Oxygen free radical and antioxidant defense mechanism in cancer
Gilberto Pérez Trueba 1 and
Gregorio Martínez Sánchez 2
TABLE OF CONTENTS
1. Abstract
2. Introduction
3. ROS in the initiation, promotion
and progression of cancer, general aspects
3.1. ROS-induced DNA
damage mechanisms (initiation)
3.2. ROS in tumor promotion
3.3. ROS in tumor
progression
3.3.1.
ROS and apoptosis
3.3.2.
Further mechanisms of ROS-induced tumor progression
4. Antioxidants defense systems in
carcinogenesis
4.1. Antioxidant therapy
5. Miconutrients as chemopreventive
agents
5.1. Carotenoids and
vitamin A
5.2. Vitamin E
5.3. Vitamin C
5.4. Selenium
6. Directions for future research
7. Acknowledgements
8. References
1. ABSTRACT
The reactive oxygen
species (ROS) can damage the nucleic acids. The oxidative modification of the
DNA constitutes the fundamental molecular event in carcinogenesis and that is
why the interest in the study of the involvement of ROS in that process. On the other hand,
oxidative DNA damage-induced mutagenesis is widely hypothesized to be a
frequent event in the normal human cell. The enormous evidence suggests an
important role of ROS in the expansion and progression of tumor clones, being
considered a relevant class of carcinogens. In addition, the use of
immunohistochemical techniques has showed that the various types of cancer
examined to date manifest an imbalance in their antioxidant mechanisms to
respect the primary cell.
In the near future
new insights in cancer therapies, based on modulation of cellular redox status,
may lead the way to additional tools against carcinogenesis from ROS.
2. INTRODUCTION
In the last twelve years there has been a growing interest in
understanding the role of free radicals in biomedicine. Particularly
interesting are the Reactive Oxygen Species (ROS), of which, the hydroxyl radical
(.OH) is most damaging of this chemical species; which also include
superoxide anions (O.2.), singlet oxygen (1O2)
and hydrogen peroxide (H2O2). ROS can be formed in the
aerobic life not only during oxidative phosphorylation, through the action of
mixed function oxidases, and as byproducts of normal metabolism by enzymes such
as superoxide dismutase (SOD), NADPH oxidase, and xanthine oxidase (XO) in
neutrophils, but can also be generated from redox cycling of certain drugs and
by radiation. Fortunately, the organism is endowed by an antioxidant defense
system that allows a balance between the generation of oxidants and
antioxidants. When this balance is disrupted a condition referred as oxidative
stress develops, and despite the antioxidants defense mechanism to counteract
the ROS-related deleterious effects, damage to macromolecules does occur as a
result of these reactions. Oxidative damage accumulates during the life cycle
and lead to different pathological processes such as: atherosclerosis, myocardial
infarction, rheumatoid arthritis, neurodegenerative disorders, and cancer,
among others.
Since oxidative DNA damage is considered the most important molecular
factor in carcinogenesis (1), recent studies are focussing on the role of ROS
in the induction, promotion and progression of this multistage process.
3. ROS IN THE INITIATION, PROMOTION AND PROGRESSION OF CANCER. GENERAL
ASPECTS
Cancer development, as a multistage process, requires the cumulative
action of multiple events that occur in one cell clone. These events include a
three stage model: a permanent change in one somatic cell genetic material
(initiation); 2-the expansion of the mutated cell clone (promotion) and
3-the malignant conversion into cancer (progression) (Figure 1). ROS can
stimulate carcinogenesis by acting at all three stages (2-6).
Figure 1. Pathways to cancer. Multistage process, which simplified, comprises
initiation (attack by ROS, carcinogen), accumulation of carcinogenic mutations,
progresses trough preneoplastic stages by the acquisition of more mutations,
promotion by a tumor promoter, progression and development of angiogenic
potential leading to expression of tumor
3.1. ROS-induced DNA damage mechanisms (initiation)
The initiation step requires a permanent change in one-cell genetic
material. DNA replication and subsequent cell division transform chemical
damage to an inheritable change in genetic material (mutation). Oxidative DNA
damage can occur by the following processes: 1-Through hydroxyl radical (.
OH), which is produced from H2O2 in the presence of
metal ions (Fe2+) or (Cu2+), present or in close
proximity to DNA, or released from their normal sequestration sites.
2-Increases in intracellular free calcium (Ca2+), as a result
of their release from the intracellular Ca2+ stores and
through the influx of extracellular Ca2+. A high level of
oxidative stress, which may in turn deplete the endogenous antioxidant
reserves, is an important signal leading to Ca2+ mobilization. An
effect of ROS-related Ca2+ changes is the activation of
endonucleases, which can cause DNA fragmentation (a normal process during
apoptosis) (7) (Figure 2). These mechanisms may occur simultaneously.
In living cells, there is a
steady formation of DNA lesions. . OH attack upon DNA generates a
whole series of DNA damage by a variety of mechanisms. These include sugar and
base modifications, strand breaks and DNA-protein cross-links. Modified DNA
bases (pyrimidine and purine) constitute one of the most common lesions. Some
of them have mutagenic properties being potentially able to damage the
integrity of the genome (2, 8). 8-hydroxyguanine (8-OH-Gua) represents one of
the most studied lesions, leading to GC
TA transversions and mutagenesis, unless repaired prior to DNA
replication (9). Several other modified bases, which have also been shown to
possess miscoding potentials and thus perhaps premutagenic properties, include
2-hydroxyadenine, 8-hydroxyadenine, 5-hydroxycytosine, and 5 hydroxyuracil. DNA
base damage is thought to be repaired mainly by base-excision repair (10). At
the same time, singlet oxygen can induce DNA damage selectively at guanine
residues (11).
A great number of evidences indicate a direct correlation between
8-OH-Gua generation and carcinogenesis in vivo (12). Furthermore, the
GC TA transversions have been
frequently detected in the tumor suppressor p53 gene and ras
protooncogene. Through the inactivation of tumor suppressor gene or the
activation of oncogenes, ROS-related mutations may lead to the initiation.
Recent investigations of benign tumors supported the idea that oxidative
DNA damage might be a causative factor in cancer development, and that a
positive correlation between the size of the tumor and the amount of 8-OH-Gua,
and possibly other base lesions, may be a risk factor that may determine the
transformation of benign tumors to malignant tumors (13).
Finally, while high doses of ROS increase the possibility of cancer
initiation through mutagenesis (14, 15), one single ROS may cause cell death if
it attack an essential gene for the cell viability, and in dependence on the
composition of the ROS involved, the presence of other carcinogens, and the
cell cycle position at the moment of exposure (5).
3.2. ROS in tumor promotion
The oxidative stress is strongly involved in this stage of
carcinogenesis. In summary, a number of tumor promoter classes are thought to
act either by stimulating endogenous oxygen radical production or by altering
cellular metabolic processes. Moreover, many tumor promoters have a strong and
immediate inhibitory effect on cellular antioxidant defense systems such as
SOD, CAT and GSH-Px activities (16). ROS can stimulate the expansion of mutated
cell clones by temporarily modulating gene related to proliferation or cell
death. While an overload from high levels of oxidative stress halts
proliferation by citotoxic effects, low levels can stimulate cell division and
promote tumor growth (17). Thus, the stimulation of the intracellular
production of ROS is considered the main way to promote the ROS-related tumors
(5).
ROS can also induce large increases in cytosolic Ca2+ through
the mobilization of intracellular Ca 2+ stores and through the
influx of extracellular [Ca2+] (18). The
ROS-related changes in intracellular [Ca2+] may account through
a direct or indirect action. The induction of the proto-oncogenes c-fos
was found to be directly while an example of an indirect effect represents the
phosphorylation of transcription factors by Ca2+-dependent
protein kinases (PKC). The activation of PKC and other protein kinases leads to
phosphorylation and the activation of other kinases, which regulate the
activity of transcription factors (7, 19).
Other studies have found ROS can directly modulate PKC activity through
the oxidation of cysteine residues in the regulatory domain of the enzyme. In
mammals, direct effects of ROS have been shown to regulate the activity of the
transcription factor NF-kappa B. This factor controls cell growth and
oncogenesis, in part, from the induction of gene products that controls
proliferative
Figure 2. ROS–induced DNA damage. Hypothetical mechanisms are shown in the figure
and discussed in the text
responses and
suppress apoptotic cascades, such as those induced by tumor necrosis factor
(TNF-alfa), expression of oncoproteins and genotoxic stress (20-22). NF-kappa B
activation also potentiates proliferation by blocking differentiation in
certain settings, and this phenomenon may also promote oncogenesis (22).
In in vitro experiment, DNA bindings of p53, AP-1 and NF-
kappa B are all activated in a reductive condition and repressed in an
oxidative condition. However, it is noted that certain transcription
factors are activated by oxidation while others are repressed by oxidation
(23).
Additionally, redox regulation is associated with Ca2+
signaling and protein phosphorylation. The key reaction is the reversible
reduction/oxidation of the sulfydryl function of the highly conserved cysteine
residues in the DNA-binding domain of these proteins.
Recent results from in vitro studies have shown H2O2
acts as a tumor promoter in non-neoplastic ephitelial cells (T51 B cell
line) in rat livers. The induced expression of early response genes c-fos,
c-jun, c-myc and egr-1, and
the inhibition of gap junctional communication could to be the H2O2
–mediated tumor promotion mechanisms (24).
3.3. ROS-induced tumor progression
The third step of carcinogenesis comprises the acquisition of malignant
properties by the tumor. Progression is distinguished by accelerate cell
growth, escape from immune surveillance, tissue invasion and metastasis (25).
Since the generation of large amounts of ROS may contribute to the
ability of some tumors to mutate, inhibit antiproteases and injure local
tissues, it has
Figure 3. Role of p53 in the cycle cell.
Consequences of p53 loss functions
together with the increases in the level of oxidatively modified DNA
bases (27). Conversely, the increased levels of modified DNA bases may
contribute to the genetic instability and metastatic potential of tumor cells
in fully developed cancer (28). However, another studies report while on one
hand an intense oxidative stress may kill cells being less effective in
introducing DNA modifications in a cell population (5), by the other hand there
may be cases in which oxidative DNA damage levels are increased, but cancer
development does not ensue (29-31). It has been suggested that perhaps
oxidative DNA base damage alone is insufficient to cause cancer development, or
damage over only a certain range is effective, excessive damage having an
anti-cancer effect by promoting apoptosis (32).
3.3.1. ROS and apoptosis
Over 70% of human cancers have defects in genes upstream or downstream
of p53 function as one of the most frequent mutations found in human
cancer (33, 34). p53 controls cell cycle and induces cell death by a
multitude of molecular pathways that include apoptosis through transcriptional
regulation of pro- and anti-apoptotic proteins. ROS are powerful inductors of p53
activity, triggering apoptosis by mechanisms requiring transcription and also
by transcription-independent mechanisms (35). Alterations of the p53
pathway influence the sensitivity of tumor cells to apoptosis (36). In the
presence of ionizing radiation or other sources of ROS-related DNA damage, the
expression of p53 increases, and a delay of cycle cell does occur, which
allows DNA repair before replication (Figure 3). In contrast, cells lacking
functional p53 proceed with cell divisions and thus permit DNA damage to
be carried out in the following generations, leading to continued chromosome
rearrangement from the initial DNA damage (Figure 3) (5). Recent reports have
revealed a possible ROS-induced apoptosis mechanism. ROS seem to have the
ability to signal p53 translocation to the nucleus and this ROS-induced
translocation of p53 could be an indication of DNA damage by these
species. Once in the nucleus p53, by DNA repair, maintains the integrity
of the genome. This observation is supported by several reports that point to a
marked translocation of p53 to the nuclear compartment after exposure to
H2O2 (37-39). At the same time, the genotoxic-induced p53
relocalization appeared to be cell cycle-specific, since cells in the G0/G1
stage had more abundant nuclear-associated p53 and were also more susceptible
to H2O2-induced apoptosis than the cells in G1/S phase
(35). These findings may contribute to the reports from several studies
suggesting one of the role of p53 consist of protecting cells from
spontaneously generated ROS-induced carcinogenesis (40).
3.3.2. Further mechanisms of ROS-induced tumor
progression
Several models of
environmentally induced lung endothelial injury have shown the regulatory roles
of ROS in the endothelial cells during the vascular phase of cancer metatasis.
The authors have suggested that other pathways for ROS involvement in
metastasis include the generation of reactive oxygen intermediates by cancer
cells, damage to vascular basement membranes mediated by endothelial
injury or perturbation, and direct activation of latent matrix
metalloproteinases. Human cancer cells exhibit constitutive production of H2O2
in levels that are comparable to those formed after perturbation of
leukocyte populations’ (11).
Most of the experimental tumors present increased levels of inducible
nitric oxide synthase (iNOS); thus, the nitric oxide (NO.) released
enhance vascular permeability, which enhance tumor progression and angiogenesis
(41, 22).
Angiogenesis constitutes one of the most significant events in the
development and subsequent expansion of cancer cells (Figure 4). Hypoxia is
present in regions of malignant tumors and is though to result from an
inadequate rate of angiogenesis. The presence and extent of these hypoxic
microenvironments have shown to influence in cancer progression by regulating
both cell survival and the expression of key angiogenic molecules (42). Recent
studies showed that short hypoxia-reoxygenation episodes over the human
endothelial lead to the generation of ROS and stimulated NF-kappa B
transcriptional activity. An increase in tubular morphogenesis or
neovascularitation, which describes angiogenesis, was found after NF-kappa B
been postulated these species may promote tumor heterogeneity, invasion and
metastasis (26).
It has been estimated that most
human cancers contain a large number of mutations (14). At least 11,000
individual DNA mutations exist in a single carcinoma cell of colorectal tumors
(15). ROS-induced DNA damage may represent one potential source of this large
number of mutations, which may arise during the development of the disease and
may contribute to the metastatic potential of tumor cells. This observation is
supported by evidences from breast cancer tissues, in which the potential of
metastasis increased
Figure 4. Role of angiogenesis in growth and proliferation of cancer cell.
1-Mutagenic cell forms a clone. 2- Evolution of tumor (releasing mediators
increases the angiogenic potential. 3- New blood vessels and capillaries supply
tumor irrigation, invasion and metastasis of transformed cell to other organs
Table 1. Tumors strongly related with an oxidant-antioxidant imbalance
Cancer
|
Key References
|
Breast
|
11, 45, 46
|
Colorectum
|
11, 45, 47, 48
|
Oesophagus
|
49
|
Blood (acute lymphoblastic leukaemia)
|
50-52
|
Pancreas
|
45
|
Bowel
|
11, 53
|
Lung
|
11, 54
|
Prostate
|
55
|
Skin
|
56
|
Ovary
|
45
|
Testis
|
45
|
Liver
|
11
|
Kidney and Bladder
|
45
|
Hepatobiliar
|
45
|
Bladder
|
11
|
Stomach
|
45
|
stimulation (43). The activation of NF-kappa B may also contribute to a
pro-malignant phenotype by upregulating gene products that control cell
proliferation and angiogenesis. This transcription factor is known to regulate
certain genes associated with metastasis. Thus, it has been postulated a
relevant role of NF-kappa B in later stage of oncogenesis may be to promote
metastasis (22). In addition, ROS-induced mutations in p53 may play an
important role in regulating the adaptive response of cells to hypoxia by
enhancing their survival and release of proangiogenic factors (44).
Finally, a great number of tumors can stimulate a variable intensity of
immune response. It depends on the intensity of response and tumor
susceptibility, the activated leukocytes-generated ROS can generate a chronic
inflammation, which instead of eliminating cancer development may increase
tumor progression or induce cell death through citotoxicity or apoptosis (5).
4. ANTIOXIDANTS DEFENSE SYSTEMS IN CARCINOGENESIS
Supporting the idea that ROS may be increased in tumoral cells, the
phenomena described above are in consonant with disturbance activities of antioxidant
enzyme (40). Table 1 show several kinds of tumors strongly related with
an oxidant-antioxidant imbalance.
Antioxidant enzymes and
detoxifiers have the ability to inhibit tumor promotion and initiation in
vivo and in vitro assays (57, 58). The initial studies on the
antioxidant enzymes, through biochemical methods in tumors homogenates, were
contradictory due to, in part, the methods were used could not differentiate
between the enzymatic activity of tumoral cells and other types of cells.
Recent development of inmunohistochemistry offered a better comprehension in
relation to the enzymatic behavior in tumor. So, analysis of these inmunohistochemical
studies have revealed that: 1-there is no translocation in the subcellular
location of the enzymes in the human cells under study; and 2-in cells with low
Mn-SOD levels, a decreased mRNA level for this enzyme was also indicated (59).
Mn-SOD constitutes an enzyme with variable activity in tumors. A
significant overexpression of Mn-SOD has been found in gastric and colorectal
adenocarcinoma. Similarly, other studies have revealed a significant increase
of Mn-SOD mRNA in both oesophageal and gastric cancers, compared to normal
tissue (60). Overexpression of Mn-SOD reduces the levels of intracellular ROS
and prevents cells death (61). In addition, it has been speculated that tumors
with high SOD levels resist ROS-generating therapies through ionizing radiation
(62).
However, the increased activity of SOD in some tumor cells is not a
characteristic of all tumors (63, 64). Thus, Mn-SOD is reduced in a variety of
tumor cells and the lowest activity of total SOD (Cu-SOD and Mn-SOD) has been
associated with fastest growing tumor (65).
There are some evidences that tend to ascribe the deficiency of the
Mn-SOD activity to a defect in the expression of the gene rather than to its
deletion. It is speculated that in the early stage of carcinogenesis an
impairment of the signal transduction machinery might cause the defect in the
Mn-SOD gene expression, taking into account the second messenger function of
ROS which activates transcription factors. Therefore, transition metals have
found to be highly reduced in several tumors. This observation, combined with
the deficiency of these two transition metals, may result in the limiting the
binding of transcription factors like AP-1 and NF- kappa B to the DNA,
leading to a defect in the genetic expression of Mn-SOD (66).
On the other hand, some studies
have detected a downregulation of Mn-SOD by p53. In fact, while a
significant increase in the enzyme activity was observed after gene
suppression, a significant reduction in Mn-SOD m RNA expression was also
confirmed after transient p53 transfection in Hela cells, which leads to
a decrease in the enzyme activity. Since an abnormally increased SOD expression
does occur after protein p53 lack function in most of human cancers, the
enzyme represents an attractive target for protein p53 (35, 36).
Studies in tissue cultures have shown cDNA for Mn-SOD transfection from
tumoral cell lines (melanoma, breast carcinoma, squamous cell carcinoma) (59,
62, 67) suppresses tumor development through an increase in the Mn-SOD in
vitro and in vivo activity. Despite the fact the mechanisms
by which this suppression occurs are not well established, some evidences
appear to indicate a decrease in the O2-. levels and an
increase in the H2O2 levels respectively, instead of cell
death induction (68). It has been suggested these changes may exert
some disturbance on the cell redox environment, which may induce changes in
relevant physiological pathways resulting in some reduction in tumor
development (65).
Another important therapeutic repercussion is the low capacity of a
variety of tumors for detoxifying H2O2 due to a decreased
CAT and GSH-Px level (69). However, other findings have shown GSH-Px and CAT
activities significantly increased as compared to cancer-free tissues. An
overexpression in the case of GSH-Px could explain the obtained results
(70-72).
Other studies in relation to antioxidant status in human cervical
carcinoma showed a remarkable reduction in the content of GSH, vitamin E and C,
GSH-Px and SOD when compared to normal controls (P< 0.001). The
reduction was more marked in late stages (II, IV) than in early stages (I, II)
(P< 0.001) (6). However, our results on the activities of GSH and on the
antioxidant defense enzymes SOD and CAT in Jamaicans women with cervical
cancer, at early stages, showed no substantial changes in the GSH and SOD
levels in patients compared to that of controls (normal healthy women). On the
contrary, CAT activity was significantly higher in patients than that of the
controls (unpublished data).
The GSH/GSSG ratio in blood also decreases in patients bearing breast or
colon cancers. This change associates with higher GSSG levels, especially in
advanced stages of cancer progression. The results above may be due to the
increased peroxide generation, which leads to an affectation in the GSH-related
enzymes, and an increased GSSG release from different tissues within the red
blood cells (73, 74). In fact, these high GSH and peroxide levels in the cells
have been reported when a substantial proliferative activity exits. On the
other hand, this antioxidant content decreases when cell proliferation and the
rate of protein synthesis in the tumor decreases (74, 75).
Another endogenous antioxidant is coenzyme Q10 (Q). Q levels in tumor
tissues of twenty-one breast cancer patients, who underwent radical mastectomy
and were diagnosed with infiltrative ductal carcinoma, were lower than
corresponding noncancerous tissues (76). This could reflect consumption of Q
against peroxidative damage in vitro tissues, taking into account the
notable antioxidant in vitro e in vivo activity of the reduced
form of Q (QH2) (77-79).
4.1. Antioxidant Therapy
The ROS-induced disease treatment with antioxidant represents a
therapeutic approach. However the mechanisms exerted by most of the chemotherapeutic
agents and the ionizing radiation inducing tumor cell death were associated
with an enhancement of the oxidative stress effects leading to irreversible
tissue damage instead of increased antioxidant actions (64). These observations
indicate that relatively low oxidative stress levels promote cellular
proliferation often causing degenerative processes and death. Approximately
half of all cancer patients receive radiation therapy as their disease
management. It has been demonstrated that exposure of cancer patients to
therapeutic doses of ionizing radiation cause DNA base modification in
lymphocytes.
Another alternative approach in cancer treatment constitutes the use of
the anthracycline derivatives. Cytotoxicity of these drugs, such as doxorubicin,
has been attributed to the inhibition of topoisomerase II as well as
intracellular production of free radicals (80).
Other cancer therapies include the antioxidant enzymes cDNA transfection
as a method to modify the redox environment, the use of antioxidants enzymes
and low weight compounds and liposoms among others. These therapies should be
designed taking into account the tumor specifies and the cell pro-oxidant /
anti-oxidant balance (81).
As the role of ROS involvement has become clearer, there has been a
general agreement to use antioxidant interventions taking into account the
hypothesis of ROS involvement in several pathological conditions. Before
proceeding with clinical trials it is essential to consider the following
points:
- Oxidative damage involvement in the physiopathology of diseases
(measurements of the biological relevance of oxidized molecule concentrations).
- The role of disrupted oxidative balance in pathological conditions
(central or secondary).
- Possible impairs in the antioxidant defense systems.
- The oxidative damage location.
- The probability of reaching the desirable concentration in the target
by the agent.
- Impact of selected antioxidant in the oxidative conditions.
- Tolerance and safety of dosage.
Growing interest in such therapies represents the association between
high antioxidant intake and the incidence of cancer. In fact, the
epidemiological literature points to greater consumption of fruits and
vegetables to decrease cancer risk (82-84). However, is difficult to
clarify fully the effect of dietary components on oxidative stress; thus, a
total correlation can not be established between these two factors (35). The
use of flavonoids and other related compounds as alternative approaches in
relation to mutagenesis prevention are also widely discussed in the lay
literature. At the same time, special attention must be put on the molecular
biology studies, which makes it possible to increase the antioxidant enzyme’s
intracellular expression.
The foregoing sections take into consideration several relevant trials
about the relationship between dietary micronutrients consumption and cancer
risk.
5. MICRONUTRIENTS AS CHEMOPREVENTIVE
Optimum intake of micronutrients reduces the risk of cardiovascular
disease and cancer, and influences the long-term health. A deficiency in
micronutrients is a plausible explanation for the strong epidemiological
evidence that shows an association between low consumption of fruits and
vegetables and cancer. The major naturally occurring dietary free-radical
scavengers (vitamin C and E and beta-carotene) have been shown in a number of
different studies to inhibit initiation, promotion and progression. However,
evidence is becoming stronger supporting these compounds may exert an
anticarcinogenic effect through other mechanisms apart from their antioxidant
function. The foregoing sections present several micronutrients research
studies in attempting to clarify the role of these compounds in cancer risk.
5.1. Carotenoids and Vitamin A
Carotenoids are members of a family of widely distributed pigments in
fruits and vegetables. The actual knowledge of the human toxicology of
carotenoids is derived almost exclusively from works on beta-carotene. The
absorption, uptake and tissue distribution may differ among the different
carotenoids, some of which are bioavailable and others of which are not (85).
Of the 600 or so carotenoids that have been identified, beta-carotene
has received special attention. Several clinical trials have shown reduced lung
cancer incidence after increments of beta-carotene ingestion. Despite the
promising results revealed in the studies, there appears another ambiguous
clinical trials. Thus, the Functional Food Science and Defense against Reactive
Oxidative Species (85) summarizes several experimental trials in relation to
beta-carotene and the risk of cancer. The first one, a Linxian (China) trial of
29, 584 adults over a five year period revealed significant reductions in
mortality from total and stomach cancer (13 % and 21 % respectively) in the
group randomized to 15 mg beta-carotene in combination with 30 mg vitamin E and
50 mg Selenium. However, a Finnish study of 29, 133 chronic heavy smokers
tested the effects of 20 mg beta-carotene, either alone or in combination with
vitamin E, for an average of six years. There was a significant increase of lung
cancer incidence (16 %) in the group that received beta-carotene. People
smoking for over an average of thirty years were more sensitive to an increased
risk of lung cancer. Another study of 18, 314 subjects at a high risk for lung
cancer (heavy smokers, and asbestos-exposed workers), assayed the combination
of 30 mg beta-carotene and vitamin A over a four years period. The experimental
group had a significantly increased risk of lung cancer. A reduced risk of lung
cancer (relative risk 0.80) was seen in subjects who were former smokers at the
beginning of the study. On the other hand, participants with high serum
beta-carotene levels had a 31 % reduction in risk of lung cancer, when compared
with the group they were randomized to. These observations were supported by a
Physicians’ Health Study, which was conducted over 12 years in 22, 071 male
physicians who consumed 50 mg beta-carotene every other day. There was no
beneficial influence of this micronutrient on cancer incidence.
Beta-carotene has also received
special attention with respect to photoprotection. Experimental studies had
shown that beta-carotene provided significant protection to UV-carcinogenesis
(86-88). At the same time, almost all of the large number of prospective and
retrospective epidemiological studies of either the intake of foods rich in
beta-carotene, or high levels of blood beta-carotene, have reported a strong
association with reduced risks of skin cancer (89, 90). However, in this case
the role of beta-carotene as an anticancer dietary supplement has also been
questioned as a result of a clinical trial in which incidence of nonmelanoma
skin cancer was unchanged in patients receiving 50mg/day of beta-carotene
supplement for a five years period (91). Further, recent experimental
studies have failed to demonstrate a photoprotective effect of beta-carotene to
UV-carcinogenesis (92) and, on the contrary, a significant exacerbation of
UV-carcinogenic expression, with respect to tumor latent period and
multiplicity, has been reported (93).
Carotenoids beta-criptoxanthine,
lycopene, lutein and zeoxanthine may also have a protective role in breast
cancer as suggested by a recent finding (94).
The mechanisms by which carotenoids
carry out their protective effects in cancer are not completely understood.
Scientific results indicate that beta-carotene is a powerful singlet oxygen
quencher and exhibits strong antioxidant properties (95, 96). In
addition, it has also been reported their inhibitory properties on the
arachidonic acid metabolism, on chromosome instability, and on ornitin
decarboxilase, adenilate and guanilate ciclase activities (97). But, by the
other hand, beta-carotene can act as a prooxidant at high oxygen concentration
and it has been seen that, under oxidative stress conditions, carotenoids
exhibits either limited antioxidant properties or a prooxidant effect (98-100).
Therefore, the response to beta-carotene supplementation might depend on the presence
and interaction with other dietary compounds, as well as the concentration
(ineffectual or exacerbated) of these dietary factors and the absent of some of
them. In fact, a short-term phase I toxicity trial of supplemental
beta-carotene in a small number of human volunteers demonstrated a continued
statistically significant decrease in serum vitamin E concentration during
supplementation for 9 months with 15, 30, 45 and 60 mg beta-carotene/d.
Although, other studies have demonstrated no such interaction (85).
Additionally, a mechanism indicating a
possible interaction between among beta-carotene, alpha-tocopherol and vitamin
C was proposed. In this context alpha-tocopherol, in terminating the
radical-propagating reaction, forms alpha-tocopherol radical cation, which in
turn, would be repaired by beta-carotene to form the carotenoid radical cation.
This radical would be repaired by ascorbic acid (101). Because of it is
hydrophilic characteristics it is anticipated that the ascorbate radical would
be formed in the hydration shell surrounding the membrane (102).
Another factor to consider could be the life style, taking into account
the high risk for lung cancer in heavy smokers and asbestos-exposed workers as
discussed above.
Finally, since the expression and
function of gap junctions is very frequently downregulated in cancer cells, and
growth inhibitory signals is believed to pass through these connexons
facilitating aberrant proliferation, it could be interesting to evaluate the
carotenoids gap junctions-related effects. This observation is based on
carotenoids-induced increase communication and thus, limiting aberrant
proliferation (65). In addition, it has been postulated from in vivo
studies conducted in rats liver, protective effects of alpha-carotene,
beta-carotene and lycopene in cancer promotion could be due to their
enhancement of gap junctional communications. At the same time these effects
appear to be critically dose-dependent, with suboptimal doses having no effect
and excessive doses causing inhibition instead of enhancement (103). However,
in view of the complexity of the measure of nutrients in human tissues, the
studies on diet-related effects on gap junctional communications appear to be
difficult.
5.2. Vitamin E
Vitamin E is the major fat-soluble antioxidant in the cellular
membranes. The hepatic alpha-tocopherol transfer protein recognizes only the
2R-alpha-tocopherol forms and not 2S or other naturally ocurring vitamin E
forms, such as ganma-tocopherol or tocotrienols. The RDA is 15 mg
alpha-tocopherol, or 22 IU of natural RRR-or 33 IU of synthetic all
rac-alpha-tocopherol (104).
Epidemiological studies have been shown that people taking vitamin E
supplements appear to lower their risk for different types of cancers, such as
colon cancer (105, 106), esophageal cancer (107) and prostate cancer (82, 108,
109). Several reports have demonstrated that the intake of vitamin E (200
UI/day) reduces the incidence of colon cancer (110, 111). It has been
postulated that alpha-tocopherol can lead to apoptosis in colorectal cancer
cells by inducing p21wafi/cip1, a powerful cell cycle inhibitor (107). On the
other hand, promising results have been obtained in the esophageal cancer
reduction by consuming vitamin E in combination with Selenium (Se) and
beta-carotene (112).
The protective effect of vitamin E in cases of oxidative DNA damage may
result from the inhibition of free radical formation and activation of
endonucleases that can be triggered by intracellular oxidative stress, as well
as by increasing the rate of the removal of damaged DNA (113-115).
Alpha-to-copherol has been shown to reduce the generation of . OH
induced by H2O2 with the subsequent DNA base modification
in human cells from oral epithelium (116) and the DNA strand breaks in VH 10
cell lines from the skin (117). Furthermore, it has been demonstrated the
inhibition exerted by this micronutrient against lipid peroxidation in HL-60
cells and the prostaglandin F2 and LPS-induced apoptosis in ovine
corporal luteal cells and in human endothelial cells respectively (118-120).
The mechanisms underlying the apoptosis inhibition by vitamin E could be
explained through their antioxidant actions, taking into account that apoptosis
constitutes one of the possible mechanisms for the preventive effect of
antioxidants on cancer development (115).
Despite the data available that collectively suggest vitamin E protects
against cancer, several reports point to perplexing results obtained from
interactions of vitamin E and vitamin C. Thus, when alpha-tocopherol (30 mM) or ascorbate (600
mM)
are added separately, each vitamin has a protective effect against the
oxidative DNA damage in human sperm (121). Nevertheless the same study reported
the addition of both vitamins together caused damaging effects. When vitamins
were mixed by using a concentration of 30 mM and 60 mM for vitamin E and
vitamin C respectively, while neither a harmful nor beneficial activity on H2O2-induced
DNA damage in human lymphoblastoid cells was revealed, an increased radiation-induced
genome damage was evident (122). Other study showed negative results for
vitamin E in combination with vitamin C and beta-carotene to prevent colorectal
cancer adenoma over a period of 4 years (123). And another trial revealed no
effects of supplementation with vitamin E, ascorbic acid, and coenzyme Q on
oxidative DNA damage, estimated by 8-oxo-7, 8-dihydro-2’-deoxyguanosine
excretion in smokers (124). Finally several others data point to disappointing
results in the vitamin E afforded protection against oxidative damage in
humans (125-128). Since vitamin C regenerates vitamin E from it’s reduced form
(tocopheroxy radical), it has been suggested that the addition of vitamin E
hinders the protective effect of vitamin C against the oxidative DNA damage
(5). However, an exhaustive analysis in the vitamins high dosage effects and
the time of treatment in cancer patients should be carried out.
5.3. Vitamin C
Vitamin
C (ascorbate), a water-soluble antioxidant, has a prominent in vitro
antioxidant action. At the same time several studies have pointed out
ascorbate inhibits the formation of carcinogenic nitrosamines, stimulates the
immune system, protects against chromosomal breakage, and regenerates vitamin E
as part of the antioxidant defense system (85). The epidemiological
evidence for a risk-reducing role of vitamin C in cancer is not very strong.
However, a consistent protective effect of vitamin C has been found in
studies of some types of cancer such as: oesophageal, lung, stomach, colon and
rectal (129-132). Moreover, additional studies showed that subjects with low
serum levels of vitamin C have a 50 % increased risk of gastric metaplasia or
chronic gastritis, which are both precancerous lesions (133).
Another studies have revealed the protective effects of this
micronutrient against the oxidative DNA damage in vivo. Thus, perhaps,
the antioxidative properties could be, in part, responsible for the effects of
ascorbate in cancer, though other properties of ascorbate appear to contribute
(134, 135). However, data from biomarkers of oxidative DNA damage are not
sufficiently convincing, except perhaps in subjects with very low vitamin C
intakes such as the heavy smokers (137-139). A plausible explanation of these
observations appears to be due to the variability of tissue saturation (84,
125, 139).
Other reports suggest vitamin C also offers protection from stomach
cancer (125), but limited evidence was provided by several populations (140).
Such reduction may be exerted through vitamin C-induced inhibitory action in
the generation of n-nitroso compounds by interrupting the reaction between
nitrites and amine groups (141).
An study in which 2 g/day 5, 6-benciliden-L-ascorbate (BA) was
intravenously administered in patients with advanced malignant tumor, showed a
fast and important reduction in the tumor size with no adverse reactions. A
plausible explanation could be the BA-induced in vivo tumor apoptosis,
which was not blocked either by CAT or cysteine analogues (142).
A controlled intervention trial with daily doses of vitamin C (500 mg),
giving in combination with alpha-tocopherol (200 mg) and coenzyme Q10 or
placebo did not reveal any change in the rate of DNA oxidation, as measured by
urinary excretion of 8-oxodG (124). By the other hand, recent studies suggest
that ascorbate sometimes increases DNA damage in humans. Although there is no
evidence that these effects are deleterious to humans, it is an important point
to consider in future studies, taking into account other reports has postulated
vitamin C exhibits prooxidant properties (143, 144).
Finally, the conclusion from an exhaustive survey of the literature is
that oral intake of high (up to 600 mg/day, i.e. six times the current RDA)
levels of vitamin C are safe and entirely free from side effects. At the
same time, levels up to 2000 mg/day have not been consistently reported to
result in side effects (85). But, taking into consideration that minor reports
have shown vitamin C may exert prooxidant actions, an attentive precaution should
be considered with the use of high intake of this antioxidant vitamin.
5.4. Selenium
Several investigations have revealed the preventive role of selenium
(Se) against cancer in a variety of organs and species. Despite the association
between low selenium level and advanced tumor disease, it yet to be decided
whether this phenomenon is more likely to be a consequence or a
causative factor for development and course of the disease (145-147).
Foods such as meat, seafood, grains and poultry, constitute the major
source of Se. Some of the studied functions for this micronutrient in mammals
include that to be an essential component of the GSH-Pxs and thioredoxin
reductase. The structures of the organoselenium compounds in foods have not
been completely elucidated. Currently, the US Food and Drug Administration only
approve selenium-enriched yeast as a supplement for human usage. Several
clinical intervention trials (148, 149) have used Se compounds such as
selenomethionine, Se-methylselenocysteine, selenocysteine and selenoethionine
which have been identified in selenium enriched yeast. However, the form
of Se that is responsible for cancer prevention remains undefined (145).
Two clinical intervention trials, both conducted in China, used dietary
supplements containing 50 mg Se/day in combination with
other nutrients to prevent esophageal cancer. The former, giving 50 mg Se/day as
selenium-enriched yeast and combined with beta-carotene and alpha-tocopherol,
showed a significant reduction and a lower mortality from stomach cancer in
relation to placebo groups (150). The other trial, giving 50 mg Se/day as
inorganic selenium, in combination with another 25 vitamins, did not detect a
significant effect on the development of esophageal cancer (151). Another
randomized controlled trial was carried out in the US to 1312 patients with a
history of basal cell or squamous cell carcinomas of the skin. The aim
consisted in to determine whether a nutritional supplements of Se (200 mg/day) decreases the
incidence of cancer. The results of this study did not show that Se
supplementation reduces the risk of carcinoma of the skin. However, Se
supplements revealed to be associated with significant reductions in secondary
end points of total cancer incidence (lung, colorectal and prostate) and lung
cancer mortality (148). Since supplementation in rodents with inorganic
selenium or various forms of organoselenium compounds have shown inhibit
formation of 8-OH-dG, it has been postulated the reduction of lung, colon and
prostate cancers in the clinical trials that employed selenium-enriched yeast
could be due to, in part, to a reduction in various kinds of oxidative stress,
including 8-OH-dG (145).
Several in vitro studies and others, conducted in rodents, have
shown that various levels and forms of Se compounds inhibit carcinogen-induced
covalent DNA adduct formation and DNA oxidative damage (152-155). However,
since some features of Se metabolism are specific to humans, these results need
to be demonstrated in human populations (145, 156).
In a study of Se intake and colorectal cancer individuals in the lowest
quartile of plasma Se had four times the risk of colorectal adenomas compared
to those in the highest quartile (157). By the other hand, in a nested,
case-control prospective study on ovarian cancer, serum Se was associated with
decreased risk (158).
Selenium and GSH-Px levels were found to be lowered in patients with
carcinoma of uterine cervix (159, 160). Since GSH-Px is a Se-dependent enzyme,
it seems to be clear a Se deficiency may be the cause of the reduction in their
levels, and thus contribute to cancer development among probably other
mechanisms unrelated to the activities of the selenoenzymes.
Experiments employing cell cultures have showed Se induces apoptosis and
inhibits cell growth in transformed cells (161, 162). In addition, induction of
the p53 gene by selenium compounds was demonstrated. However, another
reports indicate the induction of apoptosis by Se may not be entirely due to
the response of p53 (163).
Finally, the recommended daily allowance is 50-70 mg Se per day for
healthy adults, but intake of 200 mg Se per day have been used
with safety in clinical trials in relation to cancer. However, despite the use
of up to about 700 mg Se per day with no apparently adverse clinical
symptoms (164-166), the intake of an excess of Se may result in oxidative
damage and genome instability (167).
6. DIRECTIONS FOR FUTURE RESEARCH
While many details regarding the role of ROS-induced DNA damage in the
etiology of complex multifactorial diseases like cancer are yet to be
discovered, it is evident that oxidants act at several stages in the malignant
transformation, since they can induce permanent DNA changes. Thus, it is
becoming increasingly clear that oxidative DNA damage plays a role in the
development of cancer. In addition, most human cancers contain large numbers of
mutations and severe oxidative stress may serve as an efficient source of
mutations during tumor progression. However, to date no one has
successfully proved that oxidative DNA damage constitutes a valid biomarker for
cancer development. It would need measuring DNA of healthy human subjects over
many years to see who develops cancer (168).
Diets rich in fruits and vegetables are commonly associated with
decreased incidence of the major human cancers. As described above, multiple
mechanisms can account for this, but some other studies have revealed no
effects in decreasing oxidative DNA damage, at least in the population
examined, which was supplemented with high intake of micronutrients in respect
to current RDA values. The response to antioxidant supplementation might depend
on the presence and interaction with other dietary compounds, as well as the
concentration of these dietary factors and the absent of some of them. Since
tumors generally appear in about a decades after a permanent change in one-cell
genetic material occur, it is important to take into account that clinical
trials need to be long enough to evaluate the effect on cancer. It also
might be difficult to clarify fully the effect of dietary components on
oxidative stress, because many other factors (endogenous and exogenous) have an
influence. Exogenous factors affecting oxidative stress include ionizing
and non-ionizing radiation, smoking, certain diseases such as autoinmune
problems, chronic hepatitis, alcohol intake, air pollution, physiological
stress and extraneous exercise among others.
The mechanism trough ROS plays an important role in the initiation and
progression of cancer, is not yet fully understood. By the other hand, ROS
mediated–tumor promotion needs for further experimental evidences in humans.
Finally, in the near future the use of valid biomarkers will provide new
insights in the experimental studies in relation to the qualitative and
quantitative importance of the oxidative DNA modification and cancer
development in humans. These may lead the way to elucidate possible preventive
tools.
7. ACKNOWLEDGEMENTS
The authors are grateful to Carlos
Pérez Trueba for his excellence assistance in the technical support. We
gratefully to Christine Pérez PhD from Dominican
University. Ghicago, USA; which contributed to the correction of all
typographic and grammatical mistakes throughout the text.
8. REFERENCES
1. Clemens, M.R: Free radicals in chemical carcinogenesis. Klin
Wochensche 69, 1123-1134 (1991)
2. Hussain, S.P., F. Aquilar, P. Amstad & P. Cerutti: Oxi-radicals
induced mutagenesis of hotspot codons 248 and 249 of the human p53 gene.
Oncogene 9, 2277-2281 (1994)
3. Nakamura, Y., T. Gindhart, D. Winterstein, I. Tomita, J. Seed &
N. Colburn: Early Superoxide dismutase-sensitive event promotes neoplastic
transformation in mouse epitelial JB6 cell. Carcinogenesis 9, 203-207
(1998)
4. Salim, A.S: The permissive role of oxygen-derived free radicals in
the development of colonic cancer in the rat. A new theory for carcinogenesis. Int
J Cancer 53, 1031-1035 (1993)
5. Dreher, D. & A.F. Junod: Role of oxygen free radicals in cancer
development. European J of Cancer 324, 30-38 (1996)
6. Ahmed, M.I., S.T. Fayed, H. Hossein & F.M. Tash: Lipid
peroxidation and antioxidant status in human cervical carcinoma. Dis Markers
15, 283-291 (1999)
7. Maki, A., I.K. Berezeski, J. Fargnoly, N.J. Holbrook & B.F.
Trump: Role of [Ca 2+] in the induction of
c-fos, c-jun, and c-myc mRNA in rat PTE after oxidative stress. FASEB 6,
912-924 (1992)
8. Wallace, S.S: Enzymatic processing of radiation-induced free radical
damage in DNA. Radiat Res 150, S60-S79 (1998)
9. Grollman, A.P. & M. Moriya: Mutagenesis by 8-oxoguanine: an enemy
within. Trends Genet 9, 246-249 (1993)
10. Dizdaroglu, M., P. Jaruga, M. Birincioglu & H. Rodríguez: Free
radical induced damage to DNA: mechanisms and measurement. Free Rad Biol Med
32, 1102-1115 (2002)
11. Wiseman, H. & B. Halliwell: Damage to DNA by reactive oxygen and
nitrogen species: role in inflammatory disease and progression to cancer. Biochem
J 313, 17-29 (1996)
12. Feig, D.I., T.M. Reid & L.A. Loeb: Reactive oxygen species in
tumorigenesis. Cancer Res 54, 1890s-1894s (1994)
13. Olinski, R., D. Gackowski, M. Forsinski, R. Rozalski, K. Roszkowski
& P. Jaruga: Oxidative DNA damage: assessment of the role in
carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome. Free
Radic Biol Med 33, 192-200 (2002)
14. Jackson A.L. & L.A. Loeb: The contribution of endogenous sources
of DNA damage to the multiple mutations in cancer. Mutat Res 477, 7-21
(2001)
15. Ionov, Y., M.A. Peinado, S. Malkhosyan, D. Shibata & M. Perucho:
Ubiquitous somatic mutations in simple repeated sequences reveal a new
mechanism for colonic carcinogenesis. Nature 363, 558-561 (1993)
16. Troll, W. & R. Wiesner: The role of oxygen free radicals as a
possible mechanism of tumor promotion. Annu Rev Pharmacol Toxicol 25, 509-528
(1985)
17. Burdon, R.H: Superoxide and hydrogen peroxide in relation to
mammalian cell proliferation. Free Radic Biol Med 18, 775-794 (1995)
18. Orr, W.F. & H.H. Wang: Tumor cell interactions with the
microvasculature. A rate limiting step in metastasis. Surgical Oncology
Clinics of North America 10, 357-381 (2001)
19. Werlen, G., D. Belin, B. Conne, E. Roche, D.P. Lew & M. Prentki.
Intracellular calcium and the regulation of early response gene expression in
HL-60 myeloid leukemia cells. J Biol Chem 268, 16596-16601 (1993)
20. Gilmore, T.D: Malignant transformation by mutant rel proteins. Trends
Genet 7, 318-332 (1991)
21. Toledano, M.D., & W.J. Leonard: Modulation of transcription
factor NF-kappaB binding activity by oxidation-reduction in vitro. Proc
Natl Academic Sci USA 88, 4328-4332 (1991)
22. Marty, W.M. & A.S. Baldwin: The transcription factor NF-kB: control of
oncogenesis and cancer theraphy resistance. BBA 1470, M55-M62 (2000)
23. Toyokuni, S: Reactive oxygen species-induced molecular damage and
it’s application in pathology. Pathol Int 49, 91 (1999)
24. Huang, R.P., A. Peng, M.Z. Hossain, Y. Fan, A. Jagdale & A.L.
Boynton: Tumor promotion by hydrogen peroxide in rat liver epithelial cells. Carcinogenesis
20, 485-492 (1999)
25. Toyokuni, S., K. Okamoto, J. Yodoi & H. Hiai: Persistent
oxidative stress in cancer. FEBS Lett 358, 1-3 (1995)
26. Kuo, M.L., S.G. Shiah, C.J. Wang & S.E. Chuang: Suppression of
apoptosis by Bcl-2 to enhance benzene metabolites-induced oxidative DNA damage and
mutagenesis: A possible mechanism of carcinogenesis. Mol Pharmacol 55,
894-901 (1999)
27. Malins, D.C., N.L. Polissar & S.J. Gunselman: Progression of
human breast cancer to the metastatic state is linked to hydroxyl
radical-induced DNA damage. Proc Natl Acad Sci USA 93, 2557-2563 (1996)
28. Schmielau, J. & O.J. Finn: Activated granulocytes and
granulocyte-derived hydrogen peroxide are the underlying mechanism of
suppression of t-cell function in advanced cancer patients. Cancer Res
61, 4756-4760 (2001)
29. Bashir, S., G. Harris, M.A. Denman, D.R. Blake & P.G. Winyard:
Oxidative DNA damage and cellular sensitivity to oxidative stress in human
autoimmune diseases. Ann Rheum Dis 52, 659-666 (1993)
30. Halliwell, B: Oxygen radicals, nitric oxide and human inflammatory
joint disease. Ann Rheum Dis 54, 505-510 (1995)
31. Thomas, E., D.H. Brewster, R.J. Black & G.J. Macfarlane. Risk of malignancy
among patients with rheumatoid conditions. Int J Cancer 88, 497-502
(2000)
32. Halliwell, B: Effect of diet on cancer development: is oxidative DNA
damage a biomarker ?. Free Radic Biol Med 32, 968-974 (2002)
33. Le Page, F., A. Margot, A.P. Grollman, A. Sarasin & A. Gentil:
Mutagenicity of a unique 8-oxoguanine in a human Ha-ras sequence in mammalian
cells. Carcinogenesis 16, 2779-2784 (1995)
34. Levine, A.J: p53 the cellular gatekeeper for growth and division. Cell
8, 323-331 (1997)
35. Das, U.N: A radical approach to cancer. Med Sci Monit 8, 79-92 (2002)
36. Frederiik, H. &. P.H. Krammer: Death and anti-death: tumour
resistance to apoptosis. Nature Reviews Cancer 2, 277-288 (2002)
37. Arakaki, N: Involvement of oxidative stress in tumor cytotoxic
activity of hepatocyte growth factor/scatter factor. J Biol Chem 274,
13541-13546 (1999)
38. Zimmerman, R.J., Jr B.J. Marafino & A. Chem: The role of oxidant
injury in tumor cell sensitivity to recombinant human tumor necrosis factor in
vivo. Implications for mechanisms of action. J Immunol 142,
1405-1409 (1989)
39. Kitamura, Y., T. Ota & Y. Matsuoka: Hydrogen peroxide-induced
apoptosis mediated by p53 protein in glial cells. Glia 25, 154-164
(1999)
40. Punnonen, K., H. Asaishi, M. Hyoty, R. Kudo & M. Ahotupa: Anti-oxidant enzyme
activities and oxidative stress in human breast cancer. J Cancer Res Clin
Oncol 120, 374-377 (1994)
41. Maeda, H. & T. Akaike: Nitric oxide and oxygen radicals in infection, inflammation
and cancer. Biochemistry 63, 854-865 (1998)
42. Matés, J.M., P.C. Gómez, I. Núñez de Castro, M. Asenjo & J. Márquez:
Glutamine and its relationship with intracellular redox status, oxidative
stress and proliferation/death. IJBCB 1217, 1-20 (2001)
43. Lelkes, P.I., K.L. Hahn, D.A. Sukovich, S. Karniol & D.H. Schmidt: On
the possible role of reactive oxygen species in angiogenesis. Adv Exp Med Biol 454, 295-310 (1998)
44. Royds, J.A., S.K. Dower, E.E. Qwarnstrom & C.E. Lewis: Response of tumor
cells to hypoxia: role of p53 and NF-KappaB. Mol Pathol 51, 55-61 (1998)
45. Hristozov, D., V. Gadjeva, T. Vlaykova & G.Dimitrov: Evaluation
of oxidative stress in patients with cancer. Arch Physiol Biochem 109,
331-336 (2001)
46. Lee, Y.J., S.S. Galoforo & C.M. Berns: Glucose deprivation–induced
citotoxicity and alterations in mitogen-activated protein kinase activation are
mediated by oxidative stress in multidrug-resistant human breast carcinoma
cells. J Biol Chem 273, 5294-5299 (1998)
47. Chinery, R., R.D. Beauchamp, Y. Shyr, S.C. Kirkland & R.J.D. Coffey:
Antioxidants reduce cyclooxygenase-2 expression, prostaglandin production and
proliferation in colorectal cancer. Cancer Res 58, 997-1003 (1998)
48. Yamamoto, H., H. Sawai, T.K. Weber, M.A. Rodriguez-Bigas & M. Perucho: Somatic
frameshift mutations in DNA mismatch repair and proaptosis genes in hereditary
nonpolyposis colorectal cancer. Cancer Res 56, 997-1003 (1999)
49. Torzewski, M., M. Sarbia, H. Heep, P. Dutkowski, R. Willers & H.E. Gabbert:
Expression of Bcl-X(L), an antiapoptotic member of the Bcl-2 family, in
esophageal squamous cell carcinoma. Clin Cancer Res 4, 577-583 (1998)
50. Buschfort, C., M.R. Müller, S. Seeber, M.F. Rajewsky & J. Thomale: DNA
excision repair profiles of normal and leukemic human lymphocytes: functional
analysis at the single-cell level. Cancer Res 57, 651-658 (1997)
51. Müller, M.R., C. Buschfort, J. Thomale, C. Lensing, M.F. Rajewsky,
S. Seeber. DNA repair and cellular resistance to alkylating agents in chronic
lymphocytic leukemia. Clin Cancer Res 3, 2055-2061 (1997)
52. Sentüker, S., B. Karahalil, M. Inal, H & Yilmaz H: Oxidative DNA base
damage and antioxidant enzyme levels in childhood acute lymphoblastic leukemia.
FEBS Lett 416, 286-290 (1997)
53. Tanaka, T., K. Kawabata & M. Kakumoto: Citrus auraptene exerts
dose-dependent chemopreventive activity in rat large bowel tumorigenesis: the
inhibition correlates with suppression of cell proliferation and lipid
peroxidation and with induction of phase II drug-metabolizing enzymes. Cancer
Res 58, 2550-2556 (1998)
54. Kennedy, C.H., R. Cueto, S.A. Belinsky, J.F. Lechner & W.A. Pryor:
Overexpression of hMTH1 Mrna : a molecular marker of oxidative stress in lung
cancer cells. FEBS Lett 429, 17-20 (1998)
55. Kiningham, R.B: Physical activity and the primary prevention of
cancer. Prim Care 25, 515-536 (1998)
56. Shisler, J.L., T.J. Senkevich, M.J. Berry & B. Moss: Ultraviolet-induced
cell death blocked by a selenoprotein from a human dermatotropic poxvirus. Science
279, 40-41 (1998)
57. Guyton, K.Z. & T.W. Kensler: Oxidative mechanism in carcinogenesis. Brit Med Bull 49, 523-544 (1993)
58. O’Brien P.J: Antioxidants and cancer. Molecular mechanism. In: Free
radicals in diagnostic medicine. Eds: Armstrong D, Plenum Press, NY 215-239
(1994)
59. Oberley, T.D. & L.W. Oberley: Anti-oxidant enzyme levels in cancer.
Histology and Histopatology 12, 525-535 (1997)
60. Izutani, R., S. Asano & M. Imano: Expression of manganese
superoxide dismutase in esophageal and gastric cancers. J Gastroenterol
33, 816-822 (1998)
61. Majima, H.J., T.D. Oberley & K. Furukawa: Prevention of mitochondrial injury
by manganese superoxide dismutase reveals a primary mechanism for
alkaline-induced cell death. J Biol Chem 273, 8217-8224 (1998)
62. Church, S.L., J.W. Grant & L.A. Ridnour: Increased manganese superoxide
dismutase expression supresses the malignant phenotype of human melanoma cells.
Proc Nalt Acad Sci 90, 3113-3117 (1993)
63. Bize, I.B., L. W. Oberley LW & H.P. Morris: Superoxide
dismutase and superoxide radical in Morris Hepatoma. Cancer Res 40,
3686-3693 (1980)
64. Kong, Q. & K.O. Lillehei : Antioxidant inhibitors for
cancer therapy. Med Hypotheses 51, 405-409 (1998)
65. Bertrand, J.S: The molecular biology of cancer. Mol Aspects Med
21, 167-223 (2001)
66. Borrello, S., M.D. De Leo & T. Galeotti: Defective gene
expression of Mn SOD in cancer cells. Mol Aspects Med 14, 253-258 (1993)
67. Li, J.J., L.W. Oberley, D.K. St. Clair, L.A. Ridnour & T.D. Oberley: Phenotypic
changes induced in human breast cancer cell by overexpression of
manganese-contaming superoxide dismutase. Oncogene 10, 1989-2000 (1995)
68. Matés, J.M. & F.M. Sanchez-Jimenez: Role of reactive oxygen species
in apoptosis: implications for cancer therapy. IJBCB 32, 157-170 (2000)
69. Nakano, T., T, K. Oka & N. Taniguchi: Manganese superoxide dismutase
expression correlates with p53 status and local recurrence of cervical carcinoma
treated with radiation therapy. Cancer Res 56, 2771-2775 (1996)
70. Izutani, R., M. Katoh & S. Asano: Enhanced expression of manganese superoxide
dismutase mRNA and increased tNF and mRNA expression by gastric mucosa in
gastric cancer. World J Surg 290, 228-233 (1996)
71. Gromodniska, J: Glutathione and glutathione metabolizing enzymes in
tissue and blood of breast cancer patients. Neoplasma 44, 45-51 (1997)
72. Buser, K. & F. Jencourt: Breast cancer pretreatment drugs resistance parameter in tumor
tissue and their correlation with clinical and prognostic characteristics. Ann
Oncol 8, 335-341 (1997)
73. Carretero, J. & E. Obrador: Growth-associated changes in glutathione
content correlate with liver metastatic activity of B 16 melanoma cells. Clin
Exp Metastasis 17, 567-574 (1999)
74. Navarro, J., E. Obrador & J. Carretero: Changes un
glutathione status and the antioxidant system in blood and in cancer cells
associate wiyh tumour growth in vivo. Free Radic Biol Med 26,
410-418 (1999)
75. Estrela, J.M., R. Hernández, P. Terradez, M. Asensi, I.R. Puertes & J. Viñas: Regulation of
glutathione metabolism in Ehrlich ascites tumour cells. Biochem J 286,
257-262 (1992)
76. Oytun, P., O. Ozay, E.I. Mine, B. Berrin, K. Muberra & S. Iiskender: Coenzyme
Q10 Concentrations and Antioxidant Status in Tissues of Breast Cancer Patients.
Clinical Biochemistry 33, 279-284 (2000)
77. Crane, F.I: Determination of ubiquinones. Methods Enzymol
176, 137-181 (1990)
78. Beyer, R.E: An analysis of the role of coenzyma Q in free radical
generation and as antioxidant. Biochem Cell Biol 70, 390 (1992)
79. Ernster, L. & G. Dallner: Biochemical, physiological and medical
aspects of ubiquinone function. Biochim Biophys Acta 1271, 195-204
(1995)
80. Olinski, R. & P. Jaruga: Epirubicin induced oxidative DNA damage
and evidence for its repair in lymphocytes of cancer patients who are
undergoing chemotherapy. Molec Pharm 52, 882- 885 (1997)
81. Maxwel, S.R.J: Anti-oxidant therapy: does it have a role in the
treatment of human diseases? Exp Opin Invest Drugs 6, 211-236 (1997)
82. Albanes, D., O.P. Heinonen & J.K. Huttunen: Effects of a-tocoferol and b-carotene suplements
on cancer incidence in the a-tocoferol and b-carotene Cancer
Prvention Study. Am J Clin Nutr 62, 14275-14305 (1995)
83. Ames, B.N., M.K. Shigenaga & T.M. Hagen: Oxidants, antioxidants
and the degenerative diseases of aging. Proc Natl Acad Sci USA 90,
7915-7922 (1993)
84. Duthie, S.J., A. Ma, M.A. Ross & A.R. Collins: Antioxidant
supplementation decreases oxidative DNA damage in lymphocytes. Cancer Res 56, 1291-1295
(1996)
85. Diplock, T., J.L. Charleux, G. Crozier-Willi, F.J. Kok, C.
Rice-Evans, M. Roberfroid, W. Stahl W & J. Vin a-Ribes: Functional food
science and defense against reactive oxidative species. Nutrition Society
32, 410-418 (1998)
86. Epstein, J.H: Effects of b-carotene on UV-induced skin
cancer formation in the hairless mouse skin. Photochem Photobiol 25,
211-213 (1977)
87. Mathews-Roth, M.M. & N.I. Krinski: Carotenoid dose level and
protection against UB-B-induced skin tumors. Photochem Photobiol 42,
35-38 (1985)
88. Mathews-Roth, MM: b-carotene: In: Clinical
aspects. In: Protective Role for Selected Nutrients. Eds: Spiller GA, Scala J, Liss, NY 17-38 (1989)
89. IARC Working group on the Evaluation of Cancer Preventive: IARC
Handbooks of Cancer Prevention: Carotenoids. IARC Lyon 2 (1998)
90. Kune, G.A., S. Bannerman & B. Field B: Diet, alcohol,
smoking, serum b-carotene, and vitamin A in male nonmelanocytic skin
cancer patients and controls. Nutr Cancer 18, 237-244 (1992)
91. Greenberg, E.R., J.A. Baron, M.M. Stukel & the skin Cancer
Prevention Study Group. A clinical trial of b-carotene to prevent
basal-cell and squamous-cell cancer of the skin. N Engl J Med 323, 789-795 (1990)
92. Gensler, H.L. & M. Magdaleno: Topical vitamin E inhibition of
immunosuppresion and tumorigenesis induced by ultraviolet irradiation. Nutr
Cancer 15, 97-106 (1991)
93. Black, H.S: Radical interception by carotenoids and effects on
UV-carcinogenesis. Nutr Cancer 31, 212-217 (1998)
94. Dorgan, J.F., A. Sowell & C.A. Swanson: Relationship of serum
carotenoids, retinol, µ-tocopherol, and selenium with
breast cancer risk: results from a prospective study in Columbia Missouri
(United States). Cancer Causes Control 9, 89-97 (1998)
95. Foote, C.S. & R.W. Denny: Chemistry of singlet oxygen. VII.
Quenching by b-carotene. J Am Chem Soc 90, 6233-6235 (1968)
96. Krinsky, N.I. & S.M. Deneke: Interaction of oxygen and oxy-radicals
with carotenoids. JNCI 69, 205-210 (1982)
97. Toma, S., P.L. Losardo, M. Vincent & R. Palumbo:
Effectiveness of b-carotene in cancer chemoprevention. Eur J Cancer
Prev 4, 213-224 (1993)
98. Anderson, H.J., H. Chen, L.J. Pellet & A.L. Tappel:
Ferrous-iron-induced oxidation in chicken liver slices as measured by
hemichrome formation and thiobarbituric acid-reactive substances: Effects of
dietary vitamin E and b-carotene. Free Radic Biol
Med 15, 37-48 (1993)
99. Obermuller-Jevic, U.C., P.I. Francz, F. Frank, A. Flaccus & H.K. Biesalski:
Enhancement of the UVA induction of haem oxygenase-1 expression by b-carotene in human
skin fibroblasts. FEBS Lett 460, 212-216 (1999)
100. Black, S.H: Pro-oxidant and anti-oxidant mechanism (s) of BHT and b-carotene in
photocarcinogenesis. Frontiers in Bioscience 7, 1044-1055 (2002)
101. Bohm, F., R. Edge, E.J. Land, D.J. Mc Garvey & T.G. Truscott:
Carotenoids enhance vitamin E antioxidant efficiency. J Am Chem Soc 119, 621-622 (1997)
102. Black, H.S. & C.R. Lambert: Radical reactions of carotenoids
and potential influence on UV carcinogenesis. In: Oxidants and Antioxidants in
Cutaneous Biology. Curr Probl
Dermatol. Eds: Thiele J, Elsner P, Karger, Basel 29, 140-156 (2001)
103. Bottrill, K: The Use of Biomarkers as Alternatives to Current
Animal Tests on Food Chemicals. ATLA 26, 421-480 (1998)
104. Frei, B. & G. Maret: The new US Dietary Reference Intakes for
Vitamins C and E. Redox report 6, 5-9 (2001)
105. White, E., J.S. Shannon & R.E. Patterson: Relationship between
vitamin and calcium supplement use and colon cancer, Cancer Epidemiol.
Biomarkers Prev 6, 769-774 (1997)
106. Albanes, D., N. Malila & R. R. Taylor: Effects of supplemental
alpha-tocopherol and beta-carotene on colorectal: result from a controlled
trial (Finland). Cancer Causes Control 11, 197-205 (2000)
107. Chinery R., J.A. Brockman, M.O. Peiler, Y. Skyr, R.D. Beauchamp
& R.J Coffey: Antioxidants enhance the citotoxicity of chemotherapeutic
agents in colorectal cancer: a p53-independent induction of p21. Beta Nat Med 3, 1233-1241 (1997)
108. Hartman, T.J., D. Albanes & P. Pietinen: The association
between baseline Vitamine E, selenium, and prostate cancer in the
alpha-tocopherol, beta-carotene cancer prevention study, Cancer Epidemiol
Biomarkers Prev 7, 335-340 (1998)
109. Heinonen, O.P., D. Albanes & J. Virtamo: Prostate cancer and
supplementation with alpha-tocopherol and beta-carotene: incidence and mortality
in a controlled trial. J Natl Cancer Inst 90, 440-446 (1990)
110. White, E., J.S. Shannon & R.E. Patterson: Relationship between
vitamin and calcium supplement use and colon cancer. Cancer Epidemiol Biomarkers
Prev 6, 769-774 (1997)
111. Albanes, D., N. Malila & R.R. Taylor: Effects of supplemental
alpha-tocopherol and beta-carotene on colorectal cancer: results fronm a
controlled trial (Finland). Cancer Causes Control 11, 197-205 (2000)
112. Kelloff, G.I., J.A. Crowel & C.W. Boone: Clinical development
plans for cancer chemopreventive agents. J Cell Biochem 20, 63-73 (1994)
113. Azzi, A. , & A. Stocker: Vitamin E: non-antioxidants roles. Prog Lipid Res 39, 231-255 (2000)
114. Factor, V.M., D. Laskowska, & M.R. Jensen: Vitamin E reduces
chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse
model. Proc Natl Acad Sci USA 97, 2196-2201 (2000)
115. Kate, J.C. & N.M. Simin: Vitamin E and genome stability. Mutation
Research 475, 37-44 (2001)
116. Royack, G.A., M.P. Nguyen, D.C. Tong, M. Poot & D. Oda:
Response of human oral epithelial cells to oxidative damage and the effect of
vitamin E. Oral Oncol 36, 37-41 (2000)
117. Slamenova, D., E. Horvathova, E. Kosikova, L. Rusekova & J.
Labaj: Detection of lignin biopolymer and vitamin E-stimulated reduction of DNA
strand breaks in H2O2 and MNNG-treated mammalian cells by
the comet assay. Nutr Cancer 33, 88-94 (1999)
118. Barroso, M.P., C. Gomez-Díaz, G. Lopez-Lluch, M.M. Malagen, F.L.
Crane & P. Navas: Ascorbate and alpha-tocopherol prevent apoptosisinduced
by serum removal independent of Bcl-2. Arch Biochem Biophys 343, 243-248 (1997)
119. Vierk, J.E., T.R. Hansen, K.J. Austin, E.A. Van Kirk, B.W. Hess
& W.J. Murdoch: Inhibition by tocopherol of prostaglandin-induced apoptosis
in ovine corporea lutea. Prostaglandins Other Lipid Mediat 56, 265-276
(1998)
120. Haendeler, J., A.M. Zeiher & S. Dimmeler: Vitamins C and E
prevent lipopolysaccharide-induced apoptosis in human endothelial cells by
modulation of Bcl-2 and Bax. Eur J Pharmacol 317, 407-411 (1996)
121. Hughes, C.M., S.E. Lewis, V.J. McKelvey-Martin & W. Thompson:
The effects of antioxidant supplementation during Percoll preparation on human
sperm DNA integrity. Hum Reprod 13, 1240-1247 (1998)
122. Sweetman, J.J. & V.J. McKelvey-Martin: Effect of antioxidant
vitamin supplementation on DNA damage and repair in human lymphoblastoid cells.
Nutr Cancer 29, 120-128 (1997)
123. Greenberg, E.R., J.A. Baron & T.D. Tosteson: Polyp Prevention Study Group. A
clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 331, 141-147 (1994)
124. Prieme, H., S. Loft, K. Nyyssonen, J.T. Salonen & H.E. Poulsen:
No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on
oxidative DNA damage estimated by 8-oxo-7, 8.dihydro-2’-deoxyguanosine
excretion in smokers. Am J Clin Nutr 65, 503-507 (1997)
125. McCall, M.R. & B. Frei: Can antioxidant vitamins materially
reduce oxidative damage in humans? Free Radic Biol Med 26, 1034-1053
(1999)
126. Huang, H.Y., K.J. Helzlsouer & L.J. Appel: The effects of
vitamin C and vitamin E on oxidative DNA damage: results from a randomised
controlled trial. Cancer Epidemiol Biomarkers Prev 9, 647-652 (2000)
127. Beatty, E.R., T.G. England, C.A. Geissler, O.I. Aruoma & B.
Halliwell: Effect of antioxidant vitamin supplementation on markers of DNA
damage and plasma antioxidants. Proc Nutr Soc 58, 44 A (1999)
128. Sarataho, E.P., J.T. Salonen & K. Nyyssonen: Long-term effect of vitamin E,
vitamin C, and combined supplementation on urinary 8-oxo-7,
8.dihydro-2’-deoxyguanosine, serum cholesterol oxidation products, and
oxidation products, and oxidation resistance of lipids in nondepleted men. Arterioscler
Thromb Vasc Biol 20, 2087-2093 (2000)
129. Block, G: Vitamin C and cancer prevention: the epidemiologic
evidence. Am J Clin Nutr 53, 270-282 (1991)
130. Fontham, E.T.H: Vitamin C, vitamin C-rich foods, and cancer:
epidemiologic studies. In: Natural antioxidants in human health and disease.
Eds: Frei B, Academic Press, San Diego 157-197 (1994)
131. Biesllski, H.K., H. Bohles, P. Estervaber & F. Furst:
Antioxidant vitamins in prevention. Clinical Nutrition 16, 151-155
(1997)
132. Wolk, A., P. Lindblad & H.O. Adami: Nutrition and renal cell
cancer. Cancer Causes Control 7, 5-18 (1996)
133. Carr, C.A. & F. Balz: Toward a new recommended dietary allowance for vitamin
C based on antioxidant and health effects in humans. Am J Clin Nutr 69, 1086-1097 (1999)
134. Sakagami, H. & K. Satoh: Modulation Factors of Radical
Intensity and Cytotoxic Activity of Ascorbate. Anticancer Research 17,
3513-3520 (1997)
135. Sweetman, J.J., V.J. Strain & V.J. McKelvey-Martin: Effect of
antioxidant vitamin supplementation on DNA damage and repair in human
lymphoblastoid cells. Nutr Cancer 27, 122-130 (1997)
136. Jarvinen, R. & P Knekt: Vitamin C, smoking, and alcohol
consumption. In: Vitamin C in health and disease. Eds: Packer L, Fuchs J, NY 425-455 (1997)
137. Marangon, K., B. Herbeth & E. Lecomte: Diet, antioxidant status
and smoking habits in French men. Am J Clin Nutr 67, 231-239 (1998)
138. Lykkesfeldt, J., H. Prieme, S. Loft & H.E. Poulsen: Effects of
smoking cesation on plasma ascorbica acid concentration. BMJ 313,
91(1996)
139. Levine, M., C. Conry-Cantilena & Y. Wang: Vitamin C pharmacokinetics in
healthy volunteers: evidence for a recommended dietary allowance. Proc Natl
Acad Sci USA 93, 3704-3709 (1996)
140. Kono, S. & T. Hirohata: Nutrition and stomach cancer. Cancer
Causes Control 7, 41-55 (1996)
141. Tannenbaum, S.R., J.S. Wishnock & C.D. Leaf: Inhibition of
nitrosamine formation by ascorbic acid. Am J Clin Nutr 53, 2475-2505 (1991)
142. Sakagami, H. & K. Satoh: Modulation Factors of Radical
Intensity and Cytotoxic Activity of Ascorbate. Anticancer Research 17,
3513-3520 (1997)
143. Halliwell, B:. Vitamin C: poison, prophylactic or panacea?. Trends
Biochem Sci 24, 255-259 (1999)
144. Podmore, I.D., H.R. Griffiths & T.E. Herbert: Vitamin C
exhibits prooxidant properties. Nature 392, 559 (1998)
145. El-Bayoumi, K: The protective role of selenium on genetic damage
and on cancer. Mutation Research 475, 123-139 (2001)
146. Giovannucci, E: Selenium and risk of prostate cancer. Lancet
352, 755-756 (1998)
147. Harrison, P.R., J. Lanfear, L. Wu, J. Fleming, L. Mc Garry & L.
Blower: Chemopreventive and growth inhibitory effects of selenium. Biom
Environ Sci 10, 235-245 (1997)
148. Clark, L.C., G.F Jr. Combs & B.W. Tumbull: Effects of selenium
supplementation for cancer prevention in patients with carcinoma of the skin: a
randomized controlled trial. J Am Med Assoc 276, 1957-1963 (1996)
149. Clark, L.C., B. Dalkin & Krongrad, A: Decreased incidence of
prostate cancer with selenium supplementation: results of a double-blind cancer
prevention trial. Br J Urol 81, 730-734 (1998)
150. Blot, W.J., J.Y. Li & P.R. Taylor: Nutrition intervention trial
in Linxian, China: supplementation with specific vitamin mineral combinations,
cancer incidence and disease-specific mortality in the general population. J
Natl Cancer Instit 85, 1483-1492 (1993)
151. Li, J.Y., P.R. Taylor & B. Li : Nutrition intervention
trials in Linxian, China: multiple vitamin/mineral supplementation, cancer
incidence and disease-specific mortality among adults with esophageal
dysplasia. J Natl Cancer Instit 85, 1492-1498 (1993)
152. El-Bayoumi, K: The role of selenium in cancer prevention. In:
Cancer: Principles and practice on oncology. Eds: VT De Vita Jr, S Hellman
& S.A.Rosenberg (4th edition) 1-15 (1999)
153. Combs, G.F Jr. & W.P. Gray: Chemopreventive agents: selenium. Pharmacol
Ther 79, 179-192 (1998)
154. Ip, C: Lessons from basic research in selenium and cancer
prevention. J Nutr 125, 1845-1854 (1998)
155. El-Bayoumi, K., Y.H. Chae & C. Ip: Chemoprevention of mammary
cancer by diallyl selenide, a novel organoselenium compound. Anticancer Res
16, 2911-2918 (1996)
156. Whanger, P.D: Metabolism of selenium in humans. J Trace Elem Exp Med 11, 227-240 (1998)
157. Russo, M.W., S.C. Murray, J.I. Wurrzelmann, J.T. Woosley & R.S.
Sandler: Plasma selenium levels and the risks of colorectal adenomas. Nutr
Cancer 28, 125-129 (1997)
158. Helzlsouer, K.J., A.J. Alberg, E.P. Norkus, J.S. Morris, S.C.
Hoffman & J.W. Comstock: Prospective study of serum micronutrients and
ovarian cancer. J Natl Cancer Inst 88, 32-37 (1996)
159. Bhuvaharamurthy, V., K. Balasubramanian & S. Govindasamy:
Effect of radiotherapy and chemoradiotherapy on circulating antioxidant system
on human uterine cervical carcinoma. Mol Cell Biochem 158, 17-23 (1996)
160. Guo, W.D., A.W. Hsing, J.Y. Li, J.S. Chen, W.H. Chow & W.J.
Blot: Correlation of cervical cancer mortality with reproductive and dietary
factors, and serum markers in China. Int J Epidemiol 23, 1127-1132
(1994)
161. Sinha, R., T. Said & D. Medina: Organic and inorganic selenium
compounds inhibit mouse mammary cell growth in vitro by different
cellular pathways. Cancer Lett 197, 277-284 (1996)
162. Sinha, R. & D. Medina: Inhibition of cdk2 kinase activity by
methylselenocysteine in synchronized mouse mammary epithelial tumor cells. Carcinogenesis
18, 1541-1547 (1997)
163. Lu, J., C. Pei, C. Ip, D.J. Lisk, H. Ganther & H.J. Thompson:
Effect of an aqueous extract of selenium-enriched garlic on in vitro
markers and in vivo efficacy in cancer prevention. Carcinogenesis
17, 1903-1907 (1996)
164. Lanfear, J., J. Fleming, L. Wu, G. Webster & P.R. Harrison: The
selenium metabolite selenodiglutathione induces p53 and apoptosis
relevance to the chemopreventive effects of selenium?. Carcinogenesis
15, 1387-1392 (1994)
165. Yang,G., S. Yin, R. Zhou, L. Gu , B. Yan & Y. Liu: Studies of
safe maximal daily dietary intake in a seleniferous area in China. Part II.
Relation between selenium intake and manifestations of clinical signs and
certain biological alterations. J Trace Elem Electrolites Health 3,
123-130 (1989)
166. Longnecker, M.P., P.R. Taylor & O.A. Levander: Selenium in
diet, blood and toenails in relation to human health in a seleniferous area. Am. J Clin Nutr 53, 1288-1294 (1991)
167. Spallholz, J.E: On the nature of selenium toxicity and
carcinostatic activity. Free Radic Biol Med 17, 45-64 (1994)
168. Halliwell, B: Establishing the significance and optimal intake of
dietary antioxidants: the biomarker concept. Nutr Rev 57, 104-113 (1999)
Key Words:
Cancer, Reactive Oxygen Species, Oxidative damage to DNA, Mutagenesis, p53,
Apoptosis, Review
Send correspondence to: Dr
Gilberto Pérez Trueba, Centro de Investigaciones Biomédicas, ICBP “ Victoria de
Girón” Ave. 146 No. 3102, Código Postal 11600, Ciudad de La Habana, CUBA, Tel:
271-52-80, Fax: ?????, E-mail: carlos.perez@equant.com
Dr. Jorge Donato Barros.
Médico. Nº C: 283606083. Ilustre Colegio Oficial de Médicos de Madrid
Consultorio
Calle de la Princesa 3. Duplicado. Piso 1º. Apto. 0115
Plaza de los Cubos. Madrid. Teléfono: 919 223 569
