Document 6431078

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Document 6431078

21/4/2014
Strategies for prostate cancer prevention: Review of the literature
Indian J Urol. 2008 Jul-Sep; 24(3): 295–302.
PMCID: PMC2684344
doi: 10.4103/0970-1591.42608
H. Krishna Moorthy and P. Venugopal1
Division of Urology, Lakshmi Hospital, Kochi, and Department of Surgery, Mangalore
1
Sr.Consultant in Urology, Mangalore
For correspondence: P Venugopal, 801, Symphony Apartment, Sturrock Road, Mangalore - 575 001, India. E-mail:
peeveegee2000@yahoo.com
Copyright © Indian Journal of Urology
This is an open-access article distributed under the terms of the Creative Commons Attribution License, w hich permits unrestricted use,
distribution, and reproduction in any medium, provided the original w ork is properly cited.
Abstract
The goal of primary chemoprevention is to decrease the incidence of a given cancer, simultaneously
reducing treatment-related adverse events, cost of treatment of the disease and mortality. Prostate
cancer is an attractive and appropriate target for primary prevention because of its high incidence and
prevalence, increased disease-related mortality, long latency and molecular pathogenesis and
epidemiological data indicating that modifiable environmental factors may decrease risk. Various agents
have been suggested to prevent prostate cancer and many clinical trials are currently on. Ultimately the
adoption of a preventive strategy hinges on its potential benefits weighed against the potential risks of
the specific agents used. This article is aimed to examine the experimental and epidemiological data
spanning a period of 1998 to 2007, demonstrating the chemopreventive activity, safety and toxicity of
various nutritional elements and other agents that can help prevent prostate cancer and/or slow disease
progression.
Keywords: Chemoprevention, prostate cancer
INTRODUCTION
Prostate cancer is a slow-growing tumor of older men, constituting the most common type of non-skin
cancer and the second leading cause of cancer-related deaths in American men. In the late 80s and
early 90s great attention was given to screening asymptomatic men by measuring concentration of
prostate specific antigen (PSA), which eventually led to a significant increase in the detection of
clinically insignificant tumors. Despite this increase, mortality due to prostate cancer has decreased
every year since 1992. Though the exact pathogenesis is not clear, epidemiological evidence supports a
relationship between prostate cancer and serum levels of testosterone.[1] Other risk factors include
advanced age, family history, African-American ethnicity, poor diet and cadmium exposure.[2] The
frequency of prostate cancer increases exponentially with advanced age and the natural progression to
prostate cancer tends to be more aggressive in younger men and those with a family history of the
disease.
Although controversial, strategies for decreasing prostate cancer mortality have focused on early
detection. The most important tumor marker for detection and post-treatment monitoring of prostate
cancer is PSA level. However, PSA levels have fallacies. Increased levels of serum PSA can occur in
prostate cancer, benign prostatic hyperplasia and prostatitis. Conversely, treatment with 5 alpha
reductase inhibitors lowers PSA levels to approximately 50%. However, PSA assessment still remains the
best method to detect cancers at a pre-symptomatic stage. Newer methods for increasing the sensitivity
and specificity of PSA screening tool are currently being adopted.
MATERIALS AND METHODS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684344/?report=printable
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To identify the various strategies for prostate cancer chemoprevention, a MEDLINE search (from 1970
to 2007) and bibliographic search of the English language literature was conducted.
CHEMOPREVENTION
Carcinogenesis is a multi-step molecular process induced by genetic and epigenetic changes that disrupt
the balance between cell proliferation, apoptosis, differentiation, senescence and the pathways
controlling these cellular processes. Precursor lesions that represent intermediate stages between normal
and malignant cells can arise as long as 20 years before the appearance of cancer. Chemoprevention is
defined as the use of natural or synthetic agents that reverse, inhibit or prevent the development of
cancer in cancer-free individuals.[3] Important to chemoprevention is the fact that carcinogenesis is a
process over time involving cellular growth and division and hence inhibition or slowing this process
can potentially prevent cancers from becoming clinically significant.[4] This approach relies on
targeting healthy persons at risk of developing the cancer in question and using agents with a low
probability of inducing adverse events, similar to the use of Tamoxifen for prevention of breast cancer in
high-risk women.[5] The high rate of occurrence and long lead time to development of clinically
significant prostate cancer make this disease ideal for study of chemoprevention,[6,7] though this long
lag period may not be exactly ideal for assessing the results of various scientific studies. Prostate
carcinogenesis includes progression from normal appearing epithelium to dysplasia (low-grade prostatic
intraepithelial neoplasia or LGPIN) to severe dysplasia (high-grade prostatic intraepithelial neoplasia or
HGPIN) and finally to invasive prostate cancer. Various agents are considered for preventive treatment
of prostate cancer which can either be used in primary prevention which includes the period prior to the
diagnosis of prostate cancer or in secondary prevention which may involve the prevention of recurrence
or progression of micrometastatic disease.
NUTRIENTS AND VITAMINS
Evidence from epidemiological studies suggests associations between exposure to a variety of dietary
nutrients and certain cancers including lung, colon, breast and prostate.[8] The role of dietary
constituents and vitamins in the chemoprevention of prostate cancer has been addressed in several
clinical trials. Most of the available data consist of epidemiologic or retrospective studies and should be
interpreted with attention to potential confounders.[9]
Carotenoids
There are a number of carotenoids with antioxidative activity. Lycopene is a red-orange, highly
unsaturated, acyclic isomer of beta-carotene found primarily in tomatoes and tomato-derived products
and in other red fruits and vegetables. Lycopene possesses significant antioxidant properties that may
confer some antineoplastic activity. Studies have found out that increased lycopene intake was
associated with a decreased risk of prostate cancer.[10–12] However, another study[13] did not show a
reduced risk of prostate cancer with beta-carotene supplementation. Another interesting study is that
intake of vitamin A from plant sources was associated with decreased prostate cancer risk while the
intake of vitamin A from animal sources was associated with increased risk.[14] This may be due to the
higher fat content in the diet of men with high animal vitamin A intake. An interesting study by
Giovannucci et al.,[15] has shown that eating at least two servings per week of tomato sauce can
significantly decrease the risk of developing prostate cancer. Tomato paste and other processed tomato
products are even more effective than fresh tomatoes in preventing prostate cancer[16] since tomato
processing actually increases the bioavailability of lycopene to humans. This is because processing
converts much of the trans-form of lycopene found in fresh tomatoes into the cis-form which is much
readily taken up in humans.
Dietary fat
Several studies support a positive correlation between some aspect or component of animal fat and
prostate cancer risk.[17,18] Populations with higher fat intake in diet have increased prostate cancer
relative risks by a factor of 1.6-1.9.[19] High dietary fat may have multi-factorial role in the causation of
prostate cancer. Though it is established that a high-fat diet can increase serum androgen levels, the
precise mechanism for increased production of sexual hormones is not clearly understood. Plasma
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concentrations of fatty acids are increased with increasing consumption of fat and these plasma fatty
acids inhibit binding of gonadal steroids to sex hormone binding globulins.[20] Thus a high fatty diet
may increase prostate cancer risk by causing long-term androgenic stimulation. A low-fat, high-fiber
diet increases fecal excretion of gonadal hormones and possibly lowers serum androgen levels and
thereby lowers incidence of prostate cancer.[21]
Consumption of oily fish and other foods rich in omega-3 fatty acids may help prevent the spread of
carcinoma prostate.[22] The omega-3 fatty acids interfere with functions of omega-6, which cancer
cells may use as a source of energy and prevent them from spreading beyond the prostate.
Soy
The diet in many Asian countries is especially high in plant products including soy.[23] Higher
consumption of soy milk has been found to lower the risk of prostate cancer by 70%.[24] Southeast
Asian men consume up to 50 times more soy daily than their Western counterparts and demonstrate a
10-fold lower incidence of prostate cancer and prostate cancer mortality. Several natural anticarcinogens (such as protease inhibitors, phytates, phytosterols, saponins, lignans and isofavones) have
been identified in soybeans.[25,26] After structural modifications by intestinal bacteria, isoflavones are
converted to compounds that possess weak estrogenic and anti-estrogenic properties. Phytoestrogens
found in soy products increase serum sex hormone binding globulin via increased hepatic synthesis
which then decreases bioavailability of testosterone. Isofavonoids may also prevent prostate cancer by
weakly binding androgen hormone receptors in the prostate thereby interfering with androgenic
stimulation of prostate cells.[27] Genistein, an isoflavone has also received much attention due to its
interesting antiproliferative, estrogenic and antiestrogenic effects in prostate cancer cells.[28,29]
Green tea
Epidemiological studies have shown that there is a low incidence of prostate cancer among native Asian
men with a high dietary intake of green tea and hence the polyphenols contained in green tea have been
proposed as chemopreventive.[30] Prostate cancer cell culture and gene expression experiments have
demonstrated that the major polyphenolic constituent of green tea inhibits cell growth and dysregulates
the cell cycle.[31]
Vitamin E
α-tocopherol is the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains,
nuts and other foods. It is a potent antioxidant and has been suggested as a potential preventative of
several cancers, particularly lung cancer.[32] In the Alpha Tocopherol, Beta Carotene Cancer
Prevention Study,[33] it has been suggested that α-tocopherol administration reduces prostate cancer
risk by reducing the incidence of prostate cancer and even reducing prostate cancer mortality. Many
clinicians have been in the habit of advising higher doses of vitamin E, often 400 IU/day; however,
recently published evidence suggests that the recommended dose should be < 150 IU/day.[34] Some
other studies suggest an inverse relation between blood α-tocopherol levels and prostate cancer risk.[35]
Vitamin E has been theorized to prevent progression of latent tumors to more invasive disease.[36] The
antioxidant property of vitamin E prevents the propagation of free radical damage in biologic
membranes and to critical cellular structures like DNAs and proteins. Vitamin E may also protect by
enhancing immune function and lowering the activity of protein kinase C, a cellular signal transducer
that regulates cell proliferation.
Selenium
Selenium found in many vegetables and grains grown in selenium-rich soil has antioxidant activity and
has other direct effects on tumor cells.[23] Higher level of serum selenium has been found to inhibit the
growth of prostate tumor cells in vitro.[37] One of the randomized placebo-controlled trials done on
skin cancer revealed a statistically significant reduction of prostate cancer incidence of 63% when 200
microgram per day of selenized yeast was given.[38] The protective effect of selenium appeared to be
most prominent in men with low baselines levels of PSA (< 4 ng/ml) and low baseline plasma selenium
concentrations.
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The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was started to evaluate the role of
vitamin E and selenium supplementation in preventing prostate cancer.[39] This prospective,
randomized, double-blind, placebo-controlled prevention trial involved healthy men with a normal
digital rectal examination and a serum PSA level below 4 ng/ml. Subjects were randomized to one of
four treatment groups: vitamin E (400 mg racemic α-tocopherol) plus selenium (200-μgram 1selenomethionine), vitamin E plus placebo, selenium plus placebo or placebo plus placebo. A minimum
follow-up period of seven years was planned. Enrollment of patients began in August 2001 and was
closed in June 2004 with 35,534 participants: final study results are anticipated in 2013. Unlike trials
with selenium and vitamin E reported so far, in which prostate cancer was a secondary end point,
clinical diagnosis of prostate cancer is the primary end point of SELECT.
Vitamin D
Variation in the degree of exposure to sunlight affects the blood levels of vitamin D and calcium in the
population. Studies have shown that men with higher levels of serum calcium have a four to fivefold
elevated risk of metastatic prostate cancer.[11,40] The active metabolite of vitamin D, namely calcitriol
inhibits growth of both primary cultures of human prostate cancer cells and cancer cell lines by a
mechanism not clearly understood. Calcitriol may affect cell cycle progression and also initiate
apoptosis. The current recommended dose of vitamin D is 10 μgram/day.[41] Since overdoses of
vitamin D can result in hypercalcemia, analogues of calcitriol with lesser side-effects, but having more
potent anti-proliferative effect have been developed.[42]
Summary: Food rich in lycopenes (like tomatoes especially as processed tomatoes), omega 3 fatty acids
(fish oils), isoflavonoids (soybeans), polyphenols (green tea), α-tocopherol (vegetable oils, seeds, grains,
nuts), selenium (vegetables, grains), vitamin D and fiber can significantly reduce the risk of developing
prostate cancer or even reduce the mortality due to the disease.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Non-steroidal anti-inflammatory drugs act to prevent the synthesis of endogenous prostaglandins by
inhibition of the cyclo-oxygenase (COX) enzyme. Expression of the COX-2 isoenzyme is three to five
times greater in patients with prostate cancer than in those with benign prostatic hyperplasia and is
responsible for increased angiogenesis, tumorigenesis and prostate cancer growth.[43,44] Non-steroidal
anti-inflammatory drugs (NSAIDs) such as aspirin, sulindac and ibuprofen are reported to have
prostate cancer chemopreventive activity; regular intake of NSAIDs actually reducing the prostate
cancer risk.[45] A meta-analysis of the combined results from 12 studies of NSAIDs and prostate cancer
risk found a 10% risk reduction associated with aspirin therapy,[46] although the risk associated with
other NSAIDs was more variable. However, with the recent evidence regarding increased
cardiovascular risk with selective COX-2 inhibitors, it is unclear whether continuous administration of
these agents can be justified.
Summary: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, sulindac and ibuprofen
are reported to have prostate cancer chemopreventive activity.
SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs)
Interest in SERMs as preventive agents is stimulated by an apparent role of estrogens in the
pathogenesis of prostate cancer through promotion of cell growth.[47] Furthermore, age-related
prostate disease rates parallel increases in serum estrogen levels and there is a low incidence of prostate
cancer in cultures with diets rich in phytoestrogens.[28]
Summary: Phytoestrogens and SERMs are found to have prostate cancer prevention potential in
experimental studies.
5-ALPHA-REDUCTASE INHIBITORS
It is well known that dihydrotestosterone is the principal androgen responsible for normal and
hyperplastic growth of prostate and is 10 times more potent than testosterone. 5-alpha-reductase
inhibitors prevent the conversion of testosterone to dihydrotestosterone. Of the two isoenzymes of 5alpha-reductase, Type 2 is present in normal and hypertrophic prostate tissue, whereas Type 1 is the
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predominant form in prostate cancer cells and is over-expressed in some prostate cancers. Because
androgens are required for the development of prostate cancer[48] and men with lower 5-alphareductase activity have lower rate of prostate cancer, 5-alpha-reductase inhibitors have been considered
for chemo-prevention of prostate cancer. 5-alpha-reductase inhibitors decrease the prostate levels of
dihydrotestosterone and reduce the androgenic stimulation to the prostate, although the systemic
androgenic effects are only mildly affected. In vitro studies also showed that the growth of previously
established prostate cancer lines were inhibited by 5-alpha-reductase inhibition.[49,50] Out of the two
common types of 5-alpha-reductase inhibitors available, finasteride selectively inhibits the Type 2
isoenzyme of 5-alpha-reductase, whereas dutasteride inhibits both izoenzymes. The effect of finasteride
as a chemopreventive agent has been established in the critical analysis of the Prostate Cancer
Prevention Trial (PCPT) study by Goetzl and Holzbeierlein.[51] In the PCPT study, healthy men aged
55 years or older with a normal digital rectal examination and a PSA level of 3 ng/ml or lower were
enrolled and a total of 18,882 men were randomized to receive either finasteride 5 mg/day or placebo
for seven years. Subjects were monitored annually with a digital rectal examination and PSA level
measurement. For those receiving finasteride, total PSA level was adjusted for the effect of finasteride
before being reported. The prevalence of prostate cancer was reduced by 24.8% in the finasteride arm
compared to the placebo arm. However, there was a relative increase in the frequency of invasive
tumors in the finasteride group - one explanation being that finasteride treatment effect not only
selectively inhibits low-grade tumors, but also promotes high-grade tumors. Ultimately, the adoption of
a preventive strategy always hinges on its potential benefits weighed against the potential risks and
recommendations for use of finasteride for prostate cancer prevention.[30] The potential benefits of
finasteride when used to prevent prostate cancer include the reduction in cancer prevalence, fewer
urinary symptoms and lower risk of acute urinary retention, while the drawbacks include the 1.3%
increase in high-grade tumors requiring more aggressive therapy and having potential excess mortality,
sex-related adverse effects and the cost of treatment of such conditions and cost of finasteride.
A Phase II, double-blind, placebo-controlled, dose-ranging comparative trial clearly demonstrated that
serum dihydrotestosterone suppression was significantly greater with the dual (Type 1 and 2) 5-alphareductase inhibitor dutasteride 0.5 mg/day than with finasteride 5 mg/day in men with benign prostatic
hyperplasia.[52] The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial[53] was
aimed to study the effect of dutasteride 0.5 mg/day in men with an increased risk of developing prostate
cancer. Free and total PSA levels were assessed every six months throughout the study and prostate
biopsy performed at two and four years. Study enrollment was completed in 2005 and the results are
awaited.
However, other androgen blockers like flutamide, bicalutamide and nilutamide are associated with too
many side-effects to be of practical use in the asymptomatic healthy population, unlike finasteride.[54]
Summary: 5-alpha-reductase inhibitors such as finasteride and dutasteride have been recommended as
chemotherapeutic agents for prevention of prostate cancer.
OTHER POSSIBLE AGENTS
Studies by Giovannucci and Clinton[55] have shown there was no clear association between dietary
factors like vitamin C, vitamin B1 , vitamin B2 , niacin, zinc, protein and carbohydrates with prostate
cancer. However, other drugs like nonclassic antioxidant agents including the polyphenols, the
isothiocyanates, difluromethylornithine, oltipraz and N-acetyl cysteine have been proposed as potential
chemopreventive agents.[56,57]
Many chemotherapeutic agents including Silibinin, Inositol hexaphosphate, Hecursin, Apigenin,
Acacetin and Epigallocatechin-3 gallate have been identified in laboratory studies to be of use in the
management of prostate cancers.[58] The extract of pomegranate from the tree Punica granatum
possesses strong antioxidant and anti-inflammatory properties and has been found to inhibit human
prostate cancer cell growth in in vitro and in vivo preclinical models.[59] Similarly grape seed extract
has been found to inhibit growth and induce apoptotic death of human prostate cancer cells in culture.
[60] Grape seed extract causes caspase 3 and caspase 9-mediated apoptosis.
Phytochemicals are nonnutritive components of plants that are currently being studied in
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chemoprevention of various diseases for their pleiotropic effects and non-toxicity. Various
studies[61–63] have shown the therapeutic potential of curcumin, which is the active constituent of
turmeric widely used as a spice in Indian cooking, in human prostate cancer. Curcumin has antiinflammatory, antioxidant and anti-tumor properties.[64] The mechanisms proposed are that
curcumin induces apoptosis in both androgen-dependent and androgen-independent prostate cancer
cells, inhibits proliferation and angiogenesis of LNCaP prostate cancer cells and inhibits tyrosine kinase
activity of epidermal growth factor receptor and depletes the protein.
Sanguinarine, an alkaloid derived from the bloodroot plant Sanguinaria canadensis has been shown to
possess anti-microbial, anti-inflammatory and antioxidant properties. It has been shown that
sanguinarine can cause cell cycle blockade and apoptosis of human prostate carcinoma cells via
modulation of cyclin kinase inhibitor-cyclin-cyclin dependent kinase machinery.[65] The growth
inhibitory and antiproliferative effects of sanguinarine in human carcinoma cells was irrespective of
their androgen status.
Encouragingly, it was recently proposed that the consumption of red wine might be protective against
prostate cancer.[66] Every additional glass of red wine drunk per week showed statistically significant
6% decrease in relative risk of prostate cancer and men drinking four to seven glasses per week were
almost 25% less likely to have the disease (a relative risk reduction of 48%). Resveratrol is the candidate
agent in red wine that is thought to protect against cancer. Resveratrol is a naturally occurring plant
antibiotic found in grape skins and red wine and has antioxidant activity, anti-platelet aggregation
effect, anti-atherogenic property, estrogen-like growth promoting effect, growth-inhibiting activity,
immunomodulation and chemoprevention of cancer. Resveratrol metabolizes into the anti-leukemic
agent piceatannol, which may provide a novel explanation for the cancer-preventive properties of
resveratrol. However, other alcoholic beverages did not have similar protective effects.
Eating at least five servings a week of cruciferous vegetables such as broccoli and cauliflower can
significantly decrease the risk of developing prostate cancer.[67] Sulforaphane is the compound having
chemopreventive role in these vegetables.
Zyflamend, a unique herbal preparation with non-selective COX-inhibitory activity, induces apoptosis
of prostate cancer cells that lack COX-2 expression.[68] Zyflamend is composed of 10 potency assured
herbal extracts: rosemary (Rosmarinus officianalis), turmeric (Curcuma longa), ginger (Zingiber
officinale), basil (Ocimum basilicum), green tea (Camellia sinensis), Japanese knotweed (Polygonum
cuspidatum), Chinese goldthread (Soptis spp), barberry (Berberis spp), Oregano (Origanum vulgare)
and Chinese or Baikal skullcap (Scutellaria baicalensis).
Summary: Nonclassic antioxidant agents like polyphenols, isothiocyanates, difluromethylornithine,
oltipraz and N-acetyl cysteine and chemotherapeutic agents including Silibinin, Inositol hexaphosphate,
Hecursin, Apigenin, Acacetin and Epigallocatechin-3 gallate have all been proposed to have
antineoplastic properties. The extracts of pomegranate and grape seed, curcumin, sanguinarine, an
alkaloid derived from the bloodroot plant Sanguinaria canadensis, resveratrol in red wine and
sulforaphane in cruciferous vegetables can also significantly decrease the risk of developing prostate
cancer.
THERAPEUTIC VACCINES FOR PROSTATE CANCER
Vaccines for prostate cancer, which for several years have been shown to generate immunological
responses, are beginning to show significant clinical promise.[69] Dendritic cell vaccines (DCs) are
highly proficient antigen-presenting cells that localize to multiple epithelial sites. The addition of
proteins like prostate-specific membrane antigen (PSMA-DCVax-Prostate vaccine) or prostatic acid
phosphatase GM-CSF fusion protein (Provenge) to such vaccines appears to have beneficial effects in
prolonging survival in carcinoma prostate. Whole-tumor cell vaccines have been investigated for some
years. The GM-CSF secreting vaccine GVAX is an admix of the prostate cancer cell lines PC-3 and
LNCaP whereas Onyvax-P consists of irradiated cell lines from Ony-Cap 23, LNCaP and P4E6. Both
these vaccines are currently undergoing Phase III studies following evidence that they reduce PSA
velocities, extend time to progression and are well tolerated. Pox virus-based vaccines utilizing live
recombinant vaccinia (PROSTVAC) or recombinant fowlpox, induce expression of tumor-associated
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antigens and stimulate T cell activation. However, the efficacy and long-term safety of these vaccines
are currently being assessed in various trials.
Summary: Trials on vaccines offer great promise for prevention of prostate cancer in the near future.
EPILOGUE
Identifying pharmacologic and nutritional preventive strategies for prostate cancer remains a challenge
for physicians and researchers. Though prevention of prostate cancer seems to be novel approach, it is
yet to be understood who would benefit from these drugs. It is logical to understand that people with
genetic predisposition are less likely to benefit than men at risk for sporadic cancer. The efficacy of the
drugs will also have to be proved by large randomized clinical trials of long duration. Biomarkers of
carcinogenesis, tailored to the agent under investigation are essential in the clinical development of
chemopreventive agents. Prostatic intraepithelial neoplasia (PIN) is an intraluminal proliferation of
secretory cells of the prostate duct-acinar system.[70] Common genetic alterations in PIN and prostate
cancer have been identified: gain of Chromosome 7, loss of 8p, gain of 8q and loss of 10q, 16q and 18q.
[71] While low-grade PIN has unclear predictive value for malignancy, high-grade PIN is suspected to
be the precursor to prostate carcinoma because of the similarities in histological diagnosis. Recent
speculation suggests that other histological changes such as metaplasia and atrophy may also be
important precursors for prostate cancer. However, it is not clear whether chemopreventive strategies
could be decided by an invasive test like prostate biopsy, which can pick up these lesions.
Androgen receptor (AR) plays a key role as a transcriptional factor in prostate development and
carcinogenesis. Identification of androgen-regulated genes is essential to elucidate the AR
pathophysiology in prostate cancer. By combining chromatin immunoprecipitation (ChIP) with tiling
microarrays (ChIP-chips), the androgen target genes that are directly regulated by AR in LNCaP cells
have been identified.[72] This will enable us to extend our knowledge of the diversity of the androgen
genetic network and steroid action in prostate cancer cells. Better understanding of the molecular
biology of prostate cancer is also essential to identify the best chemopreventive agent. Another
controversy would be the endpoint of these studies, whether it is the prevention of death, regression of
intraepithelial neoplasia or the decline in PSA both in men with intact prostate and in men with PSA
relapse after radical prostatectomy.[22] One interesting study by Uzzo et al.,[73] showed that a high
proportion of men at risk for prostate cancer self-initiated nutritional therapies in the form of various
nutritional, vitamin and mineral supplements. Leiberman[7] has suggested adopting a public health
approach for prevention of prostate cancer including 1. changes in dietary practices - increased fruits
and vegetables and decreased carbohydrates and charbroiled meat, 2. caloric restriction/obesity control
with reduction in serum IGF-1, 3. increased physical activity and stress reduction and 4. early detection
of precancerous lesions such as PIA (proliferative inflammatory atrophy, which is now considered as
the earliest precursor lesion for prostate cancer), IEN (intraepithelial neoplasia) and early cancer. In
addition, a cost-effective pharmacologic medically oriented translational science strategy is being
developed. This includes 1. identification of individuals at risk using clinical, histological, genetic and
proteomic profiles, 2. risk reduction by chemopreventive agents through modulation of surrogate
endpoints such as IEN, 3. suppression/reversal of promoter CpG methylation in target genes-GSTP1,
RAR-beta etc, 4. suppression/reversal of signature protein patterns of early prostate cancer with delay
in the onset of clinically active prostate cancer. The recent concept of replication-competent adenovirusmediated suicide gene therapy in which an oncolytic adenovirus armed with chemoradiosensitizing
genes is combined with intensity-modulated radiotherapy (IMRT) and used to destroy tumor cells
experimentally[74] provides a beacon of hope to provide a potential long-term benefit to patients with
carcinoma of prostate.
For the common man, the bottom line of prostate cancer prevention would be to consume a variety of
fruits and vegetables, reduce the intake of white bread, meats and saturated fat, reduce or eliminate
smoking, reduce stress, sleep well, exercise, avoid unnecessary hormone use, particularly androgens, eat
more fiber and fish oil. However, it is worthwhile for the treating physician to understand the various
agents useful in primary prevention which includes the period prior to the diagnosis of prostate cancer
and in secondary prevention which may involve the prevention of recurrence or progression of
micrometastatic disease. An ounce of prevention is worth a pound of cure.
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Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
REFERENCES
1. Ross RK, Bernstein L, Lobo RA, Shimizu H, Stanczyk F, Pike M, et al. 5 Alpha reductase activity and
risk of prostate cancer among Japanese and US white and black males. Lancet. 1992;339:887–9.
[PubMed: 1348296]
2. Pienta KJ, Esper PS. Risk factors for prostate cancer. Ann Intern Med. 1993;118:793–803.
[PubMed: 8470854]
3. Brawley OW. The potential for prostate cancer chemoprevention. Rev Urol. 2002;4:S11–7.
[PMCID: PMC1476013] [PubMed: 16986061]
4. Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, Kopelovich L, et al. Chemoprevention of
prostate cancer-concepts and strategies. Eur Urol. 1999;35:342–50. [PubMed: 10325487]
5. Fisher B, Costantino JP, Wickerman DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen
for prevention of breast cancer-report of the national surgical adjuvant breast and bowel project P-1
study. J Natl Cancer Inst. 1998;90:1371–88. [PubMed: 9747868]
6. Gupta S. Prostate cancer chemoprevention - models, limitations and potential. Int J Oncol.
2004;25:1133–48. [PubMed: 15375566]
7. Lieberman R. Evolving strategies for prostate cancer chemoprevention trials. World J Urol.
2003;21:1–11. [PubMed: 12682772]
8. Steinmetz KA, Potter JD. Vegetables, fruit and cancer. Epidemiol Cancer Causes Control. 1991;2:325–
57.
9. Lowe JF, Lawence A. Update on prostate cancer chemoprevention. Pharmacotherapy. 2006;26:353–
9. [PubMed: 16503715]
10. Norrish AE, Jackson RT, Sharpe SJ, Skeaff CM. Prostate cancer and dietary carotenoids. Am J
Epidemiol. 2000;151:119–23. [PubMed: 10645813]
11. Giovannucci E, Ascherio A, Rimm E, Stampfer M, Colditz G, Eillet W. Intake of carotenoids and
retinol in relation to risk of prostate cancer. J Natl Cancer Inst. 1995;87:1767–76. [PubMed: 7473833]
12. Zackheim HS. Tomatoes, tomato based products, lycopene and prostate cancer - review of the
epidemiologic literature. J Natl Cancr Inst. 1999;91:1331.
13. Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, et al. Effects of alpha
tocopherol and beta carotene supplements on cancer incidence in the alpha tocopherol beta carotene
cancer prevention study. Am J Clin Nutr. 1995;62:1427S–30. [PubMed: 7495243]
14. Kolonel LN, Nomura AM, Cooney RV. Dietary fat and prostate cancer-current status. J Natl Cancer
Inst. 1999;91:414–28. [PubMed: 10070940]
15. Giovannucci E, Rimm EB, Liu Y , Stampfer MJ, Willett WC. A prospective study of tomato products,
lycopene and prostate cancer risk. J Natl Cancer Inst. 2002;94:391–8. [PubMed: 11880478]
16. Gann PH, Giovannucci EL. Nutrition and prostate cancer. In: Berman S, editor. Prostate Cancer
Foundation. 2005. pp. 21–7.
17. Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and
mortality. Int J Cancer. 2000;85:60–7. [PubMed: 10585584]
18. Haenszel W, Kurihoro M. Studies of Japanese migrants. J Natl Cancer Inst. 1969;40:43–68.
[PubMed: 5635018]
19. Severson RK, Grove JS, Nomura AM, Stemmerman GN. Body mass and prostatic cancer - a
8/11
21/4/2014
prospective study. BMJ. 1988;297:713–5. [PMCID: PMC1834099] [PubMed: 3147735]
20. Bruning PF, Bonfrer JM. Free fatty acid concentrations correlated with the available fraction of
estradiol in human plasma. Cancer Res. 1989;46:2606–9. [PubMed: 3698000]
21. Pusateri DJ, Roth WT, Ross JK, Shultz TD. Dietary and hormonal evaluation of men at different
risks for prostate cancer - plasma and fecal hormone nutrient interrelationships. Am J Clin Nutr.
1990;51:371–7. [PubMed: 2155524]
22. Brown MD, Hart CA, Gazi E, Bagley S, Clarke NW. Promotion of prostatic metastatic migration
towards human bone marrow stroma by omega-6 and its inhibition by omega-3 PUFAs. Br J Cancer.
2006;94:842–53. [PMCID: PMC2361380] [PubMed: 16523199]
23. Brawley OW, Barnes ST. Potential agents for prostate cancer chemoprevention. Epidemiol Rev.
2001;23:168–72. [PubMed: 11588844]
24. 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. [PubMed: 10189040]
25. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst.
1991;83:541–6. [PubMed: 1672382]
26. Aldercruetz H, Fotsis T, Schweigerer L. Isofavonoids and 2-methoxyestradiol: inhibitors of tumor
cell growth and angiogenesis. Proc Annu Meet Am Assoc Cancer Res. 1994;35:693–4.
27. Evans BA, Griffiths K, Morton MS. Inhibition of 5 alpha reductase in genital skin fibroblasts and
prostate tissue by dietary lignans and isoflavonoids. J Endocrinol. 1995;147:295–302.
[PubMed: 7490559]
28. Denis L, Morton MS, Griffiths K. Diet and its preventive role in prostate disease. Eur Urol.
1999;35:377–87. [PubMed: 10325492]
29. Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-Kappa B activation in prostate cancer cells.
Nutr Cancer. 1999;35:167–74. [PubMed: 10693171]
30. Klein EA. Can prostate cancer be prevented? Nat Clin Pract Urol. 2005;2:24–31.
[PubMed: 16474573]
31. Adhami VM, Ahamad N, Mukhtar H. Molecular targets for green tea in prostate cancer prevention.
J Nutr. 2003;133:2417S–24S. [PubMed: 12840218]
32. Skhlar G, Oh SK. Experimental basis for cancer prevention by vitamin E. Cancer Invest.
2000;18:214–22. [PubMed: 10754990]
33. 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. [PubMed: 9521168]
34. Kirby RS, Fitzpatrick JM. How should we advise patients about the chemoprevention of prostate
cancer? BJU Int. 2005;96:231–6. [PubMed: 16042705]
35. Hsing AW, Comstock GW, Abbey H, Polk BF. Serologic precursors of cancer: Retinol, carotenoids
and tocopherol and risk of prostate cancer. J Natl Cancer Inst. 1990;82:941–6. [PubMed: 2342127]
36. Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM, Giovannucci EL. Supplemental vitamin E
intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol
Biomarkers Prev. 1999;8:887–92. [PubMed: 10548318]
37. Webber MM, Perez-Ripoll EA, James GT. Inhibitory effects of selenium on growth of DU-145
human prostate carcinoma cells in vitro. Biochem Biophy Res Commun. 1985;130:603–9.
38. Clark LC, Combs GR, Jr, Turnbull BW. Effects of selenium supplementation for cancer prevention
in patients with carcinoma of the skin: A randomized controlled trial. JAMA: 1996. Nutritional
Prevention of Cancer Study Group; pp. 1957–63. 276.
9/11
21/4/2014
39. Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. SELECT: the
Selenium and Vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer Prostatic Dis.
2000;3:145–51. [PubMed: 12497090]
40. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality: evidence for a
protective effect of ultraviolet radiation. Cancer. 1992;70:2861–9. [PubMed: 1451068]
41. Kumar NB, Besterman-Dahan K. Nutrients in the chemoprevention of prostate cancer: current and
future prospects. Cancer Control. 1999;6:580–6. [PubMed: 10756389]
42. Blutt SE, Weigel NL. Vitamin D and prostate cancer. Proc Soc Exp Biol Med. 1999;221:89–98.
[PubMed: 10352118]
43. Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H. Overexpression of cyclooxygenase-2 in
human prostate carcinoma. Prostate. 2000;42:73–8. [PubMed: 10579801]
44. Barqawi A, Thompson IM, Crawford ED. Prostate cancer prevention: An overview of United States
Trials. J Urol. 2004;171:S5–9. [PubMed: 14713745]
45. Harris RE, Beebe-Donk J, Doss H, Doss DB. Aspirin, ibuprofen and other nonsteroidal antiinflammatory drugs in cancer prevention: A critical review of non-selective COX-2 blockade. Oncol
Rep. 2005;13:559–83. [PubMed: 15756426]
46. Mahmud S, Franco E, Aprikian A. Prostate cancer and use of nonsteroidal anti-inflammatory drugs:
Systematic review and meta-analysis. Br J Cancer. 2004;90:93–9. [PMCID: PMC2395299]
[PubMed: 14710213]
47. Steiner MS, Raghow S. Antiestrogens and selected estrogen receptor modulators reduce prostate
cancer risk. World J Urol. 2003;21:31–6. [PubMed: 12756492]
48. Klein EA, Thompson IM. Update on chemoprevention of prostate cancer. Curr Opin Urol.
2004;14:143–9. [PubMed: 15069304]
49. Bologna M, Muzi P, Biordi L, Festuccia C, Vicentini C. Anti androgens and 5-alpha-reductase
inhibition of the proliferative rate in PC3 and DU145 human prostate cancer cell lines. Curr Ther Res.
1992;51:799–813.
50. Delos S, Iehle C, Martin PM, Reynaud JP. Inhibition of the activity of basic 5 alpha reductase (type
I) detected in DU 145 cells and expressed in insect cells. J Steroid Biochem Mol Biol. 1994;48:347–52.
[PubMed: 8142312]
51. Goetzl MA, Holzbeierlein JM. Finasteride as a chemopreventive agent in prostate cancer: impact of
the PCPT on urologic practice. Nat Clin Pract. 2006;3:422–9.
52. Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S. Marked suppression of
dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5-alpha-reductase
inhibitor. J Clin Endocrinol Metab. 2004;89:2179–84. [PubMed: 15126539]
53. Gomella LG. Chemoprevention using dutasteride: the REDUCE trial. Curr Opin Urol. 2005;15:29–
32. [PubMed: 15586026]
54. Stoner E. Three year safety and efficacy data on the use of finasteride in the treatment of benign
prostatic hyperplasia. Urology. 1994;43:284–92. [PubMed: 7510911]
55. Giovannucci E, Clinton SK. Tomatoes, lycopene and prostate cancer. Proc Soc Exp Biol Med.
1998;218:129–39. [PubMed: 9605211]
56. Thompson IM, Coltman CA, Brawley OW, Ryan A. Chemoprevention of prostate cancer. Semin
Urol. 1995;13:122–9. [PubMed: 7638469]
57. Singh DK, Lippman SM. Cancer chemoprevention, Part 2: Hormones non classic antioxidant
natural agents, NSAIDs and other agents. Oncology (Huntingt) 1998;12:1787–800.
[PubMed: 9874850]
58. Singh RP, Agarwal R. Mechanisms of action of novel agents for prostate cancer chemoprevention.
10/11
21/4/2014
Endocrine-Related Cancer. 2006;13:751–78. [PubMed: 16954429]
59. Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H. Proc Natl Aca Scien USA (PNAS)
2005;102:14813–8. [PMCID: PMC1253570]
60. Agarwal C, Singh RP, Agarwal R. Grape seed extract induces apoptotic death of human prostate
carcinoma DU 145 cells via caspase activation accompanied by dissipation of mitochondrial membrane
potential and cytochrome c release. Carcinogenesis. 2002;23:1869–76. [PubMed: 12419835]
61. Dorai T, Gehani N, Katz A. Therapeutic potential of curcumin in human prostate cancer-I. Prostate
cancer Prostatic Dis. 2000;3:84–93. [PubMed: 12497104]
62. Dorai T, Cao Y C, Dorai B, Buttyan R, Katz AE. Therapeutic potential of curcumin in prostate
cancer-III. Prostate. 2001;47:293–303. [PubMed: 11398177]
63. Dorai T, Gehani N, Katz A. Therapeutic potential of curcumin in prostate cancer-II. Mol Urol.
2000;4:1–6. [PubMed: 10851300]
64. Thangapazham RL, Sharma A, Maheshwari RK. Multiple molecular targets in cancer
chemoprevention by curcumin. AAPS J. 2006;8:443–9. [PMCID: PMC2761050]
65. Adhami VM, Aziz MH, Reagan-Shaw SR, Nihal M, Mukhtar H, Nihal A. Sanguinarine causes cell
cycle blockade and apoptosis of human prostate carcinoma ells via modulation of cyclin kinase
inhibitor-cyclin-cyclin-dependent kinase machinery. Mol Cancer Ther. 2004;3:933–40.
[PubMed: 15299076]
66. Schoonen WM, Salinas CA, Kiemeney AL, Stanford JL. Alcohol consumption and risk of prostate
cancer in middle aged men. Int J Cancer. 2005;113:133–40. [PubMed: 15386436]
67. Giovannucci E, Rimm EB, Liu Y , Stampfer MJ, Millet WC. A prospective study of cruciferous
vegetables and prostate cancer. Cancer Epidemiol Biomarkers Prev. 2003;12:1403–9.
[PubMed: 14693729]
68. Bemis DL, Capodice JL, Anastasiadis AG, Katz AE, Buttyan R. Induction of prostate cancer cell
apoptosis with Zyflamend. Nutr Cancer. 2005;52:202–12. [PubMed: 16201851]
69. Tarassoff CP, Arlen PM, Gulley JL. Therapeutic vaccines for prostate cancer. Oncologist.
2006;11:451–62. [PubMed: 16720845]
70. Montironi R, Mazzucchelli R, Algaba F, Lopez-Beltran A. Morphological identification of the
patterns of prostate intraepithelial neoplasia and their importance. J Clin Pathol. 2000;53:655–65.
[PMCID: PMC1731241] [PubMed: 11041054]
71. Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Eng J Med. 2001;344:1373–7.
72. Takayama K, Kaneshiro K, Tsutsumi S, Horie-Inoue K, Ideda K, Urano T, et al. Identification of
novel androgen response genes in prostatic cancer cells by coupling chromatin immunoprecipitation
and genomic microarray analysis. Oncogene. 2007;26:4453–63. [PubMed: 17297473]
73. Uzzo RG, Brown JG, Horwitz EM, Hanlon A, Mazzoni S, Konski A, et al. Prevalence and patterns of
self-initiated nutritional supplementation in men at high risk of prostate cancer. BJU Int. 2004;93:955–
60. [PubMed: 15142142]
74. Freytag SO, Movsas B, Aref I, Stricker H, Peabody J, Pegg J, et al. Phase I trial of replicationcompetent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol
Ther. 2007;15:1016–23. [PubMed: 17375076]
Articles from Indian Journal of Urology : IJU : Journal of the Urological Society of India are provided here courtesy of
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