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Current Medicinal Chemistry 2001, 8, 1349-1362 1349
A Review of Cancer Chemopreventive Agents
M. S. Levi*, R. F. Borne and J. S. Williamson
School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, USA
Abstract:In the late 20
th
century, the treatment of cancer began to include its prevention. Today, compounds
exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where
chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having
chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen
receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogendependent tumors.
Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors.
Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The
steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a
start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to
determine the chemopreventive activity of new compounds are quite often activities of enzymes. The
identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.
INTRODUCTION developing other types of cancer. Immunotherapy involves
stimulating the body's own immune system to fight the
cancer. This area is showing promise in the fight against
cancer.
Cancer, a group of more than 100 different diseases,
manifests itself as uncontrolled cellular reproduction, local
tissue invasion and distant metastases [1,2]. The multistage
process of carcinogenesis is a gradual one that may go on for
decades and is rarely the result of one single event. The first
step in the process is initiation, which the normal cell enters
by being exposed to carcinogens such as chemical,
biological and physical agents. These agents produce genetic
damage resulting in irreversible mutations if not repaired.
The second phase is promotion, where carcinogens alter the
cellular environment favoring the mutant cell. However,
promotion is a reversible process and the target of
chemopreventive efforts. There is a point where the mutated
cell becomes cancerous (conversion). The final stage is
progression, which may take months to years to occur and
involves further cell proliferation into clinically detectable
cancer [3].
The idea of preventing cancer began in the 1950's when
researchers attempted to find substances that could prevent
tumor formation. Michael Sporn, an innovator in cancer
prevention research, coined the term "chemoprevention" in
the 1970's. The first compounds demonstrating
chemopreventive potential were found in plants such as
broccoli and green tea. Today, chemoprevention refers to the
use of both natural and synthetic compounds to inhibit
carcinogenesis. Drug development of this type now focuses
on agents that either prevent the occurrence of preneoplastic
lesions or delay or reverse their progression to invasive
cancer [4]. They must be relatively free of side effects and be
nontoxic. This review will present recent studies on both
types of chemopreventive agents.
The treatment of cancer employs surgery, radiation,
chemotherapy and immunotherapy. Treatment becomes
complicated because malignant cells are not pathogens that
have specific treatments, but are the body's own cells that
must be killed or physically removed. While surgery and
radiation work, the cancer must be localized to obtain
complete elimination. Most chemotherapeutic agents, used
to treat both the primary tumor and any metastatic disease,
have difficulty distinguishing malignant from normal cells.
Very harsh side effects are seen in chemotherapy regimens
because all cells are killed regardless. In addition, these
compounds are often mutagenic, which increases the risk of
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDs)
Pain and inflammation result when some part of the body
is injured. As early as the fifth century B.C., Hippocrates
was recommending the chewing of willow bark as an
analgesic. In 1838, salicin was extracted from willow and
poplar barks [5]. Since then, salicylic acid and its
derivatives, the most notable being aspirin 1, have proven to
be beneficial drugs.
One of the many enzymes responsible for inflammation is
cyclooxygenase (COX), which was purified in 1976 and
subsequently cloned in 1988. Among the more significant
advances of the past decade was the isolation of a second
form of the COX enzyme, whose expression is inducible by
*Address correspondence to this author at the School of Pharmacy,
Department of Medicinal Chemistry, University of Mississippi, University,
MS 38677, USA; Tel: +1-662-915-7101; Fax: +1-662-915-5638;
E-mail: mlevi@olemiss. edu
0929-8673/01 $28.00+.00 © 2001 Bentham Science Publishers Ltd.
1350 Current Medicinal Chemistry, 2001, Vol. 8, No. 11 Levi et al.
O
OH
H
3
C O
O
Aspirin 1
of the two selective COX-2 inhibitors currently on the U.S.
market, inhibits apoptosis in human prostate cancer cells by
blocking the phosphorylation, and hence, activation of a key
anti-apoptotic kinase, Akt, may be of particular therapeutic
significance.
Interestingly, the beneficial effects of reduced eicosanoid
levels may increase further with the addition of β-hydroxy-β-
methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors (HRIs).
Piroxicam
In the Apc
Min
mouse model of intestinal neoplasia,
piroxicam 2 [4-hydroxy-2-methyl-N-2-pyridinyl-2H,1,2-
benzothiazine-3-carboxamide 1,1-dioxide] (Feldene) was
tested to determine its chemopreventive potential. The long
duration groups were given 200 ppm (~33 mg/kg/day)
dietary piroxicam for either 100 or 200 days. Tumor
multiplicity in both of these groups was identical.
cytokines and growth factors [6,7]. The older constitutive
COX became COX-1 while the new inducible COX became
COX-2.
COX-2 and its isoform COX-1, along with 5-
lipoxygenase (LOX), belong to the prostaglandin
endoperoxide synthase family of enzymes. COX is
responsible for the bisoxygenation of arachidonic acid,
forming prostaglandin (PG) G
2
. It also catalyzes the
hydroperoxidation (net 2-electron reduction) of PGG
2
forming the 15-hydroxy analog PGH
2
. Most nonsteroidal
anti-inflammatory drugs (NSAIDs) are reversible,
competitive inhibitors of arachidonate binding preventing the
formation of PGG
2
. One exception is aspirin, an irreversible
inhibitor, which acetylates Ser-530. Nevertheless,
hydroperoxidase activity continues.
S
N
N
H
N
CH
3
OH
Piroxicam 2
O
OO
COX activities are the production of PGI
2
(prostacyclin)
and PGE
2
as well as thromboxane (Tx) A
2
. These
eicosanoids are important since they protect the
gastrointestinal tract, while aiding the kidneys and platelets.
PGI
2
is a vasodilator that aids the epithelial cells in the
crypts of Lieberkühn in the ileum [8]. Breakdown of these
cells can lead to gastric damage, hemorrhage and ulceration
[9].
The short interval drug treatments with established
tumors showed that the kinetics of piroxicam-induced tumor
regression are rapid. Significant reduction in multiplicity
was noted after only 4 days of 200-ppm piroxicam with
maximum suppression reached after 6. Rapid induction of
regression may be through apoptosis [21] and the high rate
of cell turnover in the intestine, which is every 2-3 days in
the mouse [22]. The study also found that rats treated with
piroxicam until 100 days old still had a 68% reduction in
intestinal tumor multiplicity, versus the control group, at
200 days old.
While the exact role of the eicosanoids in carcinogenesis
is not fully understood, their levels are often elevated in
many types of human tumors [10]. They can act as immune
system modulators, cellular signal transducers and cell
proliferators [11,12]. PGs may influence tumor progression,
and their levels are increased in adenomas and carcinomas
[13,14]. Cyclooxygenases, particularly COX-2, are also
overexpressed in a variety of tumors. Induction of COX is an
early event in the development of intestinal tumors [15], and
its role may be carcinogen activation. Also COX-2, the
inducible isoform, (but not the constitutive isoform, COX-1)
expression levels are frequently elevated in intestinal polyps
and cancers [16,17]. This overexpression of COX-2 in a
variety of cancers has led to the investigation of the use of a
number of currently available inhibitors may have use in the
treatment of these cancers. A number of possible mechanisms
by which the overproduction of COX-2 may lead to cancer
have been suggested. For example, overproduction of COX-2
appears to inhibit apoptosis leading to carcinogenesis [18].
Also, prostaglandins can promote tumorigenesis [19]. A
recent report by Hsu et al. [20] indicates that celecoxib, one
Toxicity is an important consideration in any cancer
chemoprevention trial. In human patients taking long-term
therapeutic doses of piroxicam (20 mg/day), ~20% of
individuals experience significant gastrointestinal side effects
[23]. These range in severity from dyspepsia to perforation of
the intestine. Treatment with 200 ppm piroxicam (~33
mg/kg/day) in the Apc
Min
mice for 6 or more days resulted
in gross intestinal ulceration in >90% of the animals. This
mouse model may be useful for testing other NSAIDs for
chemopreventive efficacy as well as finding any associated
gastric toxicity.
Sulindac with Lovastatin
Sulindac 3, (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinyl)
phenylmethylene]-1H-indene-3-acetic acid, (Clinoril)
A Review of Cancer Chemopreventive Agents Current Medicinal Chemistry, 2001, Vol. 8, No. 11 1351
caused regression and prevented recurrences of colorectal
adenomas. These are precursor lesions of large bowel cancer
in people with familial adenomatous polyposis (FAP)
[24,25]. Lovastatin (4), 2-methylbutanoic acid 1,2,3,7,8,8a-
hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-
2H-pyran-2-yl)ethyl]-1-naphthalenyl ester (Mevacor) was
one of the original HRIs used to reduce serum cholesterol
levels in people with coronary artery disease. Two
intermediates beyond the actions of HMG-CoA in the steroid
biosynthesis, farnesylpyrophosphate and
geranylgeranylpyrophosphate, both isoprenoids, are cellular
protein bound by isoprenylation, a posttranslational
modification. Isoprenylation of these proteins, including the
low molecular weight G proteins ras, rho and rac, is crucial
for their membrane attachment and subsequent function
[26,27]. By blocking the synthesis of isoprenoids and thus
inhibiting protein isoprenylation, HRIs have important
cellular effects, including reducing cell proliferation and
inducing apoptosis [28].
S-transferases (GSTs; EC 2.5.1.18) [30,31] and
NAD(P)H:quinone reductase (QR:EC 1.6.99.2) [32,33].
Patten and DeLong [34] measured the effect of sulindac, its
sulfide 5 and sulfone metabolites and aspirin on GST and
QR activity in HT-29 colon adenoma cells. The results
show that when cells were treated with 1200 µM sulindac,
QR activity doubled compared to the controls. Sulindac
sulfide marginally increased activity while the sulfone
metabolite increased activity 1.45 fold at a concentration of
500 µM.
Sulindac sulfone 6 (exisulind, FGN-1) was the only
sulindac derivative increasing GST activity to about 1.5-fold
over the controls. Aspirin (O-acetylsalicylic acid), at a
concentration of 3000 µM, increased QR activity to about
1.6-fold over controls. At concentrations of 1000 µM and
3000 µM, GST activity increased 2.5- and 3.5-fold,
respectively, over controls.
RH
3
C
F
CH
2
CO
2
H
CH
3
3 R=SO Sulindac
5 R=S Sulindac sulfide
6 R=SO
2
Sulindac sulfone
O
O
H
3
C
O
H
HO H
CH
3
H
CH
3
H
3
C
O
Lovastatin 4
Exisulind has no known effect on COX activity and
subsequent prostaglandin synthesis, but can promote
apoptosis and inhibit tumorigenesis. In a recent Phase I trial
[35], tolerability and safety were determined in patients with
FAP in a chemopreventive setting. Six patients each
received exisulind (200, 300, and 400 mg orally bid). In 4 of
the 6 people taking the 400-mg dose, but only 1 or 2 of the
people taking the lesser doses, was reversible hepatic
dysfunction noted. No decrease in the numbers of polyps or
significant effects on cell proliferation occurred; however,
there was a trend toward increased apoptosis. The maximum
safe dose was 300 mg. Further investigation of this class
may be warranted.
A study by Agarwal et al. [29] used 5-week-old male
F344 rats to determine the efficacy of lovastatin and sulindac.
The animals were fed their regular diet plus 50 ppm
lovastatin, 80 ppm sulindac or both. At 7 weeks of age, the
rats were given an azoxymethane injection (sc 15 mg/kg)
weekly for 2 weeks. The experimental diets were continued
until 17 weeks of age when the animals’ colons were
examined post-mortem. The results showed that the body
weight of animals given either drug or both remained the
same. No evidence of histological damage was seen upon
examination of the proximal and distal colon.
Lovastatin also induced mild apoptosis at concentrations
of 10 to 30 µmol/L in 3 different colon cancer cell lines.
Apoptosis and subsequent examination revealed chromatin
condensation and nuclear fragmentation. It is quantified as
the percentage of subdiploid cells, which increased from 2 to
27% in HCT-116 cells, 4.2 to 57.5% in SW480 cells and
7.5 to 45.3% in LoVo cells after lovastatin treatment.
Curcumin
Curcumin 7, 1,7-bis [4-hydroxy-3-methylphenyl]-1,6-
heptadiene-3,5-dione, is a naturally occurring anti-
inflammatory [36,37] agent derived from the powdered
rhizome of Curcuma longa L., that possesses a wide range of
therapy in traditional Indian medicine [38]. Besides having
antioxidant properties [39,40], topical application inhibits
benzo(a)pyrene-induced DNA adduct formation, TPA3-
induced epidermal DNA synthesis and tumor promotion in
mouse skin [41,42]. Modulating COX activity in tumorous
Sulindac and its Metabolites
In addition to the PG-inhibiting activity of the
carcinogenesis inhibitors, many have been found to increase
levels of phase II detoxification enzymes such as glutathione
1352 Current Medicinal Chemistry, 2001, Vol. 8, No. 11 Levi et al.
tissue inhibited colon carcinogenesis during the post-
initiation stage. This reinforces the idea that PGs affect
tumor growth. Dietary curcumin also inhibits phospholipase
A2 in colonic mucous and in tumors decreasing arachidonate
release from phospholipids [43]. LOX activity is also
altered. One LOX metabolite, 12(S)-hydroxyeicosatetraenoic
acid (HETE), has been found to promote tumor cell adhesion
and stimulate metastasis by augmenting the metastatic
potential [44,45]. A positive correlation was found between
8(S)-HETE, another metabolite of LOX, hypoproliferation
and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced
tumor development [46]. An in vitro study by Hanif et al.
[47] suggested that curcumin inhibited colon cancer cell
proliferation in human HT-29 and HCT-15 lines,
independent of COX.
Curcumin has also been found to mediate apoptosis in
AK-5 tumor cells by penetrating the cytosol and plasma
membrane thus effecting the membrane lipid bilayer. During
the first hour of treatment, hyperproduction of superoxide
(O
2
-
) was found in the extracellular space. Earlier, reactive
oxygen species (ROS) O
2
-
, hydroxyl radicals (●OH) and
H
2
O
2
, were implicated in curcumin mediated apoptosis [53].
They are known to damage most biomolecules, such as
DNA, proteins and lipid membranes [54]. Superoxide can
also react with nitric oxide (NO) yielding peroxynitrite
(ONOO
-
), which is more reactive and powerful that either of
the two [55]. This leads to the idea that ROS cause
apoptotic tumor cell death [56]. Curcumin treated AK-5 cells
did not release NO nor was there expression of inducible
nitric oxide synthase (iNOS). Thus, AK-5 cells preferentially
chose the ROS-mediated apoptotic pathway when exposed to
curcumin.
O O
OH
OCH
3
HO
H
3
CO
Curcumin 7
SELECTIVE ESTROGEN RECEPTOR
MODULATORS (SERMs)
In 1936, Professor Antoine Lacassagne was the first to
suggest that an estrogen antagonist could be used to prevent
breast cancer if it were in fact caused by a hereditary
sensitivity to estrogen [57]. That was the beginning of ideas
on the causes and treatment of one type of cancer. However,
at that time, there was no estrogen antagonist nor was there a
known target.
In one study by Kawamori et al. [48] some rats were
dosed with 0.2% curcumin in their diets from 2 weeks prior
to, during, and after carcinogen treatment (initiation and
post-initiation stages). Others were dosed with 0.2 or 0.6%
curcumin at 14 weeks after carcinogen treatment
(promotion/progression stage). No tumors developed in the
control group. In those rats administered only the carcinogen
azoxymethane (AOM) 15 mg/kg sc, ~9% and 82%
developed adenomas and adenocarcinomas, respectively. The
0.2% curcumin dose during initiation and post-initiation
stages resulted in reduced incidence of noninvasive
adenocarcinomas (59% inhibition), multiplicities of
noninvasive adenocarcinomas (71% inhibition) and total
colon adenocarcinomas (34% inhibition). The 0.2%
curcumin dose during the promotion/progression stages
greatly inhibited the incidence of invasive colon
adenocarcinomas (54% inhibition). The 0.6% curcumin dose
during the promotion/progression stage also greatly affected
the incidence of noninvasive carcinomas (78% inhibition)
and multiplicities of noninvasive (85% inhibition) and
invasive (45% inhibition) colon adenocarcinomas.
Tamoxifen
Tamoxifen 8, (Z)-1-{4-[2-(dimethylamino)ethoxy]
phenyl}-1,2-diphenyl-1-butene, (TAM, Nolvadex) is the
result of work that began in 1962 when Jensen reasoned that
an estrogen receptor (ER) was required for estrogen action in
its target tissue. The ER was soon isolated as a soluble
protein by Gorski’s group [58,59]. Jensen et al. [60] and
Gorski et al. [61] developed subcellular models describing
how estrogen initiated an action in target cells’ nuclei.
Jensen’s group went farther and suggested that the
measurement of ERs in breast tumors could identify
hormone-responsive breast cancer for endocrine therapy [62].
The first antiestrogen was MER-25, a postcoital
O
N
Tamoxifen 8
Curcumin has also been found to induce a p53-dependent
apoptosis in human basal cell carcinoma (BCC) cells [49].
In 1996, the LD
50
of curcumin was shown to be 20 µM for
in human leukemia cells and 50 µM in human
hepatoblastoma cells [50,51]. Jee et al. [52] treated BCC
cells with 50 µM curcumin and noted the morphologic
alterations: disappearance of microvilli, cell shrinkage,
chromatin condensation and appearance of membrane
blebbing. Control cells did not show these changes. The
results showed that BCC cells exposed to 50 µM curcumin
for 24, 48 and 72 h, apoptosis rate was 30%, 50% and 63%,
respectively.
A Review of Cancer Chemopreventive Agents Current Medicinal Chemistry, 2001, Vol. 8, No. 11 1353
contraceptive in lab animals [63]. Due to its toxicity at
clinical doses [64] drug development shifted to MRL-41, a
triphenylethylene named clomiphene [65]. Chemically
related to MRL-41 was ICI-46,474, the trans-isomer of a
substituted triphenylethylene, found to have potential as an
antitumor agent [66]. It is now being widely used as first-
line hormone therapy for people having any stage of breast
cancer [67] and as a chemopreventive agent in women who
are at high risk for developing breast cancer [68,69]. The
predisposition to breast cancer can be found in germline
mutations BRCA1 and BRCA2, respectively located on
chromosomes 17q and 13. In women having these genetic
mutations, there is a 60% to 80% risk of developing breast
cancer [70,71]. However, most cases do not result from the
presence of these mutations.
concluded that further exploration into the metabolites'
properties was needed. Fan et al. [88] acquired data that
show the quinone methide formation to make little
significant contribution to the cytotoxic and genotoxic effects
of TAM.
O
N
O
TAM Quinone methide 10
The in vitro mechanism of action of tamoxifen is the
inhibition of estrogen promotion of MCF-7 cancer cell lines.
The molecular conformation closely resembles the steroid
nucleus. While it is the prototype of the antiestrogens, its
estrogenic properties in the endometrium have been
associated with increased incidence of endometrial cancer
[72,73]. The breast cancer prevention trials used a dose of 20
mg/day of TAM, which greatly reduced the risk of cancer
development in 45% [74] of high-risk women. The
compound is reported to reduce the risk of invasive breast
cancer by 49% [75]. The still unclear factor is whether newly
forming tumors are prevented or the occult disease is treated.
Bernardes’s group demonstrated that a decrease in
proliferative activity of the normal human breast lobule,
when measured by the mitotic index and nuclear volume, is
equally reached with half the dose [89,90]. Bernardes et al.
[91] set out to determine if 10 mg/day would provide the
same chemopreventive benefit on breast epithelial cells while
reducing the incidence of side effects. To confirm their
previous finding, his group estimated the proliferative
activity of the normal human breast lobule, in response to a
22-day therapy with either the half dose or full dose. A good
marker of cell proliferation is proliferative cell nuclear antigen
(PCNA), a 36-kDa nuclear polypeptide which is generally
expressed in the S phase of the cell cycle and subsequently
quantified. Also studied before and during TAM treatment
were plasma levels of progesterone, estradiol, luteinizing
hormone (LH), follicle stimulating hormone (FSH) and
prolactin to compare women's endocrine responses to
different doses of TAM.
O
N
H
+
TAM Carbocation 9
O
N
O
O
TAM o-quinone 11
While the carcinogenic effects may be due to hormonal
properties, the metabolites of TAM may act as chemical
carcinogens by binding to cellular macromolecules [76,77].
Three different electrophilic metabolites of TAM are a
carbocation 9 [78], a quinone methide 10 [79], and an o-
quinone 11 [80]. The quinone methide is the likely the
result of a P450-catalyzed aromatic hydroxylation giving 4-
hydroxyTAM which undergoes 2-electron oxidation of the π
system producing the quinone methide [81,82]. The o-
quinone, which can alkylate amino acid residues on proteins
[83], results when the catechol metabolite, 3,4-
dihydroxyTAM [84,85], is oxidized. A possibility exists
that the o-quinone, because of its high redox activity, has the
potential to oxidize the sugar-phosphate backbone, leading
to single-strand cleavage and/or oxidation of the bases [86].
Zhang et al. [87] developed an in vitro method for
investigating the potentially carcinogenic pathway and
The results showed that the percentage of cells expressing
PCNA in the placebo group was 50.3%. For those on TAM
it was 24.1% and 23.2% (10 and 20 mg/day, respectively).
Both doses of TAM increased the plasma levels of estradiol
1354 Current Medicinal Chemistry, 2001, Vol. 8, No. 11 Levi et al.
and progesterone. The sex hormone binding globulin
(SHBG) concentration increased 38% and 49% using a 10 or
20 mg/day dose, respectively.
the retinoid X receptor (RXR) and the retinoic acid receptor
(RAR).
RXR-Selective Targretin
Raloxifene
Bischoff et al. [106] designed RXR-selective synthetic
ligands, such as targretin 13, 4-[1-(3,5,5,8,8-pentamethyl-
5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic acid,
(LGD1069), which does not show any of the side effects
commonly associated with retinoid therapy [107]. These
compounds were tested in animal models using Sprague-
Dawley rats. The rats were exposed to MNU, a promoter of
multiple mammary tumor formation. Six weeks into the
study, tumors began to form. Animals were then treated
daily with vehicle, targretin or TAM. Control animals
showed no spontaneous complete regressions, in fact, 87% of
tumors continued progression. Animals with primary tumors
subsequently treated with targretin showed 72.2% of tumors
completely regressed and 16.7% partially regressing while
only 11.1% continued progression. Animals receiving TAM
showed 33.3% of primary tumors completely regressed,
33.3% partially regressed, 4.8% remained static and 28.6%
continued progression.
Raloxifene 12, [6-hydroxy-2-(4-hydroxy-phenyl)-
benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-
methanone, (Evista) belongs to a new class of compounds
that bind and interact with estrogen receptors [92]. They can
act as either agonists or antagonists. This group of
compounds is being used to replace the more traditional
estrogen replacement therapy (ERT) or estrogen/progesterone
therapy (HRT) given to postmenopausal women. While
HRT does relieve some of the symptoms associated with
decline in estrogen levels, [93,94] it is frequently
discontinued [95]. The most common reasons for
discontinuation are the expyramidal effects of uterine
bleeding and breast pain along with fear of breast cancer [96].
The benefit of raloxifene is that it preserves the beneficial
effects of estrogen. Unlike tamoxifen, it has not been found to
stimulate the endometrium [97].
N
O
O
S
OH
HO
Raloxifene 12
COOH
Targretin 13
The dose/response for targretin is evident in that 10.5%,
27.8% and 72.2% of tumors showed complete regression at
10, 30 and 100 mg/kg. Also demonstrated in the study was
the prevention of the appearance of additional new tumors.
The anti-tumor effect caused regression of tumors by
stopping proliferation. Unlike tamoxifen, targretin shows no
sign of resistance. It also inhibits estrogen, thus stimulating
uterine growth.
Both raloxifene and tamoxifen were developed as
antagonists of estrogen-dependent breast cancers. They both
effectively inhibit estrogen-induced proliferation of human
breast cancer cell line (MCF-7 cells) [98]. Raloxifene has
been found to stop the growth of mammary tumors induced
by carcinogens such as N-methyl-N-nitrosourea (MNU) [99]
and 7,12-dimethylbenz(a)anthracene (DMBA) [100] and in
xenografts of tumor cells in athmic mice [101]. Raloxifene
has demonstrated anti-tumor properties in women with
breast cancer who were treated for up to 18 months
[102,103].
RAR-Selective Fenretinide and its Derivatives
Like 9-cis-retinoic acid and targretin, fenretinide 14 [N-(4-
hydroxyphenyl) retinamide] (4-HPR) is an effective inhibitor
of mammary carcinogenesis in the animal model and in
premenopausal women. Recent studies have shown that 9-
cis-retinoic acid and targretin also have inhibitory effects on
established mammary tumors attributed to its O-glucuronide
metabolite (4-HPROG) [108]. The palpable mammary
tumors were used as the end-point biomarkers.
Retinoids
The derivatives of vitamin A, retinoids, are efficacious as
chemopreventive and chemotherapeutic agents both in
preclinical models and human clinical trials. However, their
usefulness is marred by side effects like mucocutaneous
toxicity and hypertriglyceridemia, along with teratogenicity
[104,105]. The two subtypes of retinoic acid receptors are
A study by Green et al. [109] sought to find if fenretinide
would selectively suppress the development and progression
of various ductal hyperplastic and premalignant lesions and if
some of these lesions could be potential end-point
A Review of Cancer Chemopreventive Agents Current Medicinal Chemistry, 2001, Vol. 8, No. 11 1355
biomarkers in chemoprevention studies. One group of
Sprague-Dawley rats was dosed with fenretinide (2mM/kg
diet) beginning either 2 days or 4 weeks after the second
dose of MNU (50 mg/kg). The control group was given only
vehicle in the diet. Of the 23 control rats in the study, 22
developed mammary hyperplasia, carcinoma in situ (CIS)
and/or invasive carcinoma (CA). In those rats treated with
fenretinide beginning 2 days after MNU, 7 of 20 were free of
mammary gland lesions. In the animals treated with
fenretinide there were identified 2 groups, one (35% of
animals) where it was highly effective (within the first 10
weeks) and the other (65%) where it was less effective.
symptomatic reversible nyctalopia while 16 of 22 had
reversible changes in dark adaptation. TAM administration
had no effect on plasma concentrations of 4-HPR or N-(4-
methoxyphenyl) retinamide 15 (4-MPR). Thus a combina-
tion of the two compounds had acceptable tolerability.
Fenretinide Derivatives
A derivative of fenretinide is the C-linked glucuronide
analog 16 (4-HPRCG) of 4-HPROG. This compound was
synthesized to determine the necessity of hydrolysis of 4-
HPROG to 4-HPR for activity. The C-glucuronide was not a
substrate for the β–glucuronidase enzyme, nor is the sugar
cleaved under acidic conditions. Early results show the C-
glucuronide analog to have superior chemopreventive
activity in rats during the early initiation phase of DMBA-
induced tumorigenesis [111] .
4-HPR modulated the morphology of various lesions,
including carcinomas. In the periphery of lesions, cell loss
and disintegration of cellular structures was found. This
suggests that there is a higher concentration of 4-HPR or its
metabolites in the periphery. Also suggested is the
effectiveness in areas of high cell proliferation.
A study by Abou-Issa et al. [112] compared activity of
the O-glucuronide 17 to that of the C-glucuronide. Female
Sprague-Dawley rats were divided into the control, 4-
HPROG and 4-HPRCG groups. For rats other than the
control group, the dose was 2 mmol/kg in the diet. The
compounds were given the diet for 10 days prior to
intragastric administration of DMBA. The diets containing
the drugs were continued for 80 days. At 3-4 weeks post
dose the animals were palpated twice weekly for presence of
mammary tumors. Tumor incidence in the control, 4-
HPROG and 4-HPRCG groups after 80 days was 79, 57 and
27%, respectively. The latency period of mammary tumor
induction also increased from 40 days in control group to 48
in the 4-HPROG group and 55 in the 4-HPRCG group. In
addition, the prolonged supplemented diets did not
significantly affect the animal’s weight or food intake. This
indicates that the observed chemopreventive effects must be
due to specific actions of the compounds. Thus the stable 4-
HPRCG, having higher potency and lower toxicity, is
advantageous to 4-HPR and the natural glucuronide.
Greene’s model suggests 3 potential levels of inhibition
of mammary carcinogenesis. (i) 4-HPR suppresses the
occurrence of hyperplastic lesions [terminal end bud
hyperplasia (TEBH) and ductal hyperplasia (DH)] preventing
the development of neoplastic process. (ii) 4-HPR inhibits
progression of TEBH, DH and ductal alveolar hyperplasia
(DAH) into CIS and/or CA. (iii) 4-HPR suppresses
progression of CIS towards CA. This suggests that 4-HPR
may interrupt the early neoplastic process in the mammary
gland. Later, it may interrupt the level of progression of
hyperplastic lesions and CIS towards CA. This study also
found that that the consistent inhibition of TEBH and CIS
by 4-HPR suggests that they could be used as end-point
biomarkers in breast cancer chemoprevention studies.
N
H
OR
O
14 R=H Fenretinide, 4-HPR
15 R=CH
3
4-MPR
At high concentrations, the mechanisms of action may be
activation of RAR-mediated pathways or liberation of RA,
which interacts with the nuclear receptors. An alternative
mechanism is one that is retinoid independent and may be
the one of 4-HPR [113].
Recently, 4-HPR and TAM were used together in a pilot
trial to determine safety, tolerability, and retinoid levels in
32 high-risk women [110]. The doses were four cycles of 4-
HPR (200 mg orally for 25 days of each 28-day cycle) and
TAM (20 mg orally per day for 23 months beginning after 1
mon x 4 of 4-HPR alone). Two patients did develop
SULFUR CONTAINING COMPOUNDS
The organosulfur compounds have recently received
much attention because of their chemopreventive properties.
N
H
X
O
O
HO
OH
OH
COOH
16 X=C 4-HPRCG
17 X=O 4-HPROG
1356 Current Medicinal Chemistry, 2001, Vol. 8, No. 11 Levi et al.
In 1915, Frederick L. Hoffman wrote, "Based upon more
general considerations, the opinion has frequently been
advanced by ancient and modern writers that there is a direct
relationship between diet and cancer frequency" [114]. For
hundreds of years there has existed a search for the foods that
would prevent cancer and other disease. Brassica plants
(broccoli) have provided many sulfur-containing compounds
reported to possess anticarcinogenic and antimutagenic
activities [115]. Some are hepatoprotectants that upregulate
P-450 IA1 [116]. This led to the discovery of more natural
organosulfur compounds and even to some that are synthetic.
Sulforaphane and oltipraz are two compounds with potential
and are currently being investigated.
N
N
S
S
CH
3
S
Oltipraz 19
Lymphoma
Sulforaphane
In rats, Rao et al. [128] determined that lymphomas were
suppressed by the addition of oltipraz (200 and 400 ppm) to
their diets. Lymphomas were induced by the oral
administration of 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (PhIP). This carcinogen is a heterocyclic amine
found in pyrolysate products of meat and fish. The incidence
of lymphoma decreased 90-100%.
Epidemiological observations have shown that
sulforaphane 18, [1-isothiocyanato-4-(methylsulfinyl)butane],
contained in fruits and vegetables is associated with a
reduced risk of cancer [117]. Studies on the components
responsible for these activities indicated the presence of large
amounts of sulfur-containing compounds such as
isothiocyanates (R-NCS) and their glucosinolate precursors
[118,119] and indole-based compounds, such as indole-3-
carbinol; 3,3’-diindolylmethane and indole-3-acetonitrile
[120,121]. Some of these compounds were found to induce
enzymes in cell culture and rodent tissue responsible for
metabolizing drugs. Chemopreventive activity was a result
of increased detoxification of xenobiotics and carcinogens
[122,123]. Recently, an extract from broccoli, sulforaphane,
an aliphatic isothiocyanate, was found to be the major
inducer of Phase II drug-metabolizing enzymes having potent
in vivo chemopreventive properties [124,125]. Sulforaphane
also inhibits cytochrome P450 (CYP) 2E1, which is
responsible for activating a variety of genotoxic chemicals
[126].
Liver
Cancer of the liver can be caused by aflatoxin (AF) B
1
, a
potent hepatocarcinogen produced by Aspergillus flavus.
Food contamination is the method by which humans are
exposed. Liu et al. [129] found that rats pretreated with
dietary oltipraz (0.075%) had the mortality associated with
AFB1 exposure (10 mg/kg) reduced 47%. The
chemoprotective activity is attributed to the enhanced
induction of glutathione S-transferase (GST) A1, A2 and
M1, along with the suppressed activation of AFB1 to the
inhibition of CYP 1A2 and 3A4 [130].
Lung
Pulmonary adenomas induced by diethylnitrosamine and
uracil mustard exposure can have their incidence rate reduced
30% by the administration of oltipraz (500 mg/kg) 48 h
prior to exposure. Wattenberg and Bueding [131] determined
its effectiveness to be even better in reducing benzo(a)pyrene
induced pulmonary adenomas (64% reduction) and
forestomach tumors (62% reduction). Oltipraz is also
effective in inhibiting lung tumors induced by carcinogen
MNU [132] but not 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-
butanone [133]. This indicates that oltipraz is effective
against three classes of carcinogens, nitroso compounds,
alkylating agents and polyaromatic hydrocarbons.
S
NCS
Sulforaphane 18
O
Trachea
Oltipraz
Moon determined that hamsters receiving dietary oltipraz
from 1 week prior to exposure until the end of the
experiment had decreased incidence of tumors of the trachea
[134]. The tumors were induced by MNU and the incidence
rate decrease from 65% for the control group to 34.6%.
Oltipraz 19, [5-(2-pyrazinyl)-4-methyl-1,2-dithiolthione],
is similar to those dithiolthiones found in cruciferous
vegetables. Originally marketed by Rhone-Poulenc for
schistosomiasis, it is now beyond Phase II clinical trials as a
chemopreventive agent. One of its actions is depleting
glutathione while elevating detoxification enzymes [127]. Its
effects can be seen in lymphomas and cancers of the liver,
lung, trachea, breast, pancreas, bladder, colon and skin.
Breast
Oltipraz was most effective when administered 1 week
prior to carcinogen, DMBA, exposure and for the remainder
of the study (6 months). In vitro mammary organ cultures
A Review of Cancer Chemopreventive Agents Current Medicinal Chemistry, 2001, Vol. 8, No. 11 1357
suggest that oltipraz functions as an anti-initiator and is
more effective when given prior to the carcinogen [135].
Oltipraz’s efficacy in inhibiting DNA adduct formation has
been studied in vitro in human breast tumor epithelial,
MCF-7, cells [136]. These cells were exposed to 15 µM
oltipraz for 4, 8 or 16 hours prior to exposure to
dibenz(a,l)pyrene (10 nM, 24 h). Carcinogen-DNA adduct
levels were reduced 51, 58 and 78%, respectively. Decrease
in adduct formation is dose dependent with a 30 µM dose
resulting in a 95% reduction.
hepatic GST and microsomal epoxide hydrolase (mEH) gene
expression which is enhanced by oltipraz. The increase in
GST levels is associated with its chemopreventive effects
[146].
Kim et al. [147] recently discovered that oltipraz also has
radioprotective effects. This was determined by pretreating
mice with oltipraz for 2 days (100 mg/kg/day po) then
exposing them lethal doses of radiation. Thirty-day survival
rate increased from 48% to 91%. Northern blot analysis
showed that in surviving animals, 9- and 6- fold increases in
mEH and mGSTA3 mRNA levels, respectively. In mice
receiving oltipraz, there was a 12-fold increase in the mRNA
levels at 24 h post exposure.
Pancreas
The incidence of ductal pancreatic adenocarcinoma can be
reduced with oltipraz. Clapper et al. [137] reduced the
incidence rate in Syrian hamsters from 89% in the control
group to 60% in the group receiving both oltipraz and
carcinogen. The dose was 600 mg/kg in the diet while the
carcinogen was N-nitrosobis(2-oxopropyl)-amine (BOP).
There was also a large increase (60%) in the survival of
animals with metastatic disease when treated with oltipraz
compared to those receiving carcinogen only.
STEROIDS
The study of steroids and breast cancer existed as early as
1939 when testosterone proprionate's effects on mammary
carcinoma were being studied [148,149]. Since then,
dehydroepiandosterone (DHEA) has become the steroid of
choice in chemoprevention. DHEA is a potent
noncompetitive inhibitor of mammalian glucose-6-phosphate
dehydrogenase [150,151] responsible for generating most of
the extramitochondrial NADPH [152]. The benefit of this
reduction is that mixed-function oxidases required for the
metabolic activation of chemical carcinogens such as DMBA
and aflatoxin B
1
require NADPH [153] .
Bladder
In BDF mice administered oltipraz from one week prior
to N-butyl-N(4-hydroxybutyl)nitrosamine (OH-BBN) and
until the end of the study reduced the incidence of
transitional cell carcinoma by 30% [138]. In those mice that
did develop tumors, they were much less invasive.
Nevertheless, high concentrations of difuoromethylornithine
(DFMO) were equally efficacious to oltipraz .
DHEA
Colon
DHEA 20 is an adrenal steroid that can inhibit
experimental carcinogenesis in numerous tissues such as
mammary gland [[154,155], skin, [156,157] lung, [158]
liver and thyroid [159]. DHEA has been found to inhibit the
growth of human and rat prostate cancer cells in vitro [160].
Studies have been conducted to determine the
chemopreventive activity of DHEA in the prostate where
MNU was used to promote cancer of the prostate in Wistar-
Unilever rats.
In rats administered oltipraz, the incidence and
multiplicity of tumors, primarily adenocarcinomas, in the
small intestine and colon decreased 33% [139] These
tumors were induced with azoxymethane. Later work [140]
showed that tumor volume decreased 80% upon exposure to
oltipraz while subsequent exposure in the post-initiation
phase showed a significant elevation in activity of ornithine
decarboxylase activity in the colon and liver. In 1996,
Wargovich et al. [141] discovered that oltipraz was an
inhibitor of aberrant crypt foci. This adds to its potential as a
chemopreventive activity during initiation phase of colon
cancer.
O
HO
H
DHEA 20
Skin
Oltipraz was one of the most active compounds in the
human epidermal cell assay. Elmore et al. [142] used non-
toxic concentrations of propane sultone to increase cellular
growth and inhibit differentiation. Activity was determined
by reversal of propane sultone-induced biomarkers, enhanced
growth and reduced involucrin expression. From their data,
the assay is able to predict efficacy in animals with overall
accuracy of 90%.
One study administered 1g/kg and 2 g/kg diet doses 1
week prior to carcinogen, 50 mg/kg MNU, exposure. That
dose reduced the incidence of cancers originating in the
dorsolateral prostate region and all accessory glands from
53% in the control group to 29 and 22% respectively.
DHEA suppresses the progression of microscopic to
macroscopic malignancy.
In 1982, evidence [143] appeared that oltipraz produced
elevations in the detoxification potential of the host, thus
increasing cellular protection. Later studies [144,145]
showed that γ ray ionizing radiation causes alterations in
1358 Current Medicinal Chemistry, 2001, Vol. 8, No. 11 Levi et al.
The second study administered the initial dose of 2 g/kg
DHEA at 20 or 40 weeks post carcinogen (30 mg/kg, MNU)
exposure. For those animals given DHEA at week 20, total
cancer incidence in accessory sex glands fell from 80% to
50%. Likewise, the total incidence of microscopic invasive
carcinoma of accessory sex glands fell from 70% to 43%.
Considering lesions confined to the dorsolateral and anterior
prostate the incidence fell from 60% to 40%.
knowledge of both the human genome and morphology of
various cancers. This is an area still in its infancy but
already showing promise. One day, foods may exist which
have increased amounts of chemopreventive agents already
present. Some extracts may become as common as vitamins.
Baby food may one day contain some type of
chemoprotective agent, which would help protect DNA not
yet altered. Numerous areas have yet to be examined for the
effectiveness of chemoprevention. This field will continue to
grow because it has the ability to touch everyone alive. In
the new millenium, beating cancer will still be a priority,
but the war against cancer is likely to shift to prevention.
In animals given DHEA at 40 weeks, the incidence of
invasive carcinoma that was clearly confined to the
dorsolateral and anterior prostate the incidence fell from 60 to
30%. Administration of DHEA at doses of 2 g/kg showed no
gross or organ toxicity or loss of body weight [161].
Though unsupported by clinical data, this demonstrates the
efficacy of delayed administration of DHEA and its efficacy in
the reduction of invasive prostate cancer.
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