair loss and dermatitis (15).
Properties of Selenium
The exact method whereby selenium affects
carcinogenesis is unknown, but its role as an antioxidant (both alone
and incorporated as a cofactor in antioxidant enzymes) has been an area
of research focus. Other potential effects include antiproliferation,
induction of apoptosis, modulation of androgen levels, and effects on
immune function (16,17).
While many epidemiologic studies have shown
evidence of a link between low selenium levels and higher cancer incidence,
it was the Nutritional Prevention of Cancer (NPC) Trial that highlighted
its relationship to prostate cancer. The NPC Trial of 1,312 men and women
was a randomized trial of 200 mcg of daily selenium designed to test whether
such supplementation could reduce the risk of recurrent non-melanoma skin
cancer (18). While the selenium supplementation did not have an effect
on skin cancer, at the end of the trial, an analysis of the 457 men receiving
supplementation showed a significantly lower incidence of prostate cancer
than those 470 men receiving a placebo (with a mean follow-up of more
than 7 years). Among men with baseline PSA values of less than or equal
to 4 ng/mL, the results showed a significant 65% reduction in prostate
cancer incidence with selenium supplementation. Those participants with
PSA values in excess of 4 ng/mL showed no reduction in incidence. When
the data from the NPC Trial is evaluated based on baseline selenium levels,
those men in the lowest and middle tertiles (£ 123.2 ng/mL) showed
significant reductions in incidence of 86% and 61%, respectively. Researchers
have also evaluated a cohort from the Health Professionals Follow-Up Study
of 51,529 men over 8 years that showed that when the 181 case subjects
with advanced prostate cancer were segregated into five groups based on
baseline selenium levels, those men in the study in the highest quintile
of selenium level had a 51% lower risk of advanced prostate cancer than
those men in the lowest quintile of selenium level (19). Until the results
of the SELECT Trial are available, it seems that only those with low levels
of selenium (this should be tested first) are appropriate candidates for
supplementation with the mineral.
is an essential mineral that acts as a cofactor for more than seventy
enzymes. The RDA for men is 11 mg per day and approximately 7% to 8% of
men report taking it (4,5). Zinc at high levels can be toxic; intakes
of 150 to 450 mg per day have been associated with low copper status,
altered iron function, reduced immune function, reduced levels of high-density
lipoproteins, and hair loss (20). Low copper status, in turn, can cause
a sideroblastic anemia, leukopenia, and neutropenia (21). More importantly,
usage of a dosage greater than 100 mg/day seems to increase the likelihood
of advanced prostate cancer (22).
Much of the interest in zinc as an agent
for prostate cancer treatment and prevention is due to studies that have
shown a marked reduction in prostate tissue zinc levels in prostate cancer
cells versus normal prostate cells (23). In normal prostate tissue, zinc
acts as an inhibitor of an enzyme (m-aconitase), which is part of the
Krebs cycle. With the inhibition removed by the low levels of zinc, the
malignant cells are now able to complete the Krebs cycle and go from energy-inefficient
secretory epithelial cells to energy-efficient cells (24).
Unfortunately, replacing this intracellular
prostatic zinc is not as simple as ingesting it: excessive intestinal
zinc levels downregulate zinc absorption and therefore, oral zinc supplements
have little or no effect upon zinc levels in the prostate (25). The zinc
is actively transported across the prostate cell membrane and there is
evidence that the downregulation of the transporters involved is a cause
of the reduced zinc uptake and this change in gene expression may be a
factor in the development of prostate cancer. Research has shown that
the hormones testosterone and prolactin can increase zinc uptake in prostate
cells, but no human studies of this effect have been undertaken (24).
The studies on zinc and prostate cancer
have been inconclusive (26). Some studies have suggested that high intraprostatic
zinc levels may protect against prostate carcinogenesis, while other studies
show that it may increase risk by facilitating enzymes thought to be responsible
for the unlimited proliferation of tumor cells (22)
In an analysis of 14 years of data on a
cohort of 46,974 men from the Health Professionals Follow-Up Study, it
was observed that supplemental zinc intake at doses of up to 100 mg/day
was not associated with an increased prostate cancer risk (22). However,
men who consumed more than 100 mg/day did have a relative risk of advanced
prostate cancer of 2.29 greater than nonusers. Thus, zinc supplementation
could promote the development of prostate cancer. Zinc obtained from food
sources was not associated with prostate cancer risk (22).
role of soy and the beneficial effects that the phytoestrogens (specifically
the isoflavonoids) it contains have on prostate cancer have been a focus
of recent research. Only 4% to 8% of men are estimated to use soy as a
supplement (4,5). Much of the research has focused on two isoflavones
specifically, genistein and daidzein.
The research is seeking to provide understanding
of epidemiological studies that have shown lower incidence of prostate
cancer in populations with diets rich in soy products (27). It has been
reported that while Chinese and Japanese men had a lower incidence of
prostate cancer than U.S. born males, the incidence in the population
of Asian immigrants to the United States are in line with U.S. incidence
rates (28). Soy is of interest as a possible reason, as the average Asian
diet includes ten times the amount of soy products consumed in the typical
American diet (27). Isoflavone consumption is approximately 50 mg/day
in Asia versus 2 to 3 mg/day in the United States (27). A study of the
dietary habits of 12,395 American Seventh-Day Adventists, demonstrated
a 70% reduction in the risk of prostate cancer in those men who consumed
soy milk more than once a day (29).
Genistein, daidzein and their metabolites,
with their mild estrogenic activity, have been shown to inhibit benign
and malignant prostatic epithelial cell growth (30), down-regulate androgen-receptor
genes (31), and reduce tumor growth in some animal models. In addition,
genistein inhibits the growth of both androgen-dependent and androgen-independent
prostate cancer cells in vitro (12). No large-scale clinical trials using
soy or soy products as chemoprevention or therapy have been reported,
so current opinion must rely on epidemiologic studies, in vitro studies,
and in vivo studies in animal models.
While it may seem that a reduction in risk
could be achieved by increasing soy intake, a recent study showed that
the situation could be more complicated (30). In that study, equol, a
metabolite of daidzein, demonstrated inhibitory effects. Not all individuals
consuming daidzein produce equol. It is the habitual diet that determines
the bacterial strains in the gastrointestinal tract, which in turn determines
whether the individual converts daidzein to equol. This study only focused
on one metabolite, but demonstrates the difficulty in applying results
in one population to another as local intestinal flora as well as diet
can influence the presence of biologically active metabolites.
Administration of soy products may not be
without risk, as one animal study demonstrated when it showed an enhancement
in androgen-independent tumor growth in vivo when the rats were fed a
diet high in an isoflavone-rich soy protein isolate (32).
The clinical data collected to date has
been limited and equivocal. Studies have had small numbers of participants
or were limited in duration. Some have shown no impact on PSA levels or
PSA velocity in healthy men or in prostate cancer patients (33-35), while
others have demonstrated the exact opposite in a group of men with prostate
cancer (36,37). Clinically, these studies are inconclusive because they
have focused on imperfect markers of prostate cancer and not the disease
itself. Studies of soy supplementation in humans have not been performed
and are needed in order to assess clinical impact (38).
to selenium and vitamin E, lycopene is a potent antioxidant. It is a carotenoid
found primarily in tomatoes and tomato-derived products. There is no recommended
daily allowance for lycopene since it is not an essential nutrient. Miller
et al recommend the consumption of one serving per day or five servings
per week of tomato products as part of a healthy diet (39).
Epidemiological studies have suggested that
tomato products might be potential protective agents against prostate
cancer (39-42). An analysis of diet data collected from a cohort of 14,000
Seventh-Day Adventist men showed a 40% reduction in the risk of prostate
cancer in those who consumed tomatoes more than 5 times per week when
compared to those consuming less than one serving per week (39). These
observations were expanded upon by Giovannucci et al. in their 1995 prospective
study of a cohort of 47,894 men from the Health Professionals Follow-Up
Study (HPFS) (39,43). In that analysis, the only fruit and vegetable items
to be associated with a lowered prostate cancer risk were raw tomatoes,
tomato sauce, pizza, and strawberries. When the tomato groups are combined,
consumption in excess of ten servings per week compared with less than
1.5 servings per week reduced the risk of prostate cancer by 35% (39).
A more recent analysis of 450 incident prostate cancer cases versus 450
controls from the HPFS data suggested that tomato products may have a
stronger protective role in preventing sporadic prostate cancer rather
than prostate cancer with a strong familial/hereditary component (44).
While lycopene can be taken as a supplement,
a recent animal study showed a protective effect from tomato powder but
not pure lycopene, indicating that compounds in addition to lycopene are
influencing prostate carcinogenesis (45). Other animal and in vitro studies
have demonstrated that taking vitamin E (which is present in tomatoes)
along with lycopene led to synergistic inhibition of prostate cancer (46,47).
As with other antioxidants, lycopene may
have a role in limiting oxidative damage to cellular macromolecules. In
vitro laboratory studies suggest that lycopene is the best natural carotenoid
for quenching singlet reactive oxygen. The actual ways in which lycopene
works with other antioxidants and biologic systems that protect against
oxidative damage is poorly understood (39). Lycopene has also been shown
in vitro to impact insulin-like growth factor 1 (IGF-1) signaling, cell
cycle progression and cellular proliferation. High levels of IGF-1 have
been associated with an increased risk of prostate cancer (48).
A 2002 study of 26 men newly diagnosed with
prostate cancer, demonstrated that supplementation with a lycopene preparation
(which included 30 mg lycopene as well as a mixture of tomato carotenoids
and other phytochemicals, including vitamin E) 3 weeks prior to radical
prostatectomy resulted in decreased plasma PSA levels as well as reduced
the diffuse involvement of the prostate gland with HGPIN, a precursor
to prostate cancer (49). No prospective controlled clinical study of lycopene
supplementation has been performed to date.
juice is a strong antioxidant that has recently been receiving increased
research attention. It is a rich source of polyphenolic flavonoids, which
are believed to be the reason for its potent antioxidant and anti-atherosclerotic
properties. The most abundant of these polyphenols is punicalagin and
is responsible for more than 50% of the juice’s potent antioxidant
Epidemiological studies have shown that
consuming fruits and vegetables with high phenolic content correlates
with reduced cancer mortality. Pomegranate juice has been marketed as
being high in antioxidants and laboratory research has been focusing on
its potential to impact prostate cancer. Interestingly, studies have shown
commercial juice to be high in punicalagins because industrial processing
extracts some of the tannins present in the fruit rind (50). Thus, any
benefit from pomegranate is likely to come from consuming juice and not
fruit - and specifically juice that includes some processing of the fruit
Studies in breast cancer have demonstrated
the juice to have significant potential for the down-regulation of angiogenesis.
Certain fractions, especially the seed oil, are known to have estrogenic
activity. In addition, as with vitamin E, the punicic acid in pomegranate
seed oil inhibits prostaglandin formation (51). In vitro studies have
also shown a synergistic inhibition of prostate cancer cell invasion from
the application of a combination of pomegranate extracts (52,53). Recent
research has shown the beneficial effects of the various extracts of pomegranate
juice are enhanced when combined with the other polyphenols found in the
A recent 2-year, single center clinical
trial was completed for 48 men with rising PSA levels after surgery or
radiotherapy (55). Patients drank eight ounces of pomegranate juice daily.
Mean PSA doubling time significantly increased with pomegranate juice
supplementation, from a mean of 14 months to 26 months. These findings
suggest that further testing is warranted in a multi-center, randomized,
placebo controlled study (55).
to water, tea (made from the leaves of Camellia sinensis) is the most
widely consumed liquid in the world. Green, oolong and black tea are all
made from the leaves of the same plant. However, their chemical content
and flavors are very different due to their fermentation processes. Green
tea contains several polyphenolic compounds, including its primary polyphenol,
and the one that has received the most research focus, epigallocatechin
gallate (EGCG). Consumption is generally considered safe. One study of
49 patients with solid tumors concluded that a dose equivalent to 3.5
to 4 cups (28 to 32 fl. oz.) of green tea 3 times a day could be easily
tolerated and could be taken safely for at least 6 months (56). Estimates
are that green tea is used by 6% to 8% of men as complementary/alternative
Epidemiologic studies have shown that men
who regularly consume green tea have a lower incidence of prostate cancer
(57-59). This fact may contribute to the observation that Asian men, with
their far higher consumption of green tea, have lower rates of prostate
cancer then their western counterparts (60).
Research has focused on the role of the
polyphenols contained in green tea, but their mechanism of action has
not been determined. Proposed antineoplastic effects observed include:
the inhibition of proteolytic enzymes to prevent metastases, alterations
in cell communication, and antiangiogenesis. These antitumor mechanisms
require prolonged exposure to the green tea (61). EGCG has been shown
in both animal and in vitro studies to induce apoptosis and cell-growth
inhibition (62-64). In a TRAMP mouse (which spontaneously develops metastatic
prostate cancer) model, a polyphenolic fraction isolated from green tea
(green tea polyphenols or GTP) at the human equivalent of six cups of
green tea per day, caused significant inhibition of prostate cancer and
increased survival. GTP seemed to completely inhibit distant site metastases
Several clinical studies have shown no effect
by green tea on androgen independent prostate carcinoma. However, in those
studies the patient populations’ cancers may have been too advanced
to benefit from this intervention (61,66).
FISH OIL (Omega-3
fatty acids can be found naturally in the oil of cold-water fish, such
as mackerel, salmon, sardines, anchovies, and tuna, or as extracted oils
from plants, such as flaxseed, canola, or soybean. Eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) are found mainly in fatty fish and
are often referred to as marine fatty acids. Both can be synthesized in
humans from a precursor (alpha-linolenic acid). However, the conversion
of alpha-linolenic acid to EPA or DHA is inefficient, direct dietary consumption
is a more effect method of increasing serum levels of fatty acids (67).
Blood or adipose tissue levels of omega-3 fatty acids are correlated to
intake of fatty fish rather than to the intake of alpha-linolenic acid
(68). The FDA recommends that the consumption of fish oils be limited
to 3 grams or less per day because higher doses may increase the risk
of bleeding (69).
It is unclear that the consumption of marine
fatty acids can reduce the risk of prostate cancer (68). An analysis of
the diet of 47,882 men enrolled in the Health Professionals Follow-up
Study showed that eating fish more than three times per week versus less
than twice per month translated into a negligibly reduced risk of prostate
cancer (7% reduction), of advanced prostate cancer (17% reduction), and
a somewhat reduced metastatic cancer risk (44%) (70). This same study
found no association between the risk of prostate cancer and the consumption
of fish oil supplements (70). In Lancet, Terry et al. analyzed the association
of fish consumption and the risk of prostate cancer in 6,272 Swedish men
over 30 years (71). Those who ate no fish had a two to three times higher
frequency of prostate cancer than those who ate either moderate or high
amounts, as defined on a four point scale, of fatty fish. In an autopsy
study of 27 Inuits (Eskimos), no latent noninfiltrative-type carcinoma
was found; only one of the Inuit prostates showed malignant cancer, and
that was in a 73-year old who had a low omega-3 polyunsaturated fatty
acid concentration (0.9% of all fatty acids in adipose tissue compared
with 1.79% for the entire autopsy group). The absence of latent noninfiltrative-type
carcinoma was unexpected when compared with incidences of 25-35% that
are usually reported in other comparable populations, including Asians.
The authors suggested that the low incidence of prostate cancer was due
to the high selenium and omega-3 fatty acid levels (72). These results
are strongly contradicted by other epidemiological studies that show no
association between prostate cancer risk and total fish consumption nor
intake of EPA or DHA (73-75).
In contrast to the epidemiological studies,
in vitro results have been more promising. Omega-3 fatty acids have been
shown to inhibit cell growth and PSA protein expression (68). In animals,
a recent study of human prostate cancer in xenograft mice showed an inhibitory
effect of dietary fish oil (76).
EPA and DHA have both been shown to inhibit
the biological activity of eicosanoids and androgens, which are both known
to have a stimulating effect on prostate cancer cell growth (70).
Although numerous studies have been done
for cardiac disease prevention and management, none are available concerning
prostate cancer (77).
with prostate cancer or those at high risk for developing the disease
are faced with voluminous and often conflicting advice about nutritional
supplementation. Any advice to the patient must be tempered by the fact
that there is no definitive proof that any of the nutritional supplements
discussed can impact the course of prostate cancer or its development.
Dietary fat seems to have the greatest impact
on prostate cancer (78). It is clear that patients should keep their weight
within 10% of their ideal body mass index (BMI). There seems to be a positive
correlation between BMI and the risk of prostate cancer (79,80). The consumption
of red meat has been shown to increase the risk of prostate cancer (78).
Following a “heart healthy” diet of non-red meat protein (including
fatty fish) could possibly benefit those at risk for developing prostate
In terms of supplement usage, the data is
unclear. Our belief is that simply taking a standard daily multivitamin
should be sufficient to ensure that patients have the appropriate levels
of vitamins and minerals. Clearly, overutilization of vitamins, minerals,
and supplements can lead to numerous negative side effects such as the
increased risk of heart attack and stroke (vitamin E), bleeding (vitamin
E, vitamin A), decreased mental acuity (zinc, selenium), anemia (zinc),
and hair and nail loss (selenium).
Supplementation is also cautioned when looking
at the history of PC-SPES (82). In 2002, approximately 10,000 patients
with prostate cancer were using this supplement. Patients utilized the
product without close medical supervision and, in those patients, estrogenic
side effects (e.g. gynecomastia) were frequent and there were reports
of deep vein thrombosis. PC-SPES was found in several subsequent tests
to be contaminated with diethylstilbestrol (DES), ethinyl estradiol and
warfarin, among other contaminants. The contamination varied by lot examined.
The product was recalled in early 2002 and the company manufacturing it
ceased operations later that year, but not after the adverse events described
Physicians must be aware of what their patients
are taking because these supplements can interfere with the absorption
and efficacy of conventional medications. However, studies have shown
that patients using CAM usually do not inform their physician (3). Physicians
must proactively inquire about CAM usage. Patients must be educated about
the limitations and safety concerns when using CAM. More data from rigorous
new clinical trials is needed to answer the question of the efficacy of
all of these products.
- Boon H, Brown JB, Gavin A, Westlake K: Men with prostate cancer:
making decisions about complementary/alternative medicine. Med Decis
Making. 2003; 23: 471-9.
- Barqawi A, Gamito E, O’Donnell C, Crawford ED: Herbal and vitamin
supplement use in a prostate cancer screening population. Urology. 2004;
- Wilkinson S, Gomella LG, Smith JA, Brawer MK, Dawson NA, Wajsman Z,
et al.: Attitudes and use of complementary medicine in men with prostate
cancer. J Urol. 2002; 168: 2505-9.
- Boon H, Westlake K, Stewart M, Gray R, Fleshner N, Gavin A, et al.:
Use of complementary/alternative medicine by men diagnosed with prostate
cancer: prevalence and characteristics. Urology. 2003; 62: 849-53.
- Beebe-Dimmer JL, Wood DP, Gruber SB, Douglas JA, Bonner JD, Mohai
C, et al.: Use of complementary and alternative medicine in men with
family history of prostate cancer: a pilot study. Urology. 2004; 63:
- Fleshner NE: Vitamin E and prostate cancer. Urol Clin North Am. 2002;
- Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ,
Guallar E: Meta-analysis: high-dosage vitamin E supplementation may
increase all-cause mortality. Ann Intern Med. 2005; 142: 37-46.
- Badawi AF: The role of prostaglandin synthesis in prostate cancer.
BJU Int. 2000; 85: 451-62.
- Venkateswaran V, Fleshner NE, Klotz LH: Modulation of cell proliferation
and cell cycle regulators by vitamin E in human prostate carcinoma cell
lines. J Urol. 2002; 168: 1578-82.
- Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman
AM, et al.: Prostate cancer and supplementation with alpha-tocopherol
and beta-carotene: incidence and mortality in a controlled trial. J
Natl Cancer Inst. 1998; 90: 440-6.
- Zu K, Ip C: Synergy between selenium and vitamin E in apoptosis induction
is associated with activation of distinctive initiator caspases in human
prostate cancer cells. Cancer Res. 2003; 63: 6988-95.
- Klein EA: Chemoprevention of prostate cancer. Crit Rev Oncol Hematol.
2005; 54: 1-10.
- Kristal AR: Vitamin A, retinoids and carotenoids as chemopreventive
agents for prostate cancer. J Urol. 2004; 171: S54-8; discussion S58.
- Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A,
et al.: Risk factors for lung cancer and for intervention effects in
CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst.
1996; 88: 1550-9.
- Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G: Adverse health
effects of selenium in humans. Rev Environ Health. 2001; 16: 233-51.
- Klein EA, Thompson IM: Update on chemoprevention of prostate cancer.
Curr Opin Urol. 2004; 14: 143-9.
- Zhao H, Whitfield ML, Xu T, Botstein D, Brooks JD: Diverse effects
of methylseleninic acid on the transcriptional program of human prostate
cancer cells. Mol Biol Cell. 2004; 15: 506-19.
- Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs
ET, et al.: Selenium supplementation, baseline plasma selenium status
and incidence of prostate cancer: an analysis of the complete treatment
period of the Nutritional Prevention of Cancer Trial. BJU Int. 2003;
- Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm
EB, et al.: Study of prediagnostic selenium level in toenails and the
risk of advanced prostate cancer. J Natl Cancer Inst. 1998; 90: 1219-24.
- Facts About Dietary Supplements - Zinc. Clinical Nutrition Service.
Maryland, National Institutes of Health. 2002; pp. 1-11.
- Salzman MB, Smith EM, Koo C: Excessive oral zinc supplementation.
J Pediatr Hematol Oncol. 2002; 24: 582-4.
- Leitzmann MF, Stampfer MJ, Wu K, Colditz GA, Willett WC, Giovannucci
EL: Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst.
2003; 95: 1004-7.
- Costello LC, Franklin RB: Novel role of zinc in the regulation of
prostate citrate metabolism and its implications in prostate cancer.
Prostate. 1998; 35: 285-96.
- Costello LC, Feng P, Milon B, Tan M, Franklin RB: Role of zinc in
the pathogenesis and treatment of prostate cancer: critical issues to
resolve. Prostate Cancer Prostatic Dis. 2004; 7: 111-7.
- Uzzo RG, Leavis P, Hatch W, Gabai VL, Dulin N, Zvartau N, et al.:
Zinc inhibits nuclear factor-kappa B activation and sensitizes prostate
cancer cells to cytotoxic agents. Clin Cancer Res. 2002; 8: 3579-83.
- Platz EA, Helzlsouer KJ: Selenium, zinc, and prostate cancer. Epidemiol
Rev. 2001; 23: 93-101.
- Castle EP, Thrasher JB: The role of soy phytoestrogens in prostate
cancer. Urol Clin North Am. 2002; 29: 71-81.
- Lee MM, Gomez SL, Chang JS, Wey M, Wang RT, Hsing AW: Soy and isoflavone
consumption in relation to prostate cancer risk in China. Cancer Epidemiol
Biomarkers Prev. 2003; 12: 665-8.
- Jacobsen BK, Knutsen SF, Fraser GE: Does high soy milk intake reduce
prostate cancer incidence? The Adventist Health Study (United States)
Cancer Causes Control. 1998; 9: 553-7.
- Hedlund TE, Johannes WU, Miller GJ: Soy isoflavonoid equol modulates
the growth of benign and malignant prostatic epithelial cells in vitro.
Prostate. 2003; 54: 68-78.
- Bektic J, Berger AP, Pfeil K, Dobler G, Bartsch G, Klocker H: Androgen
receptor regulation by physiological concentrations of the isoflavonoid
genistein in androgen-dependent LNCaP cells is mediated by estrogen
receptor beta. Eur Urol. 2004; 45: 245-51; discussion 251.
- Cohen LA, Zhao Z, Pittman B, Scimeca J: Effect of soy protein isolate
and conjugated linoleic acid on the growth of Dunning R-3327-AT-1 rat
prostate tumors. Prostate. 2003; 54: 169-80.
- Jenkins DJ, Kendall CW, D’Costa MA, Jackson CJ, Vidgen E, Singer
W, et al.: Soy consumption and phytoestrogens: effect on serum prostate
specific antigen when blood lipids and oxidized low-density lipoprotein
are reduced in hyperlipidemic men. J Urol. 2003; 169: 507-11.
- deVere White RW, Hackman RM, Soares SE, Beckett LA, Li Y, Sun B:
Effects of a genistein-rich extract on PSA levels in men with a history
of prostate cancer. Urology. 2004; 63: 259-63.
- Adams KF, Chen C, Newton KM, Potter JD, Lampe JW: Soy isoflavones
do not modulate prostate-specific antigen concentrations in older men
in a randomized controlled trial. Cancer Epidemiol Biomarkers Prev.
2004; 13: 644-8.
- Kumar NB, Cantor A, Allen K, Riccardi D, Besterman-Dahan K, Seigne
J, et al.: The specific role of isoflavones in reducing prostate cancer
risk. Prostate. 2004; 59: 141-7.
- Dalais FS, Meliala A, Wattanapenpaiboon N, Frydenberg M, Suter DA,
Thomson WK, et al.: Effects of a diet rich in phytoestrogens on prostate-specific
antigen and sex hormones in men diagnosed with prostate cancer. Urology.
2004; 64: 510-5.
- Holzbeierlein JM, McIntosh J, Thrasher JB: The role of soy phytoestrogens
in prostate cancer. Curr Opin Urol. 2005; 15: 17-22.
- Miller EC, Giovannucci E, Erdman JW Jr, Bahnson R, Schwartz SJ, Clinton
SK: Tomato products, lycopene, and prostate cancer risk. Urol Clin North
Am. 2002; 29: 83-93.
- Giovannucci E: Tomato Products, Lycopene, and Prostate Cancer: A
Review of the Epidemiological Literature. J Nutr. 2005; 135: 2030S-1S.
- Etminan M, Takkouche B, Caamano-Isorna F: The role of tomato products
and lycopene in the prevention of prostate cancer: a meta-analysis of
observational studies. Cancer Epidemiol Biomarkers Prev. 2004; 13: 340-5.
- Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH,
et al.: Lower prostate cancer risk in men with elevated plasma lycopene
levels: results of a prospective analysis. Cancer Res. 1999; 59: 1225-30.
- Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett
WC: Intake of carotenoids and retinol in relation to risk of prostate
cancer. J Natl Cancer Inst. 1995; 87: 1767-76.
- Wu K, Erdman JW Jr, Schwartz SJ, Platz EA, Leitzmann M, Clinton SK,
et al.: Plasma and dietary carotenoids, and the risk of prostate cancer:
a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2004;
- Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK:
Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated
rats fed tomato powder, lycopene, or energy-restricted diets. J Natl
Cancer Inst. 2003; 95: 1578-86.
- Pastori M, Pfander H, Boscoboinik D, Azzi A: Lycopene in association
with alpha-tocopherol inhibits at physiological concentrations proliferation
of prostate carcinoma cells. Biochem Biophys Res Commun. 1998; 250:
- Limpens J, van Weerden WM, Kramer K, Pallapies D, Obermuller-Jevic
UC, Schroder FH: Re: Prostate carcinogenesis in N-methyl-N-nitrosourea
(NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted
diets. J Natl Cancer Inst. 2004; 96: 554; author reply 554-5.
- Chan JM, Stampfer MJ, Giovannucci E, Ma J, Pollak M: Insulin-like
growth factor I (IGF-I), IGF-binding protein-3 and prostate cancer risk:
epidemiological studies. Growth Horm IGF Res. 2000; 10 (Suppl A): S32-3.
- Kucuk O, Sarkar FH, Djuric Z, Sakr W, Pollak MN, Khachik F, et al.:
Effects of lycopene supplementation in patients with localized prostate
cancer. Exp Biol Med (Maywood). 2002; 227: 881-5.
- Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA:
Antioxidant activity of pomegranate juice and its relationship with
phenolic composition and processing. J Agric Food Chem. 2000; 48: 4581-9.
- Toi M, Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS, et al.:
Preliminary studies on the anti-angiogenic potential of pomegranate
fractions in vitro and in vivo. Angiogenesis. 2003; 6: 121-8.
- Lansky EP, Jiang W, Mo H, Bravo L, Froom P, Yu W, et al.: Possible
synergistic prostate cancer suppression by anatomically discrete pomegranate
fractions. Invest New Drugs. 2005; 23: 11-20.
- Lansky EP, Harrison G, Froom P, Jiang WG: Pomegranate (Punica granatum)
pure chemicals show possible synergistic inhibition of human PC-3 prostate
cancer cell invasion across Matrigel. Invest New Drugs. 2005; 23: 121-2.
- Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, et al.:
In vitro antiproliferative, apoptotic and antioxidant activities of
punicalagin, ellagic acid and a total pomegranate tannin extract are
enhanced in combination with other polyphenols as found in pomegranate
juice. J Nutr Biochem. 2005; 16: 360-7.
- Pantuck AJ, Leppert JT, Zomorodian N, Seeram N, Seiler D, Liker H:
Phase II study of pomegranate juice for men with rising PSA following
surgery or radiation for prostate cancer. J Urol. 2005; 173 (Suppl 4):
225-6. Abstract 831.
- Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK, et
al.: Phase I trial of oral green tea extract in adult patients with
solid tumors. J Clin Oncol. 2001; 19: 1830-8.
- Heilbrun LK, Nomura A, Stemmermann GN: Black tea consumption and
cancer risk: a prospective study. Br J Cancer. 1986; 54: 677-83.
- Jian L, Xie LP, Lee AH, Binns CW: Protective effect of green tea
against prostate cancer: a case-control study in southeast China. Int
J Cancer. 2004; 108: 130-5.
- Jain MG, Hislop GT, Howe GR, Burch JD, Ghadirian P: Alcohol and other
beverage use and prostate cancer risk among Canadian men. Int J Cancer.
1998; 78: 707-11.
- Gupta S, Mukhtar H: Green tea and prostate cancer. Urol Clin North
Am. 2002; 29: 49-57.
- Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P, et
al.: A phase II trial of green tea in the treatment of patients with
androgen independent metastatic prostate carcinoma. Cancer. 2003; 97:
- Adhami VM, Ahmad N, Mukhtar H: Molecular targets for green tea in
prostate cancer prevention. J Nutr. 2003; 133 (Suppl 7): 2417S-24S.
- Park OJ, Surh YJ: Chemopreventive potential of epigallocatechin gallate
and genistein: evidence from epidemiological and laboratory studies.
Toxicol Lett. 2004; 150: 43-56.
- Paschka AG, Butler R, Young CY: Induction of apoptosis in prostate
cancer cell lines by the green tea component, (-)-epigallocatechin-3-gallate.
Cancer Lett. 1998; 130: 1-7.
- Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H: Inhibition of prostate
carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols.
Proc Natl Acad Sci U S A. 2001; 98: 10350-5.
- Choan E, Segal R, Jonker D, Malone S, Reaume N, Eapen L, et al.:
A prospective clinical trial of green tea for hormone refractory prostate
cancer: an evaluation of the complementary/alternative therapy approach.
Urol Oncol. 2005; 23: 108-13.
- Terry PD, Terry JB, Rohan TE: Long-chain (n-3) fatty acid intake
and risk of cancers of the breast and the prostate: recent epidemiological
studies, biological mechanisms, and directions for future research.
J Nutr. 2004; 134 (Suppl 12): 3412S-20S.
- Astorg P: Dietary N-6 and N-3 polyunsaturated fatty acids and prostate
cancer risk: a review of epidemiological and experimental evidence.
Cancer Causes Control. 2004; 15: 367-86.
- Lewis CJ: Letter regarding dietary supplement health claim for omega-3
fatty acids and coronary heart disease. FDA Docket No. 91N-0103. 2000.
U.S. Food and Drug Administration. http://vm.cfsan.fda.gov/~dms/ds-ltr11.html
- Augustsson K, Michaud DS, Rimm EB, Leitzmann MF, Stampfer MJ, Willett
WC, et al.: A prospective study of intake of fish and marine fatty acids
and prostate cancer. Cancer Epidemiol Biomarkers Prev. 2003; 12: 64-7.
- Terry P, Lichtenstein P, Feychting M, Ahlbom A, Wolk A: Fatty fish
consumption and risk of prostate cancer. Lancet. 2001; 357: 1764-6.
- Dewailly E, Mulvad G, Sloth Pedersen H, Hansen JC, Behrendt N, Hart
Hansen JP: Inuit are protected against prostate cancer. Cancer Epidemiol
Biomarkers Prev. 2003; 12: 926-7.
- Gann PH, Hennekens CH, Sacks FM, Grodstein F, Giovannucci EL, Stampfer
MJ: Prospective study of plasma fatty acids and risk of prostate cancer.
J Natl Cancer Inst. 1994; 86: 281-6. Erratum in: J Natl Cancer Inst
1994; 86: 728.
- Schuurman AG, van den Brandt PA, Dorant E, Brants HA, Goldbohm RA:
Association of energy and fat intake with prostate carcinoma risk: results
from The Netherlands Cohort Study. Cancer. 1999; 86: 1019-27.
- Schuurman AG, van den Brandt PA, Dorant E, Goldbohm RA: Animal products,
calcium and protein and prostate cancer risk in The Netherlands Cohort
Study. Br J Cancer. 1999; 80: 1107-13.
- Kobayashi N, Leung P, Hong J, Barnard RJ, Freedland SJ, Elashoff D,
et al.: Inhibitory effect of dietary fish oil (omega-3 fatty acids)
on human prostate cancer progression in severe-combined immunodeficient
mice. J Urol. 2005; 173 (Suppl 4): Abstract 249, 68.
- Kris-Etherton PM, Harris WS, Appel LJ, Nutrition Committee: Fish
consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
Arterioscler Thromb Vasc Biol. 2003; 23: e20-30. Erratum in: Arterioscler
Thromb Vasc Biol. 2003; 23: e31.
- Stoeckli R, Keller U: Nutritional fats and the risk of type 2 diabetes
and cancer. Physiol Behav. 2004; 83: 611-5.
- Andersson SO, Wolk A, Bergstrom R, Adami HO, Engholm G, Englund A,
et al.: Body size and prostate cancer: a 20-year follow-up study among
135006 Swedish construction workers. J Natl Cancer Inst. 1997; 89: 385-9.
- Bradbury BD, Wilk JB, Kaye JA: Obesity and the risk of prostate cancer
(United States). Cancer Causes Control. 2005; 16: 637-41.
- Moyad MA: Dietary fat reduction to reduce prostate cancer risk: controlled
enthusiasm, learning a lesson from breast or other cancers, and the
big picture. Urology. 2002; 59 (Suppl 1): 51-62.
- Kosty MP: PC-SPES: hope or hype? J Clin Oncol. 2004; 22: 3657-9.
- Marks LS, DiPaola RS, Nelson P, Chen S, Heber D, Belldegrun AS, et
al.: PC-SPES: herbal formulation for prostate cancer. Urology. 2002;
60: 369-75; discussion 376-7.
September 12, 2005
Dr. Franklin C. Lowe
171 W 71st St.
New York, NY 10023, USA