Current Medicinal Chemistry, 2004, 11, 1657-1669 1657

Organoselenium Compounds as Potential Therapeutic and Chemopreventive

Agents: A Review
M. Soriano-García*

Departamento de Bioquímica, Instituto de Química, Universidad Nacional Autónoma de México, México D.F.,
Mexico
Abstract: Selenium is an essential trace element. It is, however toxic at concentration little above which is
required for health. Selenium is incorporated into proteins as selenocysteine, the 21 st amino acid.
Selenoproteins are found in bacteria, archaea and eukaryotes. Biochemical and physicochemical properties of
selenium result in the unique redox characteristics of selenocysteine and its use in antioxidant enzymes. In this
context of a redox reaction is the reduction of reactive oxygen metabolites by glutathione peroxidases, helping
to maintain membrane integrity, reduces the oxidative damage to lipids, lipoproteins, and DNA. Selenium has
structural and enzymatic roles. Selenium influences a number of endocrine processes, most notably, those
involved in thyroid hormone synthesis and metabolism. Se is needed for the proper functioning of the immune
system, a role in viral suppression, AIDS, and also is implicated in delaying the aging process. Its deficiency
has been linked to a number of disorders such as heart disease, diabetes, and diseases of the liver, and it is
required for sperm motility and may reduce the risk of miscarriage.
Se supplementation has recently moved from the realm of correcting nutritional deficiencies to one of
pharmacological intervention, especially in the clinical domain of cancer chemoprevention.
During the last few years, a tremendous effort has been directed toward the synthesis of stable organoselenium
compounds that could be used as antioxidants, enzyme modulators, antitumor, antimicrobials,
antihypertensive agents, antivirals and cytokine inducers.
The biochemistry and pharmacology of selenium-based compounds are subjects of intense current interest,
especially from the point of view of public heath. The purpose of this review is to discuss the recent
pharmacological applications of organoselenium compounds as therapeutic agents in the treatment of several
diseases.
Keywords: Organoselenium compounds, Antioxidants, Enzyme modulators, Antitumor, Antimicrobials, Antivirals.

INTRODUCTION lower oxidation states predominate in anaerobic conditions,

Selenium, a nonmetallic element was discovered in 1818
by the Swedish chemist Berzelius and was named after the
Greek goddess of the moon, Selene [1] and its name was
associated with tellurium, a name for earth. He observed the
element as a deposit following the oxidation of sulfur
dioxide from cooper pyrites. It ranks seventieth in abundance
among the elements and is distributed in the Earth’s crust at
concentrations averaging 0.09 mg/kg [2]. In the Periodic
Table, selenium has an atomic number 34, an atomic weight
of 78.96 and is located between sulfur and tellurium in
Group 16. Six major stable isotopes have been reported and
the most abundant in nature are 80 Se (49.6%) and 78 S e
(23.8%) [3]. In general, selenium is present in the
environment in elemental form or in the form of selenide
(Se2-), selenate (SeO42-), or selenite (SeO32-). The identity
and amounts of the various oxidation-state species in soils
depends enormously on the redox-potential conditions. The
*Address correspondence to this author at the Departamento de
Bioquímica, Instituto de Química, Universidad Nacional Autónoma de
México, Circuito Exterior, C.U., Delegación Coyoacan, México D.F.
04510, México; Tel: + 52-5622-4569; Fax: + 52-5616-2203; E-mail:
soriano@servidor.unam.mx
acidic soils, and the higher oxidation states are favored in
alkaline and aerobic conditions. Both selenites and selenates
are taken up by plants and converted to protein-bound
selenocysteine and selenomethionine, soluble inorganic
forms, several free amino acids, and volatile organoselenium
compounds. The elemental form of selenium, selenium
dioxide, and volatile organoselenium compounds produced
by industries and plants are incorporated in the environment.
Selenium occurs naturally in water in trace amounts as a
result of geochemical processes, such as weathering of rocks
and erosion of soils, and is usually present in water as
selenate or selenite; however the elemental form may be
carried in suspension [4].
Selenium has been shown to be an essential trace element
for life and to be toxic at high levels above those required
for health. Indeed, dietary levels of the desired amount of Se
are in a very narrow range: consumption of foods containing
less than 0.1 mg kg-1 of this element will result in Se
deficiency, whereas dietary levels above 1 mg kg-1 will lead
to toxic manifestations [5-6]. The essentiality of selenium
results as a necessary component of the active center of a
number of selenoenzymes. Selenium functions as a redox
center. The well-known example of this redox function of
selenium is the reduction of hydrogen peroxide and

0929-8673/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd.

1658 Current Medicinal Chemistry, 2004, Vol. 11, No. 12
damaging lipid and phospholipid hydroxiperoxides
producing water and alcohol by-products using selenium
dependent glutathione peroxidases [7-10]. This function
helps to maintain membrane integrity [9,11] protects
prostacyclin production [11] and reduces the likelihood of
propagation of further oxidative damage to biomolecules
such as lipids, lipoproteins, and DNA [9,11]. Another
interesting set of selenium-dependent proteins are the
deiodinases, a family of enzymes that exert tight control on
local and systematic availability of active thyroid hormone,
T3 [7,12]. In the case of thioredoxin reductase enzyme, it
reduces nucleotides in DNA synthesis and helps control the
intracellular redox state [8]. Another selenium containing
protein that maybe involved in oxidant defenses is
selenoprotein P [13,14]. This protein is a ubiquitously
expressed, extracellular glycoprotein that may contain up to
10 selenocysteine residues and binds to heparin and cell
membranes, and in human plasma protects against the
peroxynitrite-mediated oxidation [15]. During the
characterization of white muscle disease led to the discovery
of another selenium-containing protein that may be involved
in the antioxidant function of a cell, selenoprotein W (SelW)
[16]. This protein was found in its highest concentration in
the muscle, heart and brain of sheep, rat, mice and primates,
and its level in these tissues is influenced by selenium
concentration. Its metabolic function remains unknown;
selenium deficiency eliminates SelW from skeletal and
cardiac muscle, suggesting a link between SelW and healthy
muscle tissues [17]. Recently, a 15 kDa selenoprotein
(Sep15) was discovered when it was purified from human T
cells, a protein that was strongly radiolabeled when cells
were grown in the presence of 75Se [18]. This protein maybe
involved in the chemopreventive effect of dietary selenium
[19]. The number of selenoproteins identified thus far in
vertebrates stands at 22. The biological functions of only a
few of these proteins are known. It is clear that the
selenoproteins play critical roles in many vital cellular
functions and are therefore essential for disease prevention
such as heart disease, different kind of cancers, diseases of
the liver, and AIDS [10].
Most ingested forms of selenium ultimately are
metabolized to low molecular weight inorganic and organic
compounds that play a central role in human health either
via incorporation into selenoproteins or binding to selenium
binding proteins [20]. Therefore, a tremendous effort has
been directed toward the synthesis of stable organoselenium
compounds that could be used as antioxidants, enzyme
modulators, antitumor, antimicrobials, antihypertensive
agents, antivirals and cytokine inducers. Several excellent
books and reviews appeared in literature describing the
biological function of organoselenium compounds [21,22].
The role of organoselenium compounds as antioxidants, as
enzyme modulators, photochymotherapeutic agents, cytokine
inducers and immunomodulators, and antihypertensive and
cardiotonic agents have been recently described in literature
[22].
The biochemistry and pharmacology of selenium-based
compounds are subjects of intense current interest, especially
from the point of view of public health. Selenium has been
used in connection with the following conditions: (a)
Primary: Cancer risk reduction; (b) Secondary: Asthma,
Atherosclerosis, Dermatitis herpetiformis, Heart attack, HIV
M. Soriano-García
infection, Infertility (male), Phenylketonuria (if deficient),
Rheumatoid arthritis, Aging, Immune function; and (c)
Other: Cardiac arrhythmia, Cardiomyopathy (only for
Keshan’s cardiomyopathy), Kashin-Beck disease (an
osteoarthropathy that is endemic in a selenium and iodine
deficient area of China), Depression, Diabetes,
Hypothyroidism (if deficient), Liver cirrhosis, macular
degeneration, Osgood-Schlatter disease (an inflammation or
partial separation of the tibial tubercle, usually resulting
from overuse of the quadriceps muscle, characterized by
swelling and tenderness that increase with exercise; most
often seen in muscular, athletic adolescent boys), Pap smear
(abnormal) and Retinopathy (combined with vitamin A,
vitamin C and vitamin E).
This review is to discuss the recent pharmacological
applications of organoselenium compounds as therapeutic
agents in the treatment of several diseases.
ORGANOSELENIUM COMPOUNDS AS CANCER
PREVENTIVE AGENTS
Cancer, is a group of more than 100 different diseases,
manifest itself as uncontrolled cellular reproduction, local
tissue invasion and distant metastases. 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,
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 [23].
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 [24-25].
The basic idea that selenium is a cancer-protecting trace
element began in the 1950´s, when researchers tried to find
substances that could prevent tumor formation. The first
papers on this subject were published in the late 1960s and
early 1970s [26-29]. Leading to the proposal that cancer
mortality in the U.S. and other industrialized nations would
decline significantly if the dietary selenium intakes were
increased to approximately twice in the current average diet
[30,31].
The epidemiological literature on selenium and cancer
has been reviewed [32-34], and have suggested that an
increased risk for certain human diseases including cancer, is
related to insufficient intake of selenium, however, there
remains some inconsistency [32].
In some animal’s models, high selenium intakes reduce
the incidence of cancer [35]. In humans, some randomized
trial data have been carried out. The first trial was conducted
with poorly nourished rural Chinese [36]. The second trial,
the Nutritional Prevention Cancer Trial was randomized.
This clinical trial evaluated the efficacy of selenium as
Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents
selenized yeast (200 µg daily) in preventing nonmelanoma
skin cancer among 1312 residents of the Eastern United
States [37]. The analyses was carried out through December
31, 1993 showed striking inverse associations between
treatment and the incidence of total [hazard ratio, HR =
0.61, 95% confidence interval, CI = 0.46-0.82], lung,
prostate and colorectal cancer and total cancer mortality. The
third trial was carried out by participants in the Health
Professionals Follow-Up Study [38], by investigating the
association between risk of prostate cancer and prediagnostic
level of selenium in toenails, a measure of long-term
selenium intake. The selenium levels in toenails varied
substantially among men, with quintile medians ranging
from 0.66 to 1.14 µ g/g for control subjects. After
additionally controlling for family history of prostate cancer,
body mass index, calcium intake, lycopene intake, saturated
fat intake, vasectomy, and geographical region, the odds
ratio, OR ,was 0.35 (95% CI = 0.16-0.78.) This result
supports earlier findings that higher selenium intakes may
reduce the risk of prostate cancer [38]. Recently, it was
reported in the results of the second trial through February 1,
1996 [39]. The effects of treatment overall and within the
subgroups of baseline age, gender, smoking status, and
plasma selenium were examined using incidence rate ratios
and Cox proportional hazards models. Selenium
supplementation reduced total (HR = 0.75, 95% CI = 0.58-
0.97) and prostate (HR = 0.48, 95% CI = 0.28-0.80) cancer
incidence but was not significantly associated with lung (HR
= 0.74, 95% CI = 0.44-1.24) and colorectal ( HR 0.46, 95%
CI = 0.21-1.02) cancer incidence. The Nutritional Prevention
of Cancer trial continues to show a protective effect of
selenium on cancer incidence, although not all site-specific
cancers exhibited a reduction in incidence. This treatment
effect was restricted to males and to those with lower
baseline plasma selenium concentrations [39]. The outcome
of this trial stimulated the initiation of two large new
clinical intervention trials in three European countries, the
UK, Denmark, and Sweden (PRECISE, Prevention of
Cancer by Intervention of Selenium), and in the U.S.
(SELECT, Selenium and Vitamin E Cancer Prevention
Trial) [10].
It is clear that mammalian selenoproteins play critical
roles in many vital cellular functions [40] and are, therefore,
essential for disease prevention [10]. There is an extensive
amount of research in the use of organoselenium compounds
for cancer prevention [22, 41, 42].
Ip, Ganther and coworkers [43-47] demonstrated the anti-
tumorigenic effects of sodium selenite 1 using the 7,12-
dimethylbenzanthracene (DMBA)-induced rat mammary
tumor model. They found that the CH3SeH–precursors-
selenobetaine [(CH3)2 SeCH2COOH] 2 and Se-methyl-
selenocysteine (CH3 SeCys) 3, are anti-carcinogenic and
somewhat more efficacious than the inorganic compound,
selenite. Later work has shown that the CH3SeH precursors-
methyl-selenocyanate (CH 3 SeCN) and 3, each inhibits
mammary cell growth, arresting cells in the G1 or early S
phase and inducing apoptosis [48-50]. Various synthetic
organoselenium compounds have been tested and found to
be anti-carcinogenic. Series of alkylselenocyates
[CH 3(CH 2)nSeCN, in which n = 1 to 6] were tested using
the DMBA-induced murine mammary carcinogenesis model
and found that anti-carcinogenic efficacy varied directly with
Current Medicinal Chemistry, 2004, Vol. 11, No. 12 1659
increasing chain length up to five carbon atoms [51]. The
same group showed that Se-allylselenocysteine 4 which is
expected to yield allylselenol, a fairly hydrophobic
metabolite, has more anti-carcinogenic power than 3 and Se-
propylselenocysteine 5 in rat methylnitrosourea (MNU)
model [52]. The diallyl selenide 6 has significant anti-
carcinogenic activity using DMB-induced mammary tumor
model and 300 times more active than the diallyl sulfide, a
flavor component of garlic [53].
O
Se (CH3) 2SeCH2COOH
Na O - O- Na
1 2
H3N CH3 H3N
Se Se CH2 CH CH2
COO- COO -
3 4
H3N CH3 CH2 CH CH2 Se
Se 2
COO-
5 6
Karam El-Bayoumy was the first to synthesize aromatic
selenium compounds in cancer prevention in the 1980s.
There was a need to develop novel reagents with lower
toxicity than that of 1 and selenomethionine 7. The first
compound synthesized was p-methoxybenzeneselenol 8 and
had a successful tumor inhibition in liver, colon and kidney
of the rats treated with the carcinogen azoxymethano [54,
55]. Compound 8, however, was quickly abandoned in favor
of benzylselenocyanate 9, even though 9 was apparently
more toxic. The dosage that causes 50% mortality (LD50) of
8 and 9 in mice was 370 and 18 mg/kg body weight
respectively [56]. Subsequent studies with 9 showed that it
suppressed tumorigenesis in several models including
forestomach, colon and mammary gland, using
benzo[a]pyrene, azoxymethane (AOM) and DMBA as cancer
inducers respectively [56-58]. Although, compound 9 was
more effective and less toxic than sodium selenite 1, the rats
suffered significant growth depression. Because compound 9
has a very strong odor similar to that of burnt rubber, then
the rats avoided the food. To reduce the volatility of
compound 9, a second methyleneselenocyanate group was
added in the p a r a - position to obtain 1,4-
phenylenebis(methylene)selenocyanate 10. Compound 10 is
commonly called p-xylylselenocyanate or p-XSC.
Dietary 10 totally inhibits DMBA-DNA binding of the
mammary tissue [59]. The inhibition process of 10 reduced
levels of the major adducts derived from DMBA and in
agreement with the reported data of Milner´s group who
employed selenite in their investigation [60].
El-Bayoumy gave a complete report with evidence for the
role of selenium in the inhibition of carcinogen-induced
covalent DNA adducts formation in rats. The retardation of
oxidative damage to DNA, lipids and proteins, and for
1660 Current Medicinal Chemistry, 2004, Vol. 11, No. 12
modulating cellular, molecular events that is critical in cell
growth inhibition and in the multi-step carcinogenesis
process using rats [61].
Another synthetic selenium compound,
triphenylselenonium chloride 11 [62, 63] like compounds 9
and 10, has appreciable lipophilic character, which would
appear to be the basis for relatively slow release of selenium
from these types of compounds. In mice, compound 11 has
excellent tumor inhibitory activity but does not support the
repletion of seleno-enzymes in animals that have been
deprived of a bioavailable form of selenium [62]. However,
compound 11 does not release inorganic selenium for seleno-
protein synthesis and that its anticancer activity involves
mechanisms that are probably intrinsic to the compound
[64]. This study also shows that for the first time selenium
chemoprevention is possible in an environment of severely
depressed seleno-enzyme expression. Thus selenium
chemoprevention efficacy can be separated experimentally
from seleno-protein synthesis using this model [64].
A recent study demonstrated that administration of
compound 10 in the diet suppressed the lung metastasis of
melanoma cells in mice [65]. Furthermore, compound 10 is
a powerful chemopreventive agent against the development
of experimental colon, mammary, lung, and oral
carcinogenesis [66].
The applicability of compounds 8, 9, and 10 in tumor
control has been demonstrated in some organs using animal
models and are effective in both the initiation and post-
initiation phase. These organoselenium compounds are less
toxic and chemopreventive than inorganoseleniums and
natural organoseleniums, and can be the candidates of
excellent chemopreventive agents for human cancers.
SeH
H3N Se
CH3
COO-
7 9 in the mammary tumor model system [57]. Recent studies
OCH3
8
CH2 SeCN CH2SeCN
9 CH2SeCN
10
CH2SeCN
CH2SeCN
Se+Cl -
11 12
The form of selenium is important and determines its
efficacy and toxicity in preclinical investigations. Thus, in
an investigation of structure-activity relationship, it was
found that 1,2-phenylenebis(methylene)selenocyanate 12,
was a more effective inhibitor of DMBA-DNA adduct
formation in the rat mammary gland than 1,3-
M. Soriano-García
phenylenebis(methylene)selenocyanate 13 and 10; however ,
10 was the least toxic [67].
Previous studies showed that garlic cultivated with
selenium-enriched soils has unique attributes as cancer
preventive [42, 68]. γ-Glutamyl-Se-methyl selenocysteine
14 is the major selenium compound in natural and selenized
garlic, and is an effective carcinogenic agent against
mammary gland cancer in rats with a mechanism similar to
that of compound 3 [69]. Furthermore, compound 3 led to a
significant reduction of intra-tumoral microvessel density in
mammary carcinomas. These results indicate a potential for
selenium metabolites to inhibit key attributes (proliferation,
survival, and matrix degradation) of endothelial cells critical
for angiogenic sprouting. Therefore, inhibition of
angiogenesis associated with cancer may be a novel
mechanism for the anticancer activity of selenium in vivo,
and multiple mechanism are probably involved in mediating
the anti-angiogenic activity [70]
Colon cancer is one of the leading causes of cancer death
in Western countries, including U.S. In the U.S. nearly
56,000 deaths are attributed to this cancer annually [71]. The
clinical trials by Clark et al., 1996 [37] and Duffield et al. ,
2002 [39] demonstrated that administration of selenium-
enriched yeast significantly inhibited colon cancer incidence
in humans. An experimental study also showed that
supplementation of sodium selenite inhibits carcinogenesis
in the colon, mammary gland, pancreas and liver [72, 73].
Humans ingest organic forms of selenium as selenocysteine
15 and 7 by eating grains, vegetables, and animal products.
However, cancer prevention studies in preclinical models
have not revealed any significant differences between
inorganic forms of selenium and those naturally occurring
forms of selenium. Dietary 14 as part of selenium–enriched
yeast lacks chemopreventive efficacy against AOM-induced
colon carcinogenesis in F344 rats [74].
Compound 10, a novel organoselenium compound, was
less toxic and remarkably improved inhibitor than its analog
indicate that compound 10 significantly suppress the
genetically predisposed intestinal tumor formation in
adenomatous polyposis coli (APC min ) mice, thus the
chemopreventive efficacy of compound 10 is not limited to
chemically induced cancers [75]. It is not known whether
compound 10 or one of its metabolites is responsible for its
chemopreventive efficacy. Therefore, a glutathione conjugate
of 10 has been synthesized, N,N´-[1,4-phenyleneb i s
(methylene-selenothiol-1R-1-(carboxymethyl)aminocarbonyl)]-
2,1-ethanediyl] bis-L-glutamine, 16 [76]. Compound 16 is
stable in the diet and it seems to be the least toxic
organoselenium chemopreventive agent thus far tested in the
experimental colon carcinogenesis [76]. It is recommended
that the use of a low-fat dietary regimen, along with
chemopreventive agents, is a desirable approach for primary
prevention in the general population and for secondary
prevention of colon cancer in high-risk individual [77].
Oxaselenins compounds: 2,6-diphenyl-1,4-oxaselenin,
17, 2-phenyl-6-(4-methoxyphenyl)-1,4-oxaselenin, 18 and 2-
phenyl-6-(4-chlorophenyl)-1,4-oxaselenin 19, have
proliferative inhibitory effects against human uterine cervical
cancer cells, such as SiHa and HeLa cells, and human
ovarian cancer cell, SK-OV-3. All three compounds
Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents Current Medicinal Chemistry, 2004, Vol. 11, No. 12 1661

CH2SeCN
HOOC C
NH
NH2 Se
HOOC CH3
CH2SeCN
13 H3N + 14
SeH
COO -
15
HO2C

NH O
COO -
+ O S
H3N Se NH
+
NH Se NH3
S O
-
COO
O NH

16 CO2H

exhibited growth inhibition against SiHa and SK-OV-3 survivors compared to no survivors in the control untreated
cells. Compound 19 showed the greatest growth inhibition mice group [83, 84].
with IC50 of 45.1 and 37.5 µM respectively. Compounds 17
and 18 exhibited only weak inhibitory activities, with IC50 O
of > 100 µM. To determine the mechanism of cytotoxicity NH2
for these three compounds, the inducing effect of the early R
stage of apoptosis was studied by the method of combined Se N
annexin V-FITC and PI labeling with flow cytometric O HO
analysis on SK-OV-3 cells. These results showed that a 4- O
chlorophenyl group at the C2 position of 19 was more
Se
effective than a 4-methoxyphenyl group of 18 or an
unsubstituted 4-phenyl group of 17, at showing cytotoxicity 17 R = H ; 18 R = OCH3 OH OH 20
and apoptosis induction against the cancer cells [78]. 19 R = Cl O
O CH3
N HN
HN
ORGANOSELENIUM COMPOUNDS AS ANTI- Se
INFECTIVE AGENTS O N Se
H2 N N N
OH
There is a historical record showing that organoselenium HO O O
compounds can be used as antiviral and antibacterial agents. 22
This topic has been reviewed by Klayman [79], Shamberger 21
[80], Parnham and Graf [81], and more recently, by Mugesh, OH OH
du Mont and Sies [22].
Several selenium-substituted acyclouridine derivatives
Antiviral 22-27 were studied evaluating their antiviral activity in
human peripheral blood mononuclear (PBM) cells infected
Several interesting organoselenium compounds exhibit with HIV-1 (strain LAV) [85]. Compounds 22 and 23 are
an antiviral activity one such is selenazofurin 20 against type the least and more effective compounds against HIV virus,
1 herpes simplex virus, type 3 parainfluenza virus, and type respectively. However, when these compounds were tested in
13 rhinovirus was associated with the inhibition of guanine human PBM cells infected with HIV-2 (strain ROD-2),
nucleotide biosynthesis [81] but no antiviral activity against compound 23 was about 25-fold less active and 26 was the
Pichinde virus (PCV) in infected hamsters was found [82]. most active compound. Chemical modifications of the
acyclic side chain produced compounds 28-31. Compound
The purine analog, 7-methyl-8-selenoguanosine 21 has 31 is the most potent antiviral against HIV-1 as compare to
been tested in vivo for antiviral activity against Semliki the hydroxyl and methyl analogs [86]. The pharmacokinetics
Forest virus (SFV) infection in a mouse model with 58% and toxicity studies on compound 31 clearly shows that this
1662 Current Medicinal Chemistry, 2004, Vol. 11, No. 12 M. Soriano-García

compound can act as effective antiviral agent at low µ M). Since the viral resistance is the most important limit
concentrations without exhibiting toxicity [87]. of current anti-HIV therapy, this group studied the effect of
(-)-β-1-[2-(hydroxymethyl)-1,3-oxaselenolan-5-yl] cytosine
O O against cloned xxBRU (3TC/FTC-sensitive) and M184V
R CH3 (3TC/FTC-resistant) mutants. The results indicate that (-)-β-
HN HN 1-[2-(hydroxymethyl)-1,3-oxaselenolan-5-yl] cytosine was
cross-resistant with its sulfur analogs. In summary, this
O N Se S N Se study shows that most of the anti-HIV activity of both
OH OH cytosine and fluorocytosine nucleosides resides with the (-)
O O isomers [90].
23 R = CH3 ; 24 R = F 27
R
25 R = Cl ; 26 R = Br HN NH2 HO O
F
O N Se N Se

CH3
28 R = H ; 29 R = CH3 O O N O N
30 R = F ; 31 R = CH2-CH3
NH2 HO O HO O N
F
Se 34 Se 35
N NH2
O HO O
O N O N
N Se
HO O N
O N O N
Se
32 33 NH2
HO O N
During the past 12 years, 2´,3´-dideoxynucleoside 37
36 Se
analogs have been intensively studied as potential antiviral O
agents. Until the year 2000, the Food and Drug O HO O
Administration for the treatment of HIV infection have CH3
approved 14 antiviral agents (6 reverse transcriptase N Se
inhibitors, 3 non-nucleoside reverse transcriptase inhibitors,
and 5 protease inhibitors). Six of them are 2´,3´- O N O N
dideoxynucleoside analogs. The use of these agents in HO O N
combination with protease inhibitors has been responsible CH3
for the marked reduction of opportunistic infections and 38 Se 39
O
mortality in HIV patients [88]. Due to the side effects of
certain antiviral agents and the drug-resistant viral strains,
new anti-HIV agents are needed. Some 3’-Se-substituted
dideoxynucleosides (racemic forms and the α − and β − Antibacterial and Antifungal
anomers of oxaselenolane nucleosides) have been synthesized
For the comparability of organoselenium compounds and
and exhibited potent anti-HIV and anti-HBV activities [89,
organosulphur compounds, many organoselenium
90]. The racemic forms of cytosine (32,33); 5-fluorocytosine
compounds were synthesized and their antimicrobial activity
(34,35); uracil (36,37); thymine (38,39); adenine (40, 41),
was studied [81, 91, 92].
guanine (42, 43), and hypoxanthine (44, 45) were
synthesized from the key intermediate, (±)-2- Early studies on the quest for expanded antimicrobial
benzoyloxymethyl-1,2-oxaselenolane 5-acetate. The spectrum were centered at the skeletal modification of the
synthesized racemic nucleosides were evaluated for antiviral natural occurring β -lactam antibiotics. In this regard, the
activity against HIV virus type-1 (HIV-1) and hepatitis B optically active 1-dethia-selenapenem 46, 2-selenacephem
virus (HBV) in peripheral blood mononuclear cells and 47, and two analogous compounds of 1-dethia-selenapenem
2.2.15 cells. The racemic (±)-β−cytosine (32,33) and (±)-β− (48,49) have been synthesized and have antibacterial activity
5-fluorocytosine compounds (34,35) exhibit the most potent [93].
anti-HIV activity (EC50 2.69 and 5.55 µM respectively) and 2-Phenyl-1,2-benzoisoselenazol-3-(2H)-one, Ebselen 50
anti-HBV activity (EC 5 0 1.2 µ M for both racemic [94], a heterocyclic compound that possess anti-
compounds) with no in vitro toxicities up to 100 µ M in inflammatory, anti-atherosclerotic, cytoprotective, and
various cell lines (PBM, CEM, and Vero) [90]. The anti- antimicrobial activity against Staphylococcus aureus [95].
HIV activity of resolved α - and β -enantiomers of (32,33) Compound 50 and the p-chloro analog 51 exhibited strong
and (34,35) has been evaluated and the (-) enantiomers are inhibitory activity against the growth of Saccharomyces
more potent than their (+)-counterparts. The most potent cerevisiae Σ127-8b strains. The second compound also
compounds were (-)-β-5-fluoro-1-[2-(hydroxymethyl)-1,3- inhibited the growth of Candida albicans 258 strains.
oxaselenolan-5-yl]cytosine (EC50 0.2 µ M) and (-)-β -1-[2- However, the diaryl diselenides compounds (52, 53) or
(hydroxymethyl)-1,3-oxaselenolan-5-yl]cytosine (EC50 0.9 carboxy-alkyl (54, 55) had no inhibitory activity on fungi
Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents Current Medicinal Chemistry, 2004, Vol. 11, No. 12 1663

growth. However, the benzisoselenazolones show Staphylococcus aureus have been studied and compounds
antibacterial activities against Gram-negative E. coli K-12 (56-58) exhibited strong inhibitory activity against both
Row and Gram-positive S. Aureus 209P bacteria strains microorganism [97].
[96].
HO ButMe 2SiO
H
NH2 HO O H H
H 3C Se S
N CH3 Se
N Se N
N
O
N N N N 46 COONa O
47 COOCH3
HO O N HO
N H
41 But Me 2SiO Se
40 Se H H
NH2
Se CH3
O N
HO O CH3
48 N COO-CH2 NO2
N
N Se
COOCH3 49
H2N N N N N NH2 O
O
HO O N
N N
43 O N Cl
42 Se Se
50 51 Se
O HO O

N Se
N Since, morpholine compounds are typically bactericide
and fungicide, three selenomorpholine derivatives-N -
N N N N selenomorpholinemethyl succinimide hydrochloride 59, N-
HO O selenomorpholinemethyl succinimide 60, and N-(α -
N
N selenomorpholinebenzy) succinimide 61, were synthesized
45
44 Se and their antimicrobial activity was tested against
O
Staphylococcus aureus by microcalorimetry [98]. Judged
The antimicrobial effect of several 4H-5,6-dihydro-1,3- from the rate constant k and the half-inhibitory
selenazine derivatives against Escherichia coli and concentration, IC50, the experimental results reveal that the

O O
CH3
NH
CH3
Se Se
Se Se
H3C
53 NH
H3 C

52 O O O
O
But
O
O CH3

Se
Se
Se
Se

O
H3 C O But
54 O
O 55
H3C

Se H3C Se

N N

56 R = CH3 HO R 58 HO CH3
57 R = CH2CH2
1664 Current Medicinal Chemistry, 2004, Vol. 11, No. 12
sequence of antibiotic activity of these selenomorpholines is
59 > 60 > 61. Recently, experimental results revealed that
the sequence of antibiotic activity of new selenomorpholines
against Staphylococcus aureus by microcalorimetry is N, N’-
methylene bisselenomorpholine 62 > selenomorpholine 63,
and Na2SeO3 > selenomorpholine hydrochloride 64 [99].
O and their ability to inhibit cell growth and induce apoptosis
Se N CH2
Se N CH2 N
HCl 60
59 O The results were: (a) SCCs were found to be significantly
O more sensitive to induction of apoptosis by 65 than normal
Se N CH2
Se N CH N 62
O Se
Se NH
61
64
63
Organoselenium Compounds in Regulation of
Apoptosis
Selenium compounds that are chemopreventive in animal
models inhibit cell growth and induce apoptosis in vitro.
Primary cultures of oral carcinoma biopsies are significantly
more sensitive than normal oral mucosa cultures to
induction of apoptosis by a natural selenium metabolite,
selenodiglutathione 65, and this is associated with induction
of Fas ligand, a well-known mediator of apoptosis, and
activation of so-called stress kinase signaling pathways,
particularly in Jun NH 2 -terminal kinase (JNK). 1,4-
phenylenebis (methylene)selenocyanate 10, also induces Fas
ligand, heme oxygenase, and stress kinase pathways [100].
The synthetic compound 10 has been shown to inhibit
tobacco-specific 4-(methylnitrosoamino)-(3-pyridyl)-1-
blitanone-induced tumorigenesis in A/J mouse lungs, rat
tongue carcinogenesis and colon cancer and recently,
compound 10 induces apoptosis in cultured human colon
cancer cells. One possible mechanism for the cancer
chemopreventive activity is mediated by compound 1 0
[101].
Compound 3 has been the most extensively investigated.
It inhibits cell proliferation and induces apoptosis in several
tumor cells [42, 102, 103].
The alkylating agent, nitrogen mustard is thought to
cause apoptosis through production of free oxygen radicals.
Ebselen 50 provides an efficient protection against mustard-
induced cell death in normal and tumoral (BALB/c mouse
spleen lymphocytes and human MOLT-4 leukemia cells)
lymphocytes and might prove useful as an antidote against
alkylating agents [104].
Compounds (3-5) have been shown to be active in the
chemoprevention of experimentally induced mammary
carcinogenesis [52]. Furthermore, both compounds show in
vitro effects on cell growth inhibition apoptosis, and the
induction of DNA damage using two mouse mammary
epithelial cell lines derived from mammary hyperplasias
M. Soriano-García
[105]. Furthermore, compound 4 has been shown to inhibit
mammary carcinogenesis in vivo and cell growth in vitro.
Compound 4 is able to cause an immediate response in the
expression of cell cycle regulatory that favors an arrest in
proliferation and an augmentation in apoptosis [106].
In general, there is a correlation between the effectiveness
O of selenium compounds as chemopreventive agents in vivo
N in vitro. The signal transduction pathways affected by
selenodiglutathione 65 and 10 in biopsies of normal human
oral mucosa cells and human oral squamous carcinoma cells
O (SCCs), using a primary culture system were studied [107].
N Se
human oral mucosa cells, though the differences were
marginal with compound 10; (b) both selenium compounds
induced expression of Fas ligand in oral cells to a degree
NH
that correlated with the extent of apoptosis induction; and (c)
HCl both selenium compounds induced the stress pathway
kinases, Jun NH 2 -terminal kinase and p38 kinase, at
concentrations causing apoptosis; compound 10, and to a
lesser extent 65, also activated extracellular regulated kinases
1 & 2 and protein kinase-B or Akt [107].
The inhibitory effects of 5,6-dihydro-4H-1,3-selenazine
derivatives, 4-phenyl-2-p-tolyl-1,3-selenazole 66 and 5,6-
dihydro-4H-1,3-thiazine derivatives on the proliferation of
human HT-1080 fibrosarcoma cells were investigated [108].
The compounds 4-ethyl-4-hydroxy-2-p-tolyl-5,6-dihydro-4H-
1,3-selenazine 67 and 4-hydroxy-4-methyl-6-propyl-2-p-
tolyl-5,6-dihydro-4H -1,3-selenazine 68 exhibited the
strongest inhibitory effect on tumor cells and their EC50
were 7.76 and 8.40 µ M respectively. Compounds 66 and
5,6-dihydro-4H-1,3-thiazine derivatives had no inhibitory
effects. Compounds 6 7 and 6 8 inhibited HT-1080
proliferation through the induction of DNA fragmentation,
revealing a typical apoptosis characteristic [108].
Compounds 67 and 68 were investigated for their inhibitory
effect on the growth of 8 human tumor cell lines, including
stomach, lung, prostate and colon cancer cell lines, in vitro.
Both compounds exhibited the strongest cytotoxicity against
a gastric adenocarcinoma (TMK-1) among 8 human tumor
cell lines, and their IC50 were 2.38 µ M and 2.78 µ M
respectively. Furthermore, both compounds produce
induction of apoptosis in human gastric adenocarcinoma
cells [109].
Other Biological Activities of Selenium
Cisplatin [cis-diamminedichloroplatinum (II)] is a widely
used antitumor drug with dose limiting nephrotoxic side
effects due to selective toxicity to the proximal tubule.
Selenocysteine Se-conjugates have been shown to be very
potent chemopreventive agents in rat tumor models [42, 52].
Furthermore, Se-cysteine-conjugates were proposed as
kidney-selective prodrugs [110] because they are expected to
be actively transported into the proximal tubular cells and
bioactivated locally in the kidney due to the high renal β -
lyase activity [111]. Three selenocysteine Se-conjugates; 3,
Se-(2-methoxyphenyl)-L-selenocysteine 69, and Se-(2-
chlorobenzyl)-L-selenocysteine 70 attenuate the cisplatin-
induced loss of viability in R1J cells but not in the parental
Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents
-OOC
-OOC
Se
H3C
N
66
H3C
Se
N H
68 HO
LLC-PK1 (proximal tubule, pig kidney)cells as determined
by the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium
bromide assay and neutral red uptake. Compound 3 provided
the strongest protection against cisplatin-induced
cytotoxicity [112].
The prodrugs may be clinically useful when selenium
supplementation at supranutritional levels is indicated, such
as in cancer chemoprevention. Two new classes of
selenazolidine-4-(R)-carboxylic acids: 2-Oxoselenazolidine-
4(R)-carboxylic acid 71 and 2(R,S)-Methylselenazolidine-
4(R)-carboxylic acids 72, are latent forms of selenocysteine,
intended to provide a chemically superior delivery form for
selenium [113].
Several lines of evidence indicate that inhibition of
excess DNA (cytosine-5)-methyltransferase (Mtase) may be a
sufficient factor for the suppression or reversion of
carcinogenesis. Compounds, sodium selenite, 9 and 1 0
inhibited Mtase extracted from a human colon carcinoma
with IC50 of 3.8, 8.1 and 5.2 µM, respectively [114].
Peroxynitrite (ONOO-/ONOOH) is formed through a
reaction of nitric oxide (NO) and the superoxide anion
radical [115] and is a powerful oxidant that can induce
mutations and cause single-strand breaks in plasmid
supercoiled DNA. Compounds 7, and 15 protected DNA
from single-strand breaks more effectively than their sulfur
analogs, methionine and cysteine, and they also were more
effective than glutathione or the hydroxyl radical scavenger
mannitol [116].
Antioxidant properties of selenium producing a
protective barrier against free radicals play an important role
in numerous metabolic and immunologic processes
associated with oxidation-reduction reactions that take place
during intracellular digestion of phagocyted bacteria [117,
118]. The 4-(o-tolyl)-selenosemicarbazide of p-chlorobenzoic
acid 70 and sodium selenate were tested for their retention in
organs, and phagocytic abilities of neutrophiles as well as
Current Medicinal Chemistry, 2004, Vol. 11, No. 12 1665
O NH3+
NH
NH COO-
O
Se
O
NH COO-
NH
O NH3+
65
H3 C
Se
N
HO
67
OCH3
NH2
COOH
Se
69
antioxidant properties in neutrophiles tested with NBT test,
using Swiss mice at the dose of 10-3 g Se/kg for the period
of 10 days. The concentrations of selenium were observed in
the livers of the mice treated with sodium selenate and
selenosemicarbazide compounds were found to be higher
than in controls (18.7 µg/g of tissue and 23.2 µg/g of tissue
vs 12.0 µ g/g of tissue respectively). Analysis of the blood
cell count has shown a significant decrease in neutrophile
levels in both groups treated with selenium. The influence of
selenium compounds on phagocytosis and especially NBT
test has been determined (3.8 % of positive cells in the
controls vs 2.2% and 0.9% in the groups treated with
sodium selenate and selenosemicarbazide respectively) [119].
Prostaglandins are produced from arachidonic acid under
the influence of two forms of cyclooxygenase (COX). The
COX-1 isoform is expressed in normal tissues. In contrast,
the isoform COX-2 is not detectable in most normal tissues
and is induced by cytokines, growth factors, and phorbol
esters [120]. Increased expression of cyclooxygenase-2
(COX-2) significantly enhances carcinogenesis and
inflammatory reactions. Epidemiological and laboratory
studies suggest that a regular intake of non-steroidal anti-
inflammatory drugs that inhibit the enzyme COX reduce the
risk of some human cancers, including lung cancer [121-
123]. Their mechanisms include suppressive effects on
tumor cell proliferation and angiogenesis [124, 125], and
promotion of tumor cell apoptosis [126].
Compound 10 is a highly effective chemopreventive
organoselenium compound and COX-2 inhibitor in vivo
[127, 75] can also inhibit cell growth in vitro. Previous
work had demonstrated the growth of NCI-H460 and NCI-
H69 lung tumor cells, in athymic nude mice [128-130].
However, the experiments designed to compare directly the
growth of human-derived lung cancer cells lacking COX-2
with those overexpressing it in nude mice under identical
conditions has not been reported. Recently studies
demonstrate that inhibition of NCI-H460 growth by
1666 Current Medicinal Chemistry, 2004, Vol. 11, No. 12
compound 10, as modifier of COX-2 expression, in vitro as
well as in vivo provides the basis for developing preventive
strategies utilizing COX-2 inhibitors for the prevention of
lung cancer [131, 132]. When compared to SCLC (NCI-
H69) cell lines that lack COX-2, the high levels of COX-2
protein in NCI-H460 cells may, in part, account for the
significant difference in tumor growth in nude mice.
Furthermore, their in vitro and in vivo data support the
hypothesis that levels of COX-2 expression determine the
extent of human lung tumor growth in athymic mice [131].
Protein kinases are a large group of enzymes that catalyze
transfer of phosphate from ATP to hydroxyl groups of
serine, threonine or tyrosine. Together with protein
phosphatases, the protein kinases regulate reversible protein
phosphorylation and as a consequence, play a critical role in
many signal transduction pathways involved in various
cellular phenomena, including proliferation, differentiation,
and metabolism [133-135]. Uncontrolled regulation of
protein kinase activities is often responsible for proliferative
diseases, such as malignant tumors, atherosclerosis, and
psoriasis [136, 137]. In a multiple protein kinases assay
using a postnuclear fraction of v-src-transformed NIH3T3
cells, compound 67 and 4-hydroxy-6-isopropyl-4-methyl-2-
p-tolyl-5,6-dihydro-4H-1,3-selenazine 74 exhibited selective
inhibitory activity against eukaryotic elongation factor-2
kinase (eEF-2K) over protein kinase A, protein kinase C and
protein tyrosine kinase [137]. In further experiments using
purified kinases, compound 67 (IC50 = 0.36 µ M) and
compound 74 (IC50 = 0.31 µM) inhibited eEF-2K about 25-
fold more effectively than calmodulin-dependent protein
kinase-I, and about 6-fold compound 6 7 or 33-fold
compound 74 more effectively than calmodulin-dependent
protein kinase-II respectively [138].
Many diseases can be characterized as conditions in
which the body fails to contain the overproduction of an
undesired metabolic by-product. All mammalian life
contains reactive oxygen species as the metabolic by-product
of oxygen supporting cellular respiration. Superoxide
radicals, which were formed by side reaction of the
mitochondria electron transport chain or an NADH-
independent enzymes can be converted into H2O2 and to the
powerful oxidant, the hydroxyl radical [139]. Under normal
conditions, superoxide dismutase, glutathione peroxidase,
and catalase among others, control all reactive oxygen
species. However, in certain diseases, the production of these
reactive oxygen species is enhanced causing cell injury.
Examples of such oxidative stress-related diseases include
reperfusion injury, brain ischemia, tumor, and various types
of inflammation and physiological aging [140-142].
Stroke occurs due to hemorrhage or occlusive injury and
the results are ischemia and reperfusion injury. A variety of
destructive mechanisms are involved including oxygen
radical generation, calcium overload, cytotoxicity and
apoptosis as well as the generation of inflammatory
mediators. Compound 50 significantly enhances the
outcome in-patients who have experienced occlusive cerebral
ischemia of limited duration [143] and protects the brain
from ischemic damage in the acute stage [144].
Chronic cerebral vasospam was inhibited in a primate
model in which a relatively large amount of compound 50
was administrated for 7 days after a subarachnoid
M. Soriano-García
hemorrhage [145]. Compound 50 significantly inhibited
lung oedema and bronchoalveolar lavage (BAL) tumor
necrosis factor (TNF)-alpha levels in a dose-related manner
with no effect on endothelin-1 (ET-1) levels in a model of
sephadex-induced lung inflammation [146]. Compound 50
also decreased ozone-induced pulmonary inflammation in
rats [147].
Furthermore, compound 50 is also a suitable anti-
inflammatory agent in ocular tissues using a model of
experimental uveitis upon subcutaneous injection of
endotoxin to Lewis rats [148].
Compound 50 oxidize the thiolate ligands in the zinc
clusters of metallothionein and release zinc [149, 150].
Metallothionein is a cadmiun-binding protein involve in cell
detoxification mechanisms for various heavy atoms and a
cellular reservoir for zinc; present in mammalian tissues
including those of the liver, brain, and lungs. This
chemistry defines new cellular targets for biological forms of
selenium and suggests important interactions between zinc
and selenium, two biological essential elements. These
findings reveal a new mode of action for 50 and therefore
suggest therapeutic applications in zinc-related medical
disorders as well as a possible role of biological selenium
compounds in zinc metabolism [149, 150]. Recently, the
compound 2-nitrophenylselenocyanate 75 was used to
investigate its reaction mechanism with the zinc/thiolate
clusters of metallothionein, a protein that is a cellular
reservoir for zinc and together with its apoprotein, thionein,
is involved in zinc distribution as zinc donor/acceptor pair.
The reaction is particularly revealing as it occurs in two
steps. A selenenylsulfide intermediate is formed in the first
oxidative step, followed by the generation of 2-
nitrophenylselenol that initiates the second, catalytic step.
The findings demonstrate the high reactivity of 2-
nitrophenylselenocyanate with zinc/thiolate coordination
sites and the potent catalytic roles that selenoproteins and
selenium redox drugs may have in affecting gene expression
via modulation of the zinc content of zinc finger proteins
[151].
Se
CH2 Cl
NH2
O NH COOH
COOH
Se 71
70 H
CH3 O
Se NH NH
NH
H3 C COOH
NH Se
72 73 Cl
H3C SeCN
NO2
Se
N
75
74 HO
CONCLUDING REMARKS
The cancer therapeutic and chemopreventive properties of
selenium have been evidenced by studies conducted over the
Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents
past 20 years, mainly with rodent models of mammary and
colon carcinogenesis and are in phase II and III clinical trials
for prostate cancer prevention [152]. Both organic and
inorganic forms of selenium have been used. The prototype
forms are sodium selenite, 1 and selenomethionine, 7.
Compound 1 suffers from limitations associated with
metabolic conversion to hydrogen selenide, generation of
DNA strand breaks, and cytotoxicity [153]. In contrast,
compound 7, which is relatively nontoxic, non-DNA-
damaging [62, 153, 154] and can be administrated orally.
Compound 7 is the major component of dietary
selenium, of which the recommended daily allowance (RDA)
by the US Food and Drug Administration is 50 µ g/day.
Cancer preventive use of selenium typically consists of 200
µ g/day [155], exceeding the RDA by fourfold with no
toxicity [152].
In human tissues, it has been estimated that each cell
sustains approximately 10000 potentially mutagenic (if not
repaired) lesions per day due to endogenous DNA damage. It
has been shown that selenium in the form of
selenomethionine 7 induces a DNA repair response in
normal human fibroblasts in vitro, and protects cells from
DNA damage. A possible mechanism for the inducible DNA
repair response in which enhanced repair complex formation
was observed in selenomethionine-treated cells is proposed
[156].
Selenium in the form of selenomethionine can activate
the p53 tumor suppressor protein by a redox mechanism
independent of DNA damage. Selenomethionine induced
sequence-specific DNA binding and transactivation by p53.
Cellular responses to selenomethionine were determined in
mouse embryo fibroblasts wild-type or null for p53 genes.
The evidence suggests that the DNA repair branch of p53
pathway was activated [157] .
Food is the major source of selenium intake but limited
efforts at elucidating structures of organoselenium
compounds in common foods have been made [158-162].
Supplementing dietary selenium intake has been the aim of
few clinical trials in cancer prevention. Compounds that
have, thus far, been identified in selenium-enriched yeast,
that had been utilized in successful human clinical
intervention trial [37,38] are selenomethionine 7, Se-
methylselenocysteine 3, and selenocysteine 15 [61].
It is worthwhile to mention that in the last 17 years,
many of the molecular mysteries about the biological role of
selenium have been solved. For instance, we know that
selenium is incorporated into protein as selenocysteine, the
21st naturally occurring amino acid in protein. Unlike any of
the other 20 amino acids that are present in protein, the
biosynthesis of selenocysteine occurs on its transfer RNA.
The donation of selenocysteine to the growing selenopeptide
in protein synthesis requires a novel mRNA binding protein
and a selenocysteine-tRNA specific elongation factor in
archae and eukaryotes, while a single protein carries out both
these functions in eubacteria. Selenoproteins have clearly
evolved to take advantage of the fact that the pKa of
selenocysteine is lower than the physiological pH and
consequently, this amino acid residue is ideally suited to
participate in redox reactions, for instance in the antioxidant
enzymes [21].
Current Medicinal Chemistry, 2004, Vol. 11, No. 12 1667
As discussed in this review, a large body of evidence
indicates that organoselenium compounds are used as
therapeutic and chemopreventive agents. Their role in
different kinds of cancer; in reducing viral expression; in
combating antibacterial and antifungal infections; in the
regulation of apoptosis; as a strongest protection against
cisplatin-induced cytotoxicity; in preventing heart disease;
other cardiovascular and muscle disorders; and several other
processes, have been discussed. So far, it is generally agreed
what is known about Se and chemopreventive mechanisms,
it is likely that selenium metabolites are active forms in
animal model systems and in humans. The conceptual
framework and the properties of organoselenium compounds
have been demonstrated with experimental evidence. Present
work has focused on the recent pharmacological applications
of organoselenium compounds as therapeutic agents in the
treatment of several diseases. The bulk of our knowledge on
the role of organoselenium compounds is based primarily on
animal data and from studies conducted in in vitro systems.
These studies have greatly aided to our understanding of the
mechanisms responsible for the protective role of selenium
against several diseases. There is little information available
on the protective role of organoselenium compounds in
humans. Although, there is convincing evidence that some
features of selenium metabolism are unique to humans [163,
164].
If dietary selenium does indeed have strong influence on
the above biological processes, then the significance of
including adequate amounts of selenium in the diet may be
regarded as one of the more important discoveries in
nutrition in the last century.
ACKNOWLEDGEMENTS
I would like to thank Mrs. Cynthia Soriano for
proofreading the manuscript. I will like to apologize to
anyone who finds my description of his or her work
inadequate or whose work I have accidentally omitted.
REFERENCES
[1] Berzelius, J.J. Afhandl. Fys. Kemi Mineralogi., 1818, 6, 42.
[2] Shamberger, R. J. Selenium. In Biochemistry of the Essential
Ultratrace Elements; Earl Frieden, Ed.; Plenum Press; New York,
NY; 1984; Vol. 3, pp. 201- 237.
[3] Brasted, R. C. In Comprehensive Inorganic Chemistry: Sulfur.
Selenium, Tellurium, Polonium and Oxygen; Robert C. Brasted,
Ed.; D. Van Nostrand Co.; Princeton, NJ; 1961; pp. 2.
[4] Merian, E. Toxicol. Environ. Chem., 1984, 8, 9.
[5] Wada, O.; Kurihara, N.; Yamazaki, N. Jap. J. Nutr. Assess, 1993,
10, 199.
[6] Lobinski, R.; Edmonds, J.S.; Sukuki, K.T.; Uden, P.C. Pure Appl.
Chem., 2000, 72, 447.
[7] Sunde, R.A. Selenium. In Handbook of Nutritional Essential
Mineral Elements; Boyd L. O´Dell; Roger A. Sunde, Eds.; Marcel
Dekker Inc.; New York, NY; 1997; pp. 493-556.
[8] Allan, C.B.; Lacourciere, G.M.; Stadtman, T.C. Ann. Rev. Nutr.,
1999, 19, 1.
[9] Diplock, A.T. Mol. Aspects Med., 1994, 15, 293.
[10] Rayman, M.P. Lancet, 2000, 356, 233.
[11] Neve, J. J. Cardiovasc. Risk, 1996, 3, 42.
[12] Köhrle, J. Cell. Mol. Life Sci., 2000, 57, 1853.
[13] Burk, R.F.; Gregory, P.E. Arch. Biochem. Biophys., 1982, 213, 73.
[14] Motsenbocker, M.A.; Tappel, A.L. Biochem. Biophys. Acta, 1982,
704, 253.
1668 Current Medicinal Chemistry, 2004, Vol. 11, No. 12 M. Soriano-García

[15] Persson-Moschos, M. Cell. Mol. Life Sci., 2000, 57, 1836. [51] Ip. C.; Vadhanavkit, S.; Ganther, H.E. Carcinogenesis, 1995, 16,
[16] Whanger, P.D. Cell. Mol. Life Sci., 2000, 57, 1846. 35.
[17] Walt Ream, L.; Vorachek, W.R.; Whanger, P.D. In Selenium: Its [52] Ip, C.; Zhu, Z.; Thompson, H.J.; Lisk, D.; Ganther, H.E.
Molecular Biology and Role in Human Health; Dolph L. Hatfield, Anticancer Res., 1999, 19, 2875.
Ed.; Kluwer Academic Publishers; Boston, MA; 2001; pp. 137- [53] El-Bayoumy, K.; Chae, Y.-H.; Upadhyaya, P.; Ip, C. Anticancer
146. Res., 1996, 16, 2911.
[18] Gladyshev, V.N.; Jeang, K. T.; Wootton, J.C.; Hatfield, D. L. J. [54] Reddy, B.S.; Tanaka, T.; El-Bayoumy, K. J. Natl. Cancer Inst.,
Biol. Chem., 1998, 273, 8910. 1985, 74, 1325.
[19] Gladyshev, V.N.; Diamond, A.M.; Hatfield, D.L. In Selenium: Its [55] Tanaka, T.; Reddy, B.S.; El-Bayoumy, K. Jpn. J. Cancer Res.,
Molecular Biology and Role in Human Health; Dolph L. Hatfield, 1985, 76, 462.
Ed.; Kluwer Academic. Publishers; Boston, MA; 2001; pp. 147- [56] El-Bayoumy, K. Cancer Res., 1985, 45, 3631.
155. [57] Nayini, J.R.; El-Bayoumy, K.; Sugie, S.; Cohen, L.A.; Reddy, B.S.
[20] Thompson, H.J. In Selenium: Its Molecular Biology and Role in Carcinogenesis, 1989, 10, 509.
Human Health; Dolph L. Hatfield, Ed.; Kluwer Academic. [58] Nayini, J.R.; Sugie, S.; El-Bayoumy, K.; Rao, C.V.; Rigotty, J.;
Publishers; Boston, MA; 2001; pp. 283-297. Sohn, O.–S.; Reddy, B.S. Nutr. Cancer, 1991, 15, 129.
[21] Hatfield, D.L. In Selenium: Its Molecular Biology and Role in [59] El-Bayoumy, K.; Chae, Y.-H.; Upadhyaya, P.; Meschter, C.;
Human Health; Dolph L. Hatfield, Ed.; Kluwer Academic. Cohen, L.A.; Reddy, B.S. Cancer Res., 1992, 52, 2402.
Publishers; Boston, MA; 2001. [60] Liu, J.-Z.; Milner, J.A. J. Nutr., 1992, 122, 1361.
[22] Mugesh, G.; du Mont, W.-W.; Sies, H. Chem. Rev., 2001, 101, [61] El-Bayoumy, K., Mutation Res., 2001, 475, 123.
2125. [62] Ip, C.; El-Bayoumy, K.; Upadhyaya, P.; Ganther, H.E.;
[23] Levi, M.S.; Borne, R.F.; Williamson, J.S. Curr. Med. Chem., 2001, Vadhanavikit, S.; Thompson, H. Carcinogenesis, 1994, 15, 187.
8, 1349. [63] Lü, J.; Jiang, C.; Kaeck, M.; Ganther, H.E.; Ip, C.; Thompson, H.J.
[24] Kelloff, G.J.; Boone, C.W.; Crowell, J.A.; Steele, V.E.; Lubet, R.; Carcinogenesis, 1995, 16, 513.
Sigman, C.C. Cancer Epidemiol. Biomarkers Prev., 1994, 3, 85. [64] Ip, C.; Lisk, D.J.; Ganther, H.E. Anticancer Res., 2000, 20, 4179.
[25] Willett, W.C. Environ. Health Perspect., 1995, 103, 165. [65] Tanaka, T.; Kohno, H.; Murakami, M.; Kagami, S.; El-Bayoumy,
[26] Shamberger, R.J.; Frost, D.V. Can. Med. Assoc. J. CMAJ, 1969, K. Cancer Res., 2000, 60, 3713.
100, 682. [66] El-Bayoumy, K.; Rao, C.V.; Reddy, B.S. Nutr. Cancer 2001, 40,
[27] Schrauzer, G.N.; Rhead, W.J. Experientia, 1971, 27, 1069. 18.
[28] Shamberger, R.J.; Willis, C.E. CRC Crit. Rev. Clin, Lab. Sci., 1971, [67] Chae, Y.-H.; Upadhyaya, P.; El-Bayoumy, K. Oncol. Rep., 1997,
2, 211. 4, 1067.
[29] Schrauzer, G.N.; Rhead, W.J.; Evans, G.A. Bioinorg. Chem., [68] Ip, C.; Birringer, M.; Block, E.; Kotrebai, M.; Tyson, J.F.; Uden,
1973, 2, 329. P.C.; Lisk, D.J. J. Agr. Food Chem., 2000, 48, 2062.
[30] Schrauzer, G.N.; White, D.A.; Schneider, C.J. Bioinorg. Chem., [69] Dong, Y.; Lisk, D.; Block, E.; Ip, C. Cancer Res., 2001, 61, 2923.
1977, 7, 23. [70] Jiang, C.; Jiang, W.; Ip, C.; Ganther, H.E.; Lu, J. Mol. Carcinog.,
[31] El-Bayoumy, K.; Chung, F.-L.; Richie J. Jr.; Reddy, B.S.; Cohen, 1999, 26, 213.
L.; Weisburger, J.; Wynder, E.L. Proc. Soc. Exp. Biol. Med., [71] Landis, S.H.; Murray, T.; Bolden, S.; Wingo, P.A. Cancer
1997, 216, 211. Statistics, 2000. CA Cancer J. Clin., 1999, 50, 6.
[32] Combs, G.F.Jr.; Gray, W.P. Pharmacol. Ther., 1998, 79, 179. [72] Clark, L.C. Fed. Proc., 1986, 44, 2584.
[33] Combs, G.F.Jr.; Clark, L.C. In Nutritional Oncology; David Heber; [73] El-Bayoumy, K. In Cancer: Principles and Practice on Oncology;
George L. Blackburn; Vay Liang W. Go, Eds.; Academic Press Vincent T. DeVita, Jr.; Samuel Hellman; Steven A. Rosenberg,
Inc.; San Diego, CA, 1999; pp. 215-222. Eds.; Lippincott Co.; Philadelphia, PA; 1999; Vol. 2, pp.1-15.
[34] Vinceti, M.; Rovesti, S.; Bergomi, M.; Vivoli, G. Tumori., 2000, 86, [74] Reddy, B.S.; Hirose, Y.; Lubet, R.A.; Steele, V.E.; Kelloff, G.J.;
105. Rao, C.V. Int. J. Mol. Med., 2000, 5, 327.
[35] Medina, D. J. Am. Coll. Toxicol., 1986, 5, 21. [75] Rao, C.V.; Cooma, I.; Rosa, J.G.; Simi, B.; El-Bayoumy, K.;
[36] Blot, W.J.; Li, J.-Y.; Taylor, P.R.; Guo, W.; Dawsey, S.; Wang, Reddy, B.S. Carcinogenesis 2000, 21, 617.
G.Q.; Yang, C.S.; Zheng, S.F.; Gail, M.; Li, G.Y.; Liu, B.Q.; [76] Rao, C.V.; Wang, C.-Q.; Simi, B.; Rodriguez, J.G.; Cooma, I.; El-
Tangrea, J.; Sun, Y.H.; Liu, F.; Fraumeni, F. Jr.; Zhang, Y.H.; Li, Bayoumy, K.; Reddy, B.S. Cancer Res., 2001, 61, 3647.
B. J. Nat. Cancer Inst., 1993, 85, 1483. [77] Reddy, B.S. Cancer Epidemiol. Biomarkers Prev., 2000, 9, 239.
[37] Clark, L.C.; Combs, G.F.Jr.; Turnbull, B.W.; Slate, E.; Alberts, D.; [78] Koketsu, M.; Yang, H.O.; Kim, Y.M.; Ichihashi, M.; Ishihara, H.
Abele, D.; Allison, R.; Bradshaw, J.; Chalker, D.; Chow, J.; Curtis, Org. Lett., 2001, 3, 1705.
D.; Dalen, J.; Davis, L.; Deal, R.; Dellasega, M.; Glover, R.; [79] Klayman, D.L. In Organic Selenium Compounds: Their Chemistry
Graham, G.; Gross, E.; Hendrix, J.; Herlong, J.; Knight, F.; and Biology; Daniel L. Klayman; Wolfgang H.H. Gunther, Eds.;
Krongrad, A.; Lesher, J.; Moore, J.; Park, K.; Rice, J.; Rogers, A.; John Wiley; New York, NY, 1973; pp. 727-761.
Sanders, B.; Schurman, B.; Smith, E.; Taylor, J.; Woodward, J. J. [80] Shamberger, R.J. Biochemistry of Selenium: Plenum Press: New
Am. Med. Assoc., 1996, 276, 1957. York, NY, 1983.
[38] Yoshizawa, K.; Willett, W.C.; Morris, S.J.; Stampfer, M.J.; [81] Parnham, M.J.; Graf, E. Prog. Drug. Res., 1991, 36, 9.
Spiegelman, D.; Rimm, E.B.; Giovannucci, E. J. Natl. Cancer Inst., [82] Smee, D.F.; Gilbert, J.; Leonhardt, J.A.; Barnett, B.B.; Huggins,
1998, 90, 1219. J.H.; Sidwell, R.W. Antiviral Res., 1993, 20, 57.
[39] Duffield-Lillico, A.J.; Reid, M.E.; Turnbull, B.W.; Combs, G.F.Jr.; [83] Bonnet, P.A.; Robins, R.K. J. Med. Chem., 1993, 36, 635.
Slate, E.H.; Fischbach, L.A.; Marshall, J.R.; Clark, L.C. Cancer [84] Patani, G.A.; LaVoie, E.J. Chem. Rev., 1996, 96, 3147.
Epidem. Biomarkers Prev., 2002, 11, 630. [85] Goudgaon, N.M.; Schinazi, R.F. J. Med. Chem., 1991, 34, 3305.
[40] Gladyshev, V.N.; In Selenium: Its Molecular Biology and Role in [86] Goudgaon, N.M.; McMillan, A.; Schinazi, R.F., Antiviral Chem.
Human Health; Dolph L. Hatfield, Ed.; Kluwer Academic. Chemother., 1992, 3, 263.
Publishers; Boston, MA; 2001; pp. 99-114. [87] Ni, L.; Schinazi, R.F.; Boudinot, F.D. Antiviral Res., 1995, 27, 39.
[41] Ganther, H.E. Carcinogenesis, 1999, 20, 1657. [88] Cohen, J. Science, 1997, 276, 520.
[42] Ip, C. J. Nutr., 1998, 128, 1845. [89] Du, J.; Surzhykov, S.; Lin, J.S.; Newton, M.G.; Cheng, Y.-C.;
[43] Ip, C.; Ganther, H.E. Cancer Res., 1990, 50, 1206. Schinazi, R.F.; Chu, C.K. J. Med. Chem., 1997, 40, 2991.
[44] Ip, C.; Ganther, H.E. Carcinogenesis, 1991, 12, 365. [90] Chu, C.K.; Ma, L.; Olgen, S.; Pierra, C.; Du., J.; Gumina, G.;
[45] Ip, C.; Ganther, H.E. Carcinogenesis, 1992, 13, 1167. Gullen, E.; Cheng, Y.-C.; Schinazi, R.F. J. Med. Chem., 2000, 43,
[46] Ip, C.; Ganther, H.E. J. Inorg. Chem., 1992, 46, 215. 3906.
[47] Vanhanavikit, S.; Ip, C.; Ganther, H.E. Xenobiotica 1993, 23, 731. [91] Xu, H.; Huang, K, Chemistry and Biochemistry of Selenium and
[48] Lü, J.; Jiang, C.; Kaeck, M.; Ganther, H.E.; Vadhanavikit, S.; Ip, Its Application in Life Sciences; Huibi Xu; Kaixun Huang, Eds.;
C.; Thompson, H.J. Biochem. Pharmacol., 1995, 50, 213. Huazhong University of Science and Technology Press; Wuhan,
[49] Lü, J.; Pei, H.; Ip, C.; Lisk, D.J.; Ganther, H.E.; Thompson, H.J. 1994 (in Chinese).
Carcinogenesis, 1996, 17, 1903. [92] Kulkami, Y.D.; Rani, A.; Bishiioi, A.; Shukla, R.L.; Anan, Z.K. J.
[50] Kaeck, M.; Lü, J.; Strange, R.; Ip, C.; Ganther, H.E.; Thompson, Ind. Chem. Soc., 1995, 72, 261.
H.J. Biochem. Pharmacol., 1997, 53, 921.
Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents Current Medicinal Chemistry, 2004, Vol. 11, No. 12 1669

[93] Alpegiani, M.; Bedeschi, A.; Perrone, E.; Franceschi, G. [128] Corti, C.; Pratesi, G.; De Cesare, M.; Pellegrini, R.; Giardini, R.;
Tetrahedron Lett., 1986, 27, 3041. Supino, R.; Zunino, F. J. Cancer Res. Clin. Oncol., 1996, 122, 154.
[94] Stadtman, T.C. Annu. Rev. Biochem., 1996, 65, 83. [129] Bogden, A.E.; Taylor, J.E.; Moreau, J-P.; Coy, D.H.; Le Page, D.J.
[95] Nozawa, R.; Yokota, T.; Fujimoto, T., Antimicrob. Agents Cancer Res., 1990, 50, 4360.
Chemother., 1989, 33, 1388. [130] Ishibashi, M.; Fujisawa, M.; Furue, H.; Maeda, Y.; Fukayama, M.;
[96] Bien, M.; Blaszczyk, B.; Kalinowska, K.; Mlochowski, J.; Inglot, Yamaji, T. Cancer Res., 1994, 54, 3442.
`
A.D. Arch. Immun. Ther. Exp., 1999, 47, 185. [131] El-Bayoumy, K.; Rose, D.P.; Papanikolaou, N.; Leszczynska, J.;
[97] Koketsu, M.; Ishihara, H.; Hatsu, M. Res. Commun. Mol. Path. Swamy, M.V.; Rao, C.V. Int. J. Onc., 2002, 20, 557.
Pharmacol., 1998, 101, 179. [132] Soriano, A.F.; Helfrich, B.; Chan, D.C.; Heasley, L.E.; Bunn, P.A.
[98] Xi, L.; Yi, L.; Jun, W.; Songsheng, Q. Thermochim. Acta, 2001, Jr.; Chou, T.-C. Cancer Res., 1999, 59, 6178.
375, 109. [133] Bolen, J.B.; Brugge, J.S. Annu. Rev. Immunol., 1997, 15, 371.
[99] Xi, L.; Yi, L.; Jun, W.; Huigang, L.; Songsheng, Q. Thermochim. [134] Anderson, P. Microbiol. Mol. Biol. Rev., 1997, 61, 33.
Acta, 2002, 387, 57. [135] Pawson, T.; Scott, J.D. Science, 1997, 278, 2075.
[100] Fleming, J.; Ghose, A.; Harrison, P.R. Nutr. Cancer 2001, 40, 42. [136] Kolibaba, K.S.; Druker, B.J. Biochem. Biophys. Acta, 1997, 1333,
[101] Lee, S.K.; Heo, Y.H.; Steele, V.E.; Pezzuto, J.M. Anticancer Res., F217-F248.
2002, 22,97. [137] Levitzki, A. Eur. J. Biochem., 1994, 226, 1.
[102] Sinha, R.; Kiley, S.C.; Lu, J.X.; Thompson, H.J.; Moraes, R.; [138] Cho, S.I.; Koketsu, M.; Ishihara, H.; Matsushita, M.; Nairn, A.C.;
Jaken, S.; Medina, D. Cancer Lett., 1999, 146, 135. Fukazawa, H.; Uehara, Y. Biochim. Biophys. Acta, 2000, 1475,
[103] Kim, T.; Jung, U.; Cho, D.-Y.; Chung, A.-S. Carcinogenesis, 2001, 207.
22, 559. [139] Nohl, H. FEBS Lett. 1987, 214, 269.
[104] Holl, V.; Coelho, D.; Silbernagel, L.; Keyser, J.-F.; Waltzinger, C.; [140] Salvemini, D.; Wang, Z.-Q.; Zweier, J.L.; Samouilov, A.;
Dufour, P.; Bischoff, P.L. Biochem. Pharmacol., 2000, 60, 1565. Macarthur, H.; Misko, T.P.; Currie, M.G.; Cuzzocrea, S.; Sikorski,
[105] Zhu, Z.; Jiang, W.; Ganther, H.E.; Ip, C.; Thompson, H.J. J.A.; Riley, D.P. Science, 1999, 286, 304.
Biochem. Pharmacol., 2000, 60, 1467. [141] McIntyre, T.M.; Zimmerman, G.A.; Prescott, S.M. J. Biol. Chem.,
[106] Jiang, W.Q.; Zhu, Z.J.; Ganther, H.E.; Ip, C.; Thompson, H.J. 1999, 274, 25189.
Cancer Lett., 2001, 162, 167. [142] Ren, X.; Yang, L.; Liu, J.; Su, D.; You, D.; Liu, C.; Zhang, K.;
[107] Ghose, A.; Fleming, J.; El-Bayoumy, K.; Harrison, P.R. Cancer Luo, G.; Mu, Y.; Yan, G.; Shen, J. Arch. Biochem. Biophys., 2001,
Res., 2001, 61, 7479. 387, 250.
[108] Koketsu, M.; Ishihara, H.; Wu, W.; Murakami, K.; Saiki, I. Eur. J. [143] Parnham, M.J.; Sies, H. Exp. Opin. Invest. Drugs, 2000, 9, 607.
Pharmacol. Sci., 1999, 9, 157. [144] Ogawa, A.; Yoshimoto, T.; Kikuchi, H.; Sano, K.; Saito, I.;
[109] Wu, W.; Murakami, K.; Koketsu, M.; Yamada, Y.; Saiki, I. Yamaguchi, T.; Yasuhara, H. Cerebrovas. Diseases, 1999, 9, 112.
Anticancer Res., 1999, 19, 5375. [145] Handa, Y.; Kaneko, M.; Takeuchi, H.; Tsuchida, A.; Kobayashi,
[110] Andreadou, I.; Menge, W.M.P.B.; Commandeur, J.N.M.; H.; Kubota, T. Surg. Neurol. 2000, 53, 323.
Worthington, E.A.; Vermeulen, N.P.E. J. Med. Chem., 1996, 39, [146] Belvisi, M.G.; Haddad, E.B.; Battram, C.; Birrell, M.; Foster, M.;
2040. Webber, S. Eur.Respir. J., 2000, 15, 579.
[111] Commandeur, J.N.M.; Stijntjes, G.J.; Vermeulen, N.P.E. [147] Ishii, Y.; Hashimoto, K.; Hirano, K.; Morishima, Y.; Mochizuki,
Pharmacol. Rev., 1995, 47, 271. M.; Masuyama, K.; Nomura, A.; Sakamoto, T.; Uchida, Y.; Sagai,
[112] Rooseboom, M.; Schaaf, G.; Commandeur, J.N.M.; Vermeulen, M.; Sekizawa, K. Lung, 2000, 178, 225.
N.P.E.; Fink-Gremmels, J. J. Pharmacol. Exp. Ther., 2002, 301, [148] Bosch-Morell, F.; Roma, J.; Puertas, F.J.; Mari, N.; Diaz-Llopis,
884. M.; Romero, F.J. Free Rad. Biol. Med., 1999, 27, 388.
[113] Xie, Y.; Short, M.D.; Cassidy, P.B.; Roberts, J.C. Bioorg. Med. [149] Jacob, C.; Maret, W.; Vallee, B.L. Biochem. Biophys. Res.
Chem. Lett., 2001, 11, 2911. Commun., 1998, 248, 569.
[114] Fiala, E.S.; Staretz, M.E.; Pandya, G.A.; El-Bayoumy, K.; [150] Jacob, C.; Maret, W.; Vallee, B.L. Proc. Natl. Acad, Sci., 1999,
Hamilton, S.R. Carcinogenesis, 1998, 19, 597. 96, 1910.
[115] Beckman, J.S.; Beckman, T.W.; Chen, J.; Marshall, P.A.; [151] Chen, Y.; Maret, W. Antioxidants & Redox Sign., 2001, 3, 651.
Freeman, B.A. Proc. Natl. Acad. Sci., USA 1990, 87, 1620. [152] Nelson, M.A; Porterfield, B.W.; Jacobs, E.T.; Clark, L.C. Semin.
[116] Roussyn, I.; Briviba, K.; Masumoto, H.; Sies, H. Arch. Biochem. Urol. Oncol., 1999, 17, 91.
Biophys., 1996, 330, 216. [153] Sinha, R; Said, T.K.; Medina, D. Cancer Lett., 1996, 107, 277.
[117] Chan, S.; Gerson, B.; Subramaniam, S. Clin. Lab. Med., 1998, 18, [154] Stewart, M.S; Spallholtz, J.E.; Nelder, K.H.; Pence, B.C. Free
673. Radic. Biol. Med., 1999, 26, 42.
[118] Winnefeld, K., Med. Klin., 1997, 15, 8. [155] Patterson, B.H.; Levander, O.A. Cancer Epidemiol. Biomarkers
[119] Musik, I.; Koziol-Montewka, M.; Tós-Luty, S.; Pasternak, K.; Prev., 1997, 6, 63.
[156] Seo, Y.R.; Sweeney, C.; Smith, M.L. Oncogene, 2002, 21, 3663.
Latuszynska, J.; Tokarska, M.; Kielczykowska, M. BioMetals,
`

[157] Seo, Y.R; Kelley, M.R.; Smith, M.L. Proc. Natl. Acad. Sci. USA,
1999, 12, 369. 2002, 99, 145-48.
[120] Herschman, H.R. Cancer Metast. Rev., 1994, 13, 241. [158] Nigan, S.N.; McConnell, W.B. Biochem. Biophys. Acta, 1969, 192,
[121] Rosenberg, L. Prev. Med., 1995, 24, 104. 185.
[122] Harris, R.E.; Kasbari, S.; Farrar, W.B. Oncol. Rep., 1999, 6, 71. [159] Cat, X.J.; Block, E.; Uden, P.C.; Zhang, Z.; Quimby, B.D.;
[123] Alshafie, G.A.; Abou-Issa, H.M.; Seibert, K.; Harris, R.E. Oncol. Sullivan, J.J. J. Agric. Food Chem., 1995, 43, 1754.
Rep., 2000, 7, 1377. [160] Bird, S.M.; Ge, H.; Uden, P.C.; Tyson, J.F.; Block, E.; Denoyer, E.
[124] Tsujii, M.; Kawano, S.; Du Bois R. Proc. Natl. Acad. Sci., USA J. Chromatogr., 1997, 789, 349.
1997, 94, 3336. [161] Uden, P.C.; Bird, S.M.; Kotterbai, M.; Nohbos, P; Tyson, J.F.;
[125] Masferre, J.L.; Leahy, K.M.; Koki, A.T.; Zweifel, B.S.; Settle, Block, E.; Denoyer, E. J. Anal. Chem., 1998, 362, 447.
S.L.; Woerner, B.M.; Edwards, D.A.; Flickinger, A.G.; Moore, [162] Bird, S.M.; Uden, P.C.; Tyson, J.F.; Block, E.; Denoyer, E. J. Anal.
R.J.; Seibert, K. Cancer Res., 2000, 60, 1306. Atom Spectrom., 1997, 12, 785.
[126] Tsujii, M.; Du Bois, R.N. Cell 1995, 83, 493. [163] Whanger, P.D. J. Trace Elem. Exp. Med. Biol., 1998, 11, 227.
[127] El-Bayoumy, K. Fundam. Mol. Mech. Carcinog., 2001, 475, 123. [164] Whanger, P.D. J. Am. Coll. Nutr., 2002, 21, 223.