Download Current paradigms of cancer chemoprevention

Turkish Journal of Biology
http://journals.tubitak.gov.tr/biology/
Review Article
Turk J Biol
(2014) 38: 839-847
© TÜBİTAK
doi:10.3906/biy-1405-42
Current paradigms of cancer chemoprevention
Rajendra G. MEHTA*
Cancer Biology Division, IIT Research Institute, Department of Biological and Chemical Sciences,
Illinois Institute of Technology, Chicago, Illinois, USA
Received: 15.05.2014
Accepted: 09.07.2014
Published Online: 24.11.2014
Printed: 22.12.2014
Abstract: Cancer chemoprevention has been continually evolving ever since the term was coined in the 70s. From the original
approaches of identifying chemopreventive agents from the dietary constituents based on the epidemiological data to the current status
of adapting them from the molecular targets, significant understanding of cancer as a disease and its possible prevention has been
achieved. The identification of the chemopreventive agent from a complex mixture of natural product extracts involves numerous steps
including bioassay guided fractionation; evaluation of the extracts, fractions and isolated new chemicals selectively using in vitro and
in vivo experimental models; and understanding the mechanism of their action. This in turn provides identification of the molecular
target for the parent drug and a basis for the synthesis of more effective, nontoxic analogs. A chemopreventive agent by definition needs
to be nontoxic, since it is expected to be consumed by healthy people that may be at a higher risk of developing cancer. This makes a
case for these agents to be evaluated as possible adjuvant chemotherapeutic agents. It is expected that more selective delivery methods
to the target organs to eliminate toxicity and use of chemopreventive agents as adjuvant chemotherapeutic agent using personalized
approaches will be the next steps for chemoprevention.
Key words: Chemoprevention, biomarkers, prevention trials, discovery of chemopreventive agents
1. Introduction
It is true that the enormous effort diverted to basic and
clinical cancer research has resulted in identifying new
approaches to cancer treatment. However, the interest
in prevention of cancer has been evolving. As Benjamin
Franklin said “an ounce of prevention is worth a pound
of cure”. Over the past 30 years considerable progress has
been made in the field of cancer prevention (BilecováRabajdová et al., 2013). The word chemoprevention
was coined by Michael Sporn and was defined as “the
use of pharmacologic or natural agents that inhibit the
development of invasive breast cancer either by blocking
the DNA damage that initiates carcinogenesis, or by
arresting or reversing the progression of premalignant
cells in which such damage has already occurred.”
(Sporn et al., 1976). Since then the progress in the field of
chemoprevention has resulted in the development of the
concept of molecular chemoprevention, which includes
altered gene expression and signal transduction that in
turn can prevent cell transformation or progression of
the disease (Mehta et al., 2010). In order to understand
chemoprevention, it is essential to differentiate between
chemoprevention and chemotherapy. As shown in Figure 1,
the major difference between these 2 groups is the fact that
*Correspondence: [email protected]
absolutely no toxicity is acceptable for chemopreventive
agents, whereas most chemotherapeutic agents are more
or less toxic (Mehta et al., 2012). This is based on the
concept of risk versus benefit. As chemotherapeutic agents
are employed for cancer patients some risk of toxicity is
acceptable as compared to chemopreventive agents, which
are expected to be consumed by a high risk group of people
who are otherwise healthy. However, the demarcation
between chemoprevention and chemotherapy is very
cloudy. It is not clear where chemoprevention ends and
chemotherapy begins. Since chemopreventive agents
have been evaluated during all phases of carcinogenesis
including initiation, promotion, and progression, they can
be used in combination with chemotherapeutic agents in
order to enhance the effectiveness of chemotherapeutic
drugs and to reduce toxicity (Cabrespine-Faugeras et al.,
2010). To this end it is interesting to note that most of the
chemopreventive agents inhibit proliferation of cancer cells
in vitro, providing a rationale for their use in combination
with other drugs. Yet clinical trials for prevention of cancer
have been less successful as they require large enrolment
and the studies are cost prohibitive (Steward and Brown,
2010). Despite that, many clinical trials have been
completed with some success (Visvanathan et al., 2013).
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Prevention of
Progression
2nd Primary,
Delay of the onset
Prevention
MMOC
Cell Transformation
Colonic ACF
Experimental
Chemical
carcinogenesis
Therapy
Nontoxic, Food
Habits
Risk/Benefit
Toxicity, CTA
Xenograft models
Cancer cells.
Chemopreventive agents (CPA)
High Risk Group
Cancer Patients
Figure 1. Selective application of chemopreventive agents for both prevention and therapy and chemotherapeutic agents.
In this review, progression of the field of chemoprevention
is concisely summarized and some possible avenues of
future research in this area are highlighted.
2. Discovery of new chemopreventive agents
Healthy dietary habits, which include consumption of
fruits and vegetables and reduced intake of fatty food
and red meat, as well as refraining from smoking, have
been equated to reduced cancer incidence. The chemical
composition that has been suggested as cancer preventive
includes phytoestrogens (resveratrol), flavonoids (such as
genistein, quercetin), vitamins (retinoids (A), deltanoids
(D), alpha tocoferol (E)), organosulfurs (brassinin,
sulforaphane, isothiocyanates), minerals (such as calcium
and selenium) etc. (Khuda-Bukhsh et al., 2014). There is
significant epidemiological evidence that supports the
fact that various phytochemicals can have a protective
role against cancer development and its progression
(Kocic et al., 2013). Many of these have been evaluated
extensively in chemically induced carcinogenesis models
in vivo (Naithani et al., 2008; Smith and Muller, 2013).
Earlier the chemopreventive agents were broadly divided
into blocking agents and suppressing agents (Wattenberg,
1992). Typically the tumor blocking agents or antiinitiating agents were effective in scavenging free radicles,
suppressing inflammatory responses, enhancing phase
II metabolizing enzymes, suppressing carcinogen uptake
and metabolism, preventing alterations in the methylation
to protect the cells from oncogenic expression or from
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inactivating tumor suppressor genes, and inducing DNA
repair (Mehta et al., 2010). The suppressing agents on
the other hand can mediate their effects in a variety of
different ways including altered gene expression and
signaling cascade, induction of cell senescence, inducing
cell differentiation or apoptosis, and blocking cell cycle
(William et al., 2009). Chemically the phytochemicals
are divided into a variety of major chemical structures
including flavonoids, chalcones, isoflavanoids, flavonones,
anthocynidines, coumarines, carotinoids, organosulfurs,
polyunsaturated fatty acids, and certain glycoproteins
such as lactoferrin and selenium (Naithani et al., 2008).
The biological activities of many of these chemopreventive
agents are listed in Table 1.
During the past 20 years a major effort has been
directed towards discovering new cancer preventive agents
from natural products in systematic bioassay guided
fractionation. Several laboratories throughout the world
are engaged in such research. One such program was led
by Dr John Pezzuto at the University of Illinois, Chicago.
Several chemopreventive agents were identified as a part
of this National Cancer Institute supported program
(Mehta and Pezzuto, 2002; Gullett et al., 2010) and a few
of them have been evaluated in clinical trials. The steps to
discover a new chemopreventive agent are summarized in
Figure 2. Briefly, the plants were rationally selected from
various parts of the world based on the scientific literature
and community-identified medicinal values (Kinghorn
et al., 2010). The plant extracts were evaluated in in
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Table 1. Summary of the cancer chemopreventive mechanism of natural chemopreventive agents.
Activity
Chemopreventive agents
Antioxidant effects
Ellagic acid , vitamin C, carotenoids, flavonoids, anthocyanins, phenolic compounds
polyphenols, curcumin, anthocyanin, conjugated fatty acids
Phase I enzyme induction
Diallyl sulfide, curcumin, indole-3 carbinol, catechins
Phase II enzyme induction
Carotenoids, flavonoids, anthocyanins, phenolic compounds, polyphenols, circumin,
anthocyanin
Immunomodulatory effects
Carotenoids, flavonoids, lactoferrin
Modulation of the hormone
Genistein
Antimicrobial effect
Curcumin, sulfur compounds, sulfuraphane, isothiocyanates
Apoptosis induction
Limonene, isothiocyanates, diallyl sulfides, flavonoids, organo-selenium compounds
Anti-angiogenesis
Lactoferrin, flavonoids
Cell differentiation induction
Lariciresinol (II) and sitoindoside II
Molecular association with carcinogen
Flavonoids, anthocyanins, phenolic compounds, polyphenols, curcumin, anthocyanin
Cell cycle arrest
Genistein, DADS, DATS, and SAMC
Arachidonic acid cascade modification
PUFA , curcumin, flavonoids, resveratrol
Inhibition of DNA adduct formation
Organosulfur compounds, DAS and DADS, selenium compounds
Inhibition of polyamine metabolism
Organosulfur compounds, organoselenium compounds, DFMO
Inhibition of DNA synthesis
DHEA, fluasterone
Inhibition of oncogene activity
Perillyl alcohol, limonene, DHEA
Increase of intercellular communication
Carotenoids, retinoids
Cancer cell lines
Mechanism based
assays
HPLC
NMR, LC-MS
Microarray, proteins, genes,
signaling pathways etc.
in selected cell lines where
positive effects are identified
Phase I small number of
participants Dose selection
Phase II Large group size
(Expensive)
Phase III with Pharmaceutical
industry partner
(Very Expensive)
Rational selection of plants
Screening of plant extracts
Effective Extract (Primary screen)
Secondary screens (Active extract)
Fractionation: Selective assay(s)
Active Fraction (Confirmation)
Identification of novel CPA
In Vivo Carcinogenesis
Mechanism of action
GMP Synthesis
Preclinical Toxicity
(FDA approval)
Clinical Trials
Epidemiology, Folklore
ACF, PIN, MMOC
GGT+ Foci etc.
Assay with positive
result primary screen
Chemically induced carcinogenesis
Transgenic/gene knockout mice
Organic synthesis
under GMP guidelines
Two species rats,
primates or dogs
GLP conditions, MTD, PK,
Toxicology profile
Figure 2. Discovery of a new phytochemical as a chemopreventative agent: from bench to bedside.
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vitro bioassays to examine cell proliferation, apoptosis,
differentiation, antioxidant property, and anti-estrogenic
and anti-aromatase activities. Any extract exhibiting
positive response is then evaluated in a secondary assay,
which includes a mouse mammary gland organ culture
assay (MMOC) (Mehta et al., 2008) and aberrant crypt
foci (ACF) in a mouse colon assay (Saleiro et al., 2010).
In the MMOC assay it is determined if the test agent
inhibits development of precancerous lesions induced
by a carcinogen in organ culture. In the ACF assay it is
investigated whether the test agent inhibits formation of
azoxymethane induced ACF in mice. In contrast to cell
cultures, here the organs are involved with multiple cell
types. The extract is then fractionated into various fractions
and the active fraction is identified and characterized by
medicinal chemists. This new agent is then either isolated
or synthesized and evaluated for its efficacy in chemically
induced carcinogenesis model(s). Using this approach
we identified brassinin and deguelin for colon and breast
carcinogenesis, resveratrol for mammary carcinogenesis,
sulforamate for mammary carcinogenesis, zapotin for
lung carcinogenesis, and 4-bromophenol for mammary
carcinogenesis (Mehta et al. 2010). The synthetic chemistry
group in the program has synthesized several analogs of the
parent molecules with the intention of developing more
potent and less toxic chemopreventive agents. One such
analog of vitamin D, 1a-hydroxyvitamin D5, developed in
our laboratory was chemically synthesized and has been
approved for clinical trial by the FDA (US Food and Drug
Administration).
3. Molecular targets and signaling molecules essential
for chemoprevention
The transformation of a normal cell to a cancer cell involves
multiple molecular steps (William et al., 2009; Lee et al.,
2012). The molecular pathways regulating normal cell
functioning apparently get deregulated during the process.
Suppressors of these processes broadly, for example
synthetic or natural chemicals that will inhibit carcinogen
metabolism (Lee et al., 2012), increase DNA repair
(Mahmoud et al., 2014), and regulate cell proliferation and
programmed cell death (Wang and Zheng, 2013), would
classify as chemopreventive agents. Over the years as the
molecular mechanisms for each of these processes became
clearer, the molecular targets started to emerge (William et
al., 2009). Selectively identifying chemopreventive agents
that would specifically block or enhance the target genes
or proteins can serve as ideal chemopreventive agents. For
example, in inflammation mediated carcinogenesis the
inflammation stimulus releases TNFa, which can activate
the NFkB pathway in epithelial cells (Aggarwal et al., 2013).
The signaling cascade then would activate production
of BcL-XL and IAP-1 (Szliszka and Krol, 2011) and cell
842
cycle regulatory cyclins, such as cyclin D. During the
inflammation induced carcinogenesis, expression of Cox2 is also upregulated, resulting in increased prostaglandin
E2, which is responsible for loss of contact inhibition,
increased cell proliferation, and loss of E-cadherin.
Therefore, compounds that would block TNFa, NFkB,
or Cox-2 may serve as possible chemopreventive agents
against inflammation induced cell transformation
(Aggarwal et al., 2013; Wang et al., 2013). There are
several chemopreventive agents that have targeted Cox-2
expression, which include resveratrol, indol-3-carbinol,
epigalocatechin gallate (EGCG), curcumin, sulforaphan
etc. (Temraz et al., 2013).
It has become increasingly clear that the stromal
microenvironment plays a big role in the process of
carcinogenesis (Labarge et al., 2014). Numerous reports
have focused on targeting microenvironment regulators
for cancer chemotherapy. However, this approach has
not been extensively explored for chemoprevention.
For example, several inhibitors of VEGF and FGF
signaling such as anti-VEGFR or angiogenesis inhibitors
such as endostatin or tumstatin have been evaluated
experimentally as well as clinically for their efficacy
(Funakoshi et al., 2014; Limaverde-Sousa et al., 2014).
Moreover, many chemotherapeutic agents are targeted to
suppress expression of EGFR, FGFR, PDGFR, and cMet.
Inhibitors of extracellular matrix turnover such as suramin
and dalteparin and matrix metalloproteinase (MMP)
inhibitors have also been under investigation. It certainly is
possible that some selective chemopreventive agents may
have a similar function. For example, we recently reported
the role of deguelin in suppression of cell invasion and
metastasis of triple negative breast cancer cells (Mehta et
al., 2013). It was also observed that the effect of deguelin
was mediated by inhibiting cMet (Mehta et al., 2013).
Deguelin was originally identified as a chemopreventive
agent from an African plant and it inhibits skin, colon,
and mammary carcinogenesis at nontoxic concentrations.
An overview of many of these molecular mechanisms
for cell transformation, and progression of transformed
cells to achieve invasive and metastatic potential as well
as the molecular targets that can be identified for cancer
preventive and therapeutic agents are summarized in
Figure 3 and Table 2.
Another major category where targeting therapy has
become extremely successful in chemotherapy and to
certain extent in chemoprevention is steroid receptors.
Tamoxifen and raloxifene have been clinically used as a
treatment for steroid receptor positive breast cancer patients
(Jordan, 2014). A tamoxifen clinical trial was carried out
for chemoprevention in women at high risk of developing
breast cancer with some degree of success. Similarly,
aromatase inhibitors such as letrozole are considered a
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Growth
Transformation
Transformed
cell
Normal cell
Genetic aberration
Carcinogen
• Chromosomal
breakage
• DNA adducts
• Inflammation
• Activation of nitrogen
• Enhanced cell division
• Altered gene expression
• Altered signal transduction
Cancer cell
Transformed cell
Main actions of chemopreventive agents
• Blocking phase I and II enzymes
• DNA repair
• Scavenge activated oxygen species
Malignancy
Main actions of chemopreventive
agents
• Cell cycle arrest
• Apoptosis
• Histone deacetylase inhibition
• Antioxidant
Cancer cell
• Chromosomal abnormalities
• Expression of oncogenes
• Additional mutations
Invasion metastasis
Features of metastasis:
• Vascularization
• Invasion, detachment
• Embolization
• Survival in the circulation
• Extravasation
• Invasion of host defense
• Proliferation at distant site
Possible actions of chemopreventive agents
• Suppress expression of oncogenes and/or enhance expression of
tumor suppressors
• Inhibit angiogenesis (VEGF, HIF etc.)
• Inhibit matrix metalloproteinase (MMPs)
• Upregulate tissue inhibitor of metalloproteinase
• Modulation the epithelial to mesenchymal transition (EMT)
Figure 3. Distribution of various cellular activities during carcinogenesis and metastasis.
Table 2. Selected list of chemopreventive agents and their molecular targets.
Molecular targets
Chemopreventive agents
Nuclear receptors (ERa, ERb, PR, VDR, PPARg), EGFR
Tamoxifen, raloxifene, proellex, RU486, vitamin D analogs, deguelin
Aromatase, 5a-reductase
Enzyme inhibitors such as letrozole, finestride
AKT, NFkB, chemokines, b-catenin
EGCG, resveratrol, retinoids, curcumin, deguelin
HIF1
Apigenin, resveratrol, deguelin, sulforaphan
COX2
Celecoxib, piroxicam, aspirin, resveratrol, and many others
STAT 1,3,5, TGFb
CDDO, imidazolide
VEGF
EGCG, fenretinids, vitamin D, deguelin
NRF2
Brassinin, sulforaphan, oltipraz, resveratrol
first line of therapy for ER+ postmenopausal patients (Van
Asten et al., 2014). Like tamoxifen, aromatase inhibitors
have also been evaluated as possible chemopreventive
agents. More recently it was observed that antiprogestins
suppress development of carcinogen induced mammary
tumors in rats. This class of agents also provides a good
lead for clinical intervention. Antiprogestins to target
progesterone receptors for breast cancer patients are being
developed for chemoprevention trials (Wiehle et al., 2011).
Similarly, considerable attention is also focused on the
inducers of ERb in mammary and colon carcinogenesis
(Saleiro et al., 2012).
More recently HIF-1 (hypoxia inducible factor 1) has
been considered as a target for both cancer therapy and
prevention (Wouters et al., 2013). This is based on the fact
that tumor cells are less oxygenated as compared to normal
cells. New cancer therapeutic agents are being developed
targeting hypoxia-induced factor-1 (HIF-1). In addition to
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several cancer types including breast and prostate cancers,
HIF-1 expression is found to be elevated in premalignant
colon ACF, ductal carcinoma in situ (DCIS), and prostate
prostatic intraepithelial neoplasia (PIN). This would
then lead to a possibility that HIF can be targeted for
chemoprevention. The drugs that are being considered as
HIF-1 inhibitors so far are relatively toxic (Wouters et al.,
2013). The challenge would be to develop nontoxic HIF-1
targeting chemopreventive agents. There have been a few
reports suggesting HIF-1 inhibitory activities of genistein
and apigenin. However, these reports are very preliminary.
We observed that deguelin also inhibits HIF-1 activity in
breast cancer cells (Mehta et al., 2013). Deguelin has not
been evaluated in cancer prevention protocols for HIF-1
activity.
4. MicroRNA as possible targets for chemoprevention
MicroRNAs are small, 19–24 nucleotides in length,
noncoding RNAs that control gene expression by
triggering translation repression and RNA degradation.
There are less than 2000 miRNA regulating translational
function of about 35% of the genome (Ye and Cao, 2014).
One miRNA can regulate expression of numerous mRNAs.
Since miRNAs are differentially expressed in normal and
cancer cells they can be identified as molecular targets
for cancer chemoprevention. The miRNAs have generally
been classified as potential oncogenes or suppressors. For
example, miRNA-82 is a potential oncogene, whereas let7 is a suppressor that suppresses HMGA2 oncogene and
regulates RAS oncogene through translation repression
(Peng et al., 2008; Ouyang et al., 2014). We expect
miRNAs as possible targets for chemoprevention since
chemopreventive agents such as curcumin and folates have
been reported to modulate miRNA expression (Sarkar et
al., 2013). We reported earlier that induction of oxidative
and chemical stress in MCF7 cells altered the expression
of let-7 miRNA and the effects were reversed by vitamin
D (Peng et al., 2010). Moreover, vitamin D induced cell
differentiation was regulated by miR181 targeting p21
expression (Giangreco et al., 2013). The literature on
MicroRNA regulatory functions is constantly evolving and
will provide a logical molecular target for carcinogenesis
and chemoprevention.
5. Nanochemoprevention
The fundamental requirement for chemoprevention is
that the preventive agents have to be nontoxic. This limits
the use of many potent chemopreventive agents. Another
major issue has been bioavailability; many of the potential
cancer preventive compounds are not readily bioavailable.
To this end, recent advances in nanotechnology provide
effective ways to deliver test agents to the target sites. In one
of the reports it was observed that delivery of EGCG using
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nanoparticles retained its anticarcinogenic properties
(Khan et al., 2014). Packaging and delivery of other
chemopreventive agents including resveratrol and vitamin
D (Almouazen et al., 2013) have been accomplished.
More recently it was reported that treatment with a
solid lipid nano-encapsulated combination of curcumin,
aspirin, and sulforaphane resulted in enhanced reduction
in the incidence of chemically induced pancreatic
cancer in Syrian golden hamsters as compared to the
unmodified combination of drugs at 10 times reduced
concentrations (Grandhi et al., 2014). This study provides
a strong lead for the nanotechnological approach to
chemoprevention. Confirming such an approach for other
chemoprevention models can provide a strong rationale
for using nanotechnology for chemoprevention where
bioavailability of the drugs is often a limiting factor.
Similar drug-combination approaches can also identify
interactive molecular signaling pathways for their action
in chemoprevention.
6. Translational application of chemoprevention
The research efforts of many investigators in the field of
chemoprevention for the past 3 decades have resulted in
the application of chemoprevention approaches under
clinical settings. Like clinical trials for chemotherapy,
chemoprevention trials also need to identify safe dose
and bioavailability (phase I and II) in humans. The
randomized clinical trials (phase III) for chemoprevention
require thousands of participants and have to be carried
out over a long period. This can become cost ineffective.
Therefore, more recently some studies have utilized phase
0 clinical trials (Steward and Brown, 2013). These studies
require very low doses of the chemopreventive agent and
new approaches to study pharmacokinetics and toxicity.
Ideally the discovery of blood- or urine-based biomarkers
that can be predictive of malignancy or response to
chemopreventive agents would be extremely valuable.
Currently only a few markers are routinely used in clinical
practice (Uray and Brown, 2013). These include ACF of
the colon, colon polyps and adenomas, breast density and
mammograms, DCIS in women, PIN in men for prostate
cancer etc. However, there is a clear need for developing
new clinical noninvasive markers that can predict the
disease more accurately. There have been more than 50
cancer prevention trials reported. However, the majority
of the studies are incomplete or not supported by sufficient
numbers of participants or appropriate statistics (Naithani
et al., 2008). The most popular chemoprevention trials
include the Breast Cancer Prevention Trial (BCPT) for high
risk women. In this trial with tamoxifen more than 13,000
women participated and the results showed that there was
a significant reduction in invasive and noninvasive breast
cancer, indicating a positive outcome for tamoxifen as a
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chemopreventive agent. However, tamoxifen treatment
resulted in an increased incidence of endometrial
cancers and thromboembolic events (Cuzick et al., 2013).
Therefore, a second trial was carried out with raloxifene,
an antiestrogen similar to tamoxifen but without the side
effects of endometrial cancers. The results indicated that
raloxifene was safer than tamoxifen and did not have
any adverse effects on the endometrial cancers. However,
the effectiveness was less as compared to tamoxifen. In
addition, a few other robust clinical trials have also been
completed. These include a clinical trial with finasteride,
an inhibitor of 5a-reductase and an enzyme necessary
for the production of dihydrotestosterone. Finasteride
treatment for 7 years was effective in reducing prostate
cancer incidence by 25% (Ankrest et al., 2013). Another
chemoprevention trial was completed with aspirin, a
nonsteroidal anti-inflammatory drug (NSAID), for colon
cancers (Ishikawa et al., 2014). The results showed that
3-year treatment with a high dose of aspirin reduced colon
cancer related deaths. To achieve similar effectiveness
with a lower dose of aspirin (<300 mg daily) would
require 5-year treatment. Contrary to this, a large clinical
trial with selenium and α-tocopherol was carried out by
recruiting 35,500 men for 4 arms. The men received a
placebo, α-tocopherol, selenium, or both α-tocopherol and
selenium. This trial had to be terminated since no positive
results could be predicted (Dunn et al., 2010) and there
was an increased risk of developing prostate cancer for
people consuming α-tocopherol. These results collectively
indicate that, unlike chemotherapeutic agents, there is a
long way to go for chemoprevention trials, since they are
very costly, need a large number of participants, and the
trials have to be conducted for a long period.
7. Summary
In this review a broad brush picture of chemoprevention
is provided. Briefly the field has evolved from determining
the efficacy of dietary treatment of synthetic analogs
of analogs of vitamin A to evaluation of hundreds of
chemopreventive agents. More recently emphasis has
been directed towards determining the efficacy of
chemopreventive agents on selected molecular targets
and employing newer approaches of safe targeted delivery
that would require lower concentrations of the drugs
and have reduced toxicity. Another major focus has
been in identifying early endpoint markers that could be
determined with less invasive procedures. To this end,
some molecular marker present in blood, urine, sputum,
or biological fluids would be ideal. Clinical trials for
chemoprevention, while important and desirable, are cost
prohibitive and require large number of volunteers who
may be at high risk of developing cancer. Recent failures of
chemoprevention trials also raise concerns for such longterm expensive clinical trials.
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