Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives
In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high pathogenetic importance in the lu...
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irk-123456789-1453912019-01-23T01:23:03Z Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives Grigoryeva, E.S. Kokova, D.A. Gratchev, A.N. Cherdyntsev, E.S. Buldakov, M.A. Kzhyshkowska, J.G. Cherdyntseva, N.V. Reviews In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high pathogenetic importance in the lung carcinogenesis and can be identified in biological samples with high accuracy and reliability using highly sensitive mass spectrometry methods (TOF/TOF, TOF/MS, MS/MS). The appearance of DNA adducts in blood or tissues is the result of the interaction of carcinogenic factors, such as tobacco constituents, and the body reaction which is determined by individual characteristics of metabolic and repair systems. So, DNA adducts may be considered as a cumulative mirror of heterogeneous response of different individuals to smoking carcinogens, which finally could determine the risk for lung cancer. This review is devoted to analysis of the role of DNA adducts in lung carcinogenesis in order to demonstrate their usefulness as cancer associated markers. Currently, there are some serious limitations impeding the widespread use of DNA adducts as cancer biomarkers, due to failure of standardization of mass spectrometry analysis in order to correctly measure the adduct level in each individual. However, it is known that all DNA adducts are immunogenic, their accumulation over some threshold concentration leads to the appearance of long-living autoantibodies. Thus, detection of an informative pattern of autoantibodies against DNA adducts using innovative multiplex ELISA immunoassay may be a promising approach to find lung cancer at an early stage in high-risk groups (smokers, manufacturing workers, urban dwellers). Key Words: lung cancer, DNA adducts, tobacco smoking. 2015 Article Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives / E.S. Grigoryeva, D.A. Kokova, A.N. Gratchev, E.S. Cherdyntsev, M.A. Buldakov, J.G. Kzhyshkowska, N.V. Cherdyntseva // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 5-12. — Бібліогр.: 74 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145391 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Reviews Reviews Grigoryeva, E.S. Kokova, D.A. Gratchev, A.N. Cherdyntsev, E.S. Buldakov, M.A. Kzhyshkowska, J.G. Cherdyntseva, N.V. Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives Experimental Oncology |
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In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high pathogenetic importance in the lung carcinogenesis and can be identified in biological samples with high accuracy and reliability using highly sensitive mass spectrometry methods (TOF/TOF, TOF/MS, MS/MS). The appearance of DNA adducts in blood or tissues is the result of the interaction of carcinogenic factors, such as tobacco constituents, and the body reaction which is determined by individual characteristics of metabolic and repair systems. So, DNA adducts may be considered as a cumulative mirror of heterogeneous response of different individuals to smoking carcinogens, which finally could determine the risk for lung cancer. This review is devoted to analysis of the role of DNA adducts in lung carcinogenesis in order to demonstrate their usefulness as cancer associated markers. Currently, there are some serious limitations impeding the widespread use of DNA adducts as cancer biomarkers, due to failure of standardization of mass spectrometry analysis in order to correctly measure the adduct level in each individual. However, it is known that all DNA adducts are immunogenic, their accumulation over some threshold concentration leads to the appearance of long-living autoantibodies. Thus, detection of an informative pattern of autoantibodies against DNA adducts using innovative multiplex ELISA immunoassay may be a promising approach to find lung cancer at an early stage in high-risk groups (smokers, manufacturing workers, urban dwellers). Key Words: lung cancer, DNA adducts, tobacco smoking. |
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Article |
| author |
Grigoryeva, E.S. Kokova, D.A. Gratchev, A.N. Cherdyntsev, E.S. Buldakov, M.A. Kzhyshkowska, J.G. Cherdyntseva, N.V. |
| author_facet |
Grigoryeva, E.S. Kokova, D.A. Gratchev, A.N. Cherdyntsev, E.S. Buldakov, M.A. Kzhyshkowska, J.G. Cherdyntseva, N.V. |
| author_sort |
Grigoryeva, E.S. |
| title |
Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives |
| title_short |
Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives |
| title_full |
Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives |
| title_fullStr |
Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives |
| title_full_unstemmed |
Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives |
| title_sort |
smoking-related dna adducts as potential diagnostic markers of lung cancer: new perspectives |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2015 |
| topic_facet |
Reviews |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/145391 |
| citation_txt |
Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives / E.S. Grigoryeva, D.A. Kokova, A.N. Gratchev, E.S. Cherdyntsev, M.A. Buldakov, J.G. Kzhyshkowska, N.V. Cherdyntseva // Experimental Oncology. — 2015. — Т. 37, № 1. — С. 5-12. — Бібліогр.: 74 назв. — англ. |
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Experimental Oncology |
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Experimental Oncology 37, 5–12, 2015 (March) 5
SMOKING-RELATED DNA ADDUCTS AS POTENTIAL DIAGNOSTIC
MARKERS OF LUNG CANCER: NEW PERSPECTIVES
E.S. Grigoryeva1, 2*, D.A. Kokova1, A.N. Gratchev1, E.S. Cherdyntsev3, M.A. Buldakov2,3,
J.G. Kzhyshkowska1,4, N.V. Cherdyntseva1, 2
1National Research Tomsk State University, Tomsk 634050, Russia
2Tomsk Саnсеr Rеsеаrсh Institute, Tomsk 634050, Russia
3National Research Tomsk Polytechnic University, Tomsk 634050, Russia
4Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology,
Medical Faculty Mannheim, University of Heidelberg, Mannheim D-68167, Germany
In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA
of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high patho-
genetic importance in the lung carcinogenesis and can be identified in biological samples with high accuracy and reliability using highly
sensitive mass spectrometry methods (TOF/TOF, TOF/MS, MS/MS). The appearance of DNA adducts in blood or tissues is the result
of the interaction of carcinogenic factors, such as tobacco constituents, and the body reaction which is determined by individual charac-
teristics of metabolic and repair systems. So, DNA adducts may be considered as a cumulative mirror of heterogeneous response of dif-
ferent individuals to smoking carcinogens, which finally could determine the risk for lung cancer. This review is devoted to analysis of the role
of DNA adducts in lung carcinogenesis in order to demonstrate their usefulness as cancer associated markers. Currently, there are some
serious limitations impeding the widespread use of DNA adducts as cancer biomarkers, due to failure of standardization of mass spec-
trometry analysis in order to correctly measure the adduct level in each individual. However, it is known that all DNA adducts are im-
munogenic, their accumulation over some threshold concentration leads to the appearance of long-living autoantibodies. Thus, detection
of an informative pattern of autoantibodies against DNA adducts using innovative multiplex ELISA immunoassay may be a promising
approach to find lung cancer at an early stage in high-risk groups (smokers, manufacturing workers, urban dwellers).
Key Words: lung cancer, DNA adducts, tobacco smoking.
INTRODUCTION
Cancer is one of the leading causes of death in the
world, accounting for over 25% of all deaths in developed
countries. Lung cancer (LC) holds the top position in can-
cer morbidity and mortality among men worldwide. The
both sexes combined, LC incidence rate was 23.1 cas-
es/100 000 in the world and 28.7/100 000 cases in Central
and Eastern European countries. The LC mortality world-
wide was 19.7 cases/100 000 vs 24.1 cases/100 000 in Eu-
rope [1]. At the same time, the mortality during the first
year after diagnosis is very high and is about 67%.
Success of surgical treatment is closely related to the
opportunity for early diagnosis of LC. The importance
of early diagnosis is confirmed by the 5-year survival rate
after radical surgery. People diagnosed with stage I and
II of LC tend to have higher 5-year survival rate (63.5%,
and 43.5%, respectively) than people diagnosed with
stage III (22.9%) [1, 2].
Computed tomography is usually used for diagno-
sis and screening of LC, but this method has several
disadvantages such as a high cost and low availability
as well as a lack of sensitivity and specifi city. Diagnostic
errors occur in 25% of cases resulting in treatment delay
of up to one year. Usage of new diagnostic methods,
i.e. positron emission tomography (PET) and autofluo-
rescence bronchoscopy for the detection of LC has not
reduced the mortality [3] due to the low efficiency of these
methods at early stages of the disease.
The usage of circulating tumor-associated molecular
markers in combination with the methods of instrumental
imaging is one of the most promising trends for impro ving
the effectiveness of early diagnosis of LC [4]. Specific
molecular markers can also be used for diffe rential diag-
nosis of LC and other pathological processes in lung, for
detection of drug resistance formation, to adapt treatment
accordingly depending on what the chemotherapy drug
can be changed [5]. There are several circulating protein
markers which are practically used in diagnostics and
monitoring of LC, namely, CEA (carcino-embrionic anti-
gen), CYFRA-21–1 (CYtokeratin FRAgment), TPA (tissue
plasminogen activator), Pro-GRP (pro-gastrin-releasing
peptide), NSE (neuron-specific enolase). However, cur-
rent serological markers of LC have very low sensitivity.
For example, CEA, NSE, CYFRA-21–1 measurement can
detect non-small cell LC with a sensitivity of 55; 38 and
65% and specificity of 70; 97 and 87%, respectively [6].
In recent years, the new direction such as identification
of informative circulating markers reflecting molecular
genetic changes in the DNA of tumor cells is actively
deve loped. There is a large number of reviews high lighting
the possibility of using circulating tumor DNA for the di-
agnosis and prediction of clinical course of cancer [7–9].
These markers include tumor-specific mutations,
chromosomal aberration, methylated DNA fragments,
Submitted: December 04, 2014.
*Correspondence: E-mail: grigorieva@oncology.tomsk.ru
Abbreviations used: BPDE — benzopyrene-7,8-diol-9,10-epoxide;
LC — lung cancer; PAHs — polycyclic aromatic hydrocarbons;
PET — positron emission tomography.
Exp Oncol 2015
37, 1, 5–12
6 Experimental Oncology 37, 5–12, 2015 (March)
and DNA adducts caused by tobacco smoke carcinogens
as a main etiologic factor of LC.
DNA adducts are very promising research area, since
their chemical structures are considerably diffe rent from
mutated or methylated DNA and can be identified in clini-
cal samples with high accuracy and reliability. Currently,
there are highly sensitive mass spectrometry methods
(TOF/TOF, TOF/MS, MS/MS), to identify and quantify
smoking-related DNA adducts [10]. Continuously up-
dated information about the genotoxic effect of tobacco
smoke components indicates their high pathogenetic
importance in the tumor formation.
This review is devoted to the analysis of the role of DNA
adducts in lung carcinogenesis in order to demonstrate
their usefulness as noninvasive cancer associated mark-
ers. The perspective to use them as cancer markers
is provided by their crucial role in smoking-related lung
carcinoge nesis. The further investigations using mass
spectrometry analysis are needed to identify the most
important DNA adducts reflecting the risk of cancer devel-
opment. DNA adducts are known to be high immunogenic
substances resulting in the autoantibody formation in the
blood. The testing of autoantibodies against reliable DNA
adducts may be considered as a promising way for early
detection of LC, however further studies are required
to demonstrate clinical validity and utility for this approach.
THE ROLE OF TOBACCO SMOKING
IN THE PATHOGENESIS OF LUNG CANCER
Complex composition of tobacco smoke makes
difficult to identify the mechanisms that trigger the pro-
cess of carcinogenesis. Approximately 20 substances
in cigarette smoke have a carcinogenic effect, which are
represented by polycyclic aromatic hydrocarbons (PAHs),
nitrosamines, aldehydes, etc. [11]. All of them are on the
list of carcinogens released by IARC (International Agency
for Research on Cancer) [12]. In this review, we made
an attempt to summarize the mechanisms of carcino-
genic action of tobacco smoke components that can
cause genetic alterations in oncogenes and tumor sup-
pressor genes, as well as to show the possible causes
of the heterogeneity of the negative effects of smoking
in different subjects.
Nicotine, compound which is found in large quantities
in tobacco, has no carcinogenic effect, but it is a highly
addictive substance that leads to a constant consump-
tion and accumulation of other carcinogens of tobacco
smoke in the body. Some of the major components
of tobacco smoke such as PAHs and nitrosamines are
not carcinogens initially they need metabolic activation
to acquire carcinogenic properties. Imbalance between
metabolic activation and detoxification may lead to an in-
creased risk of LC [13]. Normally, the cell with damaged
DNA commits suicide by apoptosis, but if these mutations
occur continuously in the critical region of an oncogene,
this may lead to activation and accumulation of aberrant
cells with a loss of cell cycle regulation, and as a result
to malignant transformation.
Molecular genetic changes in LC inducing by tobacco
smoking are represented by the following events: chro-
mosomal aberrations, point mutations, dysregulation
of oncogenic signal transduction pathways, DNA methyla-
tion, etc. Active or passive exposure to tobacco smoking
equally causes multiple cytogenetic changes, including
different types of DNA and chromosome damage. Point
mutations in oncogenes and tumor suppressor genes are
quite frequently detected in the tumor tissue of LC patients
who are former smo kers. Accor ding to published data,
TP53 mutations are associated with exposure to tobacco
smoke and may cause disruption of its functional activity.
The increased frequency of nucleotide substitution
of thymine to guanine in TP53 gene in LC smokers often
observed in the so-called “hot spots” which are located
at 157, 158, 245, 248 and 273 codons [14–16]. It has been
experimentally proved that the appearance of such nucle-
otide substitution may be caused by the action of tobacco
smoke metabolite benzo[a]pyrene — benzopyrene-7,8-
diol-9,10-epoxi de (BPDE) le ading to formation DNA ad-
ducts in these regions [16, 17].
Methylation of several suppressor genes, namely,
CDKN2A (cyclin-dependent kinase inhibitor 2A),
DAPK1 (death-associated protein kinase 1), RASSF1A
(Ras association domain family 1 isoform), RARb2 (reti-
noic acid receptor B2), APC (adenomatous polyposis
coli), CDH13 (cadherin 13), MGMT (O(6)-methylguanine-
DNA methyltransferase), MLH1 (MutL homolog 1),
MSH2 (MutS protein homolog 2) and GSTP1(glutation-
S-transferase P 1) resulting in their inactivation has been
found in LC [18]. Number of studies demonstrate that
methylation of the CDKN2A gene is much less common
in non-smoking patients with LC, indicating a direct link
with smoking. Also, a lower rate of the APC gene methy-
lation (p < 0.0001) was found in patients who had never
smoked. Methylated forms of these genes are detected
in DNA from sputum, bronchoalveolar lavage fluid and
serum, suggesting the possibi lity of their use for minimally
invasive screening. The possible significance of these
markers as risk factors for LC is shown in examples
of RARB2 and CDKN2A genes, their methylated forms
are detected in bronchial biopsy samples of smokers
without tumor and serum of patients with an increased
risk of LC, and in serum of squamous cell lung carcinoma
patients 3 years before the clinical manifestation [19, 20].
Prognostic role of methyla ted DNA fragments of RASSF1A
and RARb2 suppressor genes in serum patients with
squamous LC was shown in relation to risk of relapse after
combined treatment [21, 22].
The active components of tobacco smoke affect basic
cellular functions, such as cell response to DNA damage,
induction of oxidative stress, apoptosis and inflammatory
reactions. Taking into account the involvement in these
processes a large number of functionally important genes
and signaling pathways necessary is to clarify the initial
changes caused by metabolites of tobacco smoke that
can further lead to tumor formation.
Oxidative stress is a result of an imbalance between
the formation of reactive oxygen species (ROS) and
a biological system’s ability to readily detoxify the reactive
intermediates or to repair the resulting da mage. Oxidative
stress is an important pheno menon in the pathophysio-
Experimental Oncology 37, 5–12, 2015 (March) 7
logy of cancer [23]. Oxidative stress induced by the
tobacco smoke components leads to DNA strand breaks
and oxidative modification of DNA. Tobacco smoke
contains a large number of free radicals which cause
DNA damage and gene rate oxidized base forms such
as 7,8-dihydro-8-oxo-2-deoxyguanosine (8-OH-dG),
which is a classical biomarker of oxidative DNA damage.
Inflammatory response induced by damaging effect
of tobacco smoke creates certain conditions in micro-
environment that enhances carcinogenesis [24]. These
conditions include glutathione oxidation, followed by in-
creasing of glutathione disulfide level in the lung tissue
and bronchoalveolar lavage fluid; increase in 8-OH-DG,
overexpression of mRNA of nitric oxide synthase and
endothelial nitric oxide synthase genes in the lung tissue;
reduction of antioxidants in the blood, such as methy-
lumbelliferone glucuronide and ferroxidase; increa-
sing lipid peroxidation indicators (8-Epi-prostaglandin
F2 alpha); increasing oxygen removing from leukocytes
in bronchoalveolar lavage fluid [25]. All these processes
contribute to the accumulation of genotoxic damage
and the development of chronic inflammatory response
aimed at preserving tissue integration, triggering pro-
cesses of repair and regeneration, similar to wound
healing. In this case, the inflammatory response performs
the tumor-promoting function by production of growth,
anti-apoptotic, pro-angiogenic and matrix remodeling
factors [26].
Recent studies have shown that mutations or aber-
rant expression of miRNAs that are negative post-trans-
criptional regulators of gene expression associated
with various human diseases, including cancer. Various
researches on non-small cell LC samples established
the potential association between the expression of dif-
ferent miRNAs and action components of tobacco smoke.
For example, expression of miR-218 significantly reduced
in the tumors of patients — current or former smokers,
while in tumors of patients who has never smoked such
changes were not detected. Another study showed a sig-
nificant difference in the expression levels of miR-130a
between smo king and nonsmoking patients with LC [27].
In a recent study it was found that the expression level
of miR-143 was lower in smokers than non-smokers
patients, as the authors suggest, miR-143 may play
a significant role in the etiology of LC [28]. In contrast
to the above, microarray study performed by Landi et al.
did not reveal any significant differences in the miRNAs
expression in smokers and non-smoking patients with
LC [29]. Inconsistency of the results can be explained
by a small number of the samples. Probably more de-
tailed study with strict stratification of patients according
to histological type of tumor, smoking status, gender
is required.
Still it has not been reliably established, whether to-
bacco smoke-induced LC characterized by special mo-
lecular signature or all of the molecular changes in LC are
universal. Detection of specific genetic and epigenetic
abnormalities induced by tobacco smoke will allow iden-
tifying the key genes associated with potentially high risk
for LC. This will help to carry out monitoring of patients with
pre-cancerous conditions of the lung for the early detec-
tion of the disease and to plan strategies for prevention.
CAUSES OF HETEROGENEITY
IN THE NEGATIVE EFFECTS OF SMOKING
The role of smoking in LC development was finally
proved only in the 60s of the last century, because it was
unclear why incidence of LC in smokers was extremely
low and amounted to only 10%. The subsequent develop-
ment of molecular biological research methods allowed
comes closer to the cause of such ambiguity. Appar-
ently, genetically determined (or inherited) characteristics
of metabolic system, as well as DNA repair system, make
a significant contribution to the risk of LC. In particular
tobacco smoke carcinogens undergo complex metabolic
conversions, usually via series of chemical reactions.
It is known that people who inherited different polymor-
phic variants of genes encoding enzymes involved in car-
cinogen metabolism characterized by different degrees
of resistance to their action and, accordingly, various risk
of LC development [30–32].
After entering the body PAH molecules induce the ex-
pression of Phase I and Phase II metabolic enzymes [33],
including aldo-keto reductases, cytochrome P450,
catechol-O-methyltransferase, epoxide hydrolases,
peroxidases, glutathione S-transferase (GSTM1), N-
acetyltransferases, sulfotransferases, and other enzymes
which catalyze the conjugation reaction [34]. The most
common mechanism of PAH metabolic activation, for
example, benzo[a]pyrene, is the formation of the dihydro-
diol epoxide — BPDE, which is catalyzed by cytochrome
P450 enzymes and epoxide. The main enzymes which
involved in PAHs metabolism are Cytochromes P450 CYP
1A1, CYP 1A2, CYP 1B1 and CYP 3A4. Induction of these
enzymes is significantly increased in the presence
of benzo[a]pyrene and some polyhalogenated hydro-
carbons. People who have inherited low-activity variants
of cytochrome are relatively resistant to tobacco smoke
carcinogens. In particular, it has been found that some
polymorphic variants of CYP 1A gene associated with
increased formation of DNA adducts and mutagenesis
in some populations [35].
Subsequent phase of PAH metabolism includes
conjugation of phase I metabolites with small mo lecules.
Enzymes catalyzing phase II include sulfotransferase,
UDP (Uridine 5’-diphospho)-glucuronyl transferase and
glutathione-S-transferase. Sulfotransferases (SULT)
involved in the activation of such PAH metabolites
as 7, 12-dimethylbenz(a)anthracene and its methyl-
hydroxylated derivatives in various tissues. It is shown
that polymorphic variants of sulfotransferase SULT1A1 are
associated with different levels of DNA adducts forma-
tion [36]. Conjugation of PAH metabolites with glucuronic
acid (glucuronidation) is also one of the main way of de-
toxification resulting in formation of polar conjugates,
which have higher excretion rate. Oxidized derivatives
of benzo[a]pyrene (for example, 1-hydroxypyridine) are
a substrate for UDP-glucuronosyltransferase. The re-
sulting compound 1-hydroxypyrene glucuronide can
be used as biomarker of PAH exposure [37]. Glutathione-
8 Experimental Oncology 37, 5–12, 2015 (March)
S-transferase is also involved in the conjugation pro-
cesses of PAH derivatives. Study conducted on placental
tissue samples showed that the activity of glutathione-S-
transferase determined by glutathione redox status and
the presence of genotoxic da mage that may be used
as a marker for the damaging effects of PAHs [38].
Polymorphisms in phase II metabolic enzymes genes
are correlated with the amount of DNA da mage and, there-
fore, with a risk of malignization. Thus, Binkova et al. [39]
demonstrated an association between the polymorphic
variants of a glutathione-S-transferase and the amount
of DNA adducts. Individuals who have functionally inacti-
vated glutathione transferase μ gene characterized by in-
creased susceptibility to LC. It is not surprising that the most
dangerous is combination of unfavorable genotypes of CYP
1A1 and GSTM1; individuals with such combination have
2-fold increased risk of LC development [40, 41].
The contribution of the genetic component in the for-
mation of LC risk is not limited to only the genes respon-
sible for the metabolic activation of tobacco smoke
components. A significant role is also played by the indi-
vidual characteristics of the DNA repair system. The most
common mechanisms of cell repair include: nucleotide
excision repair (NER), base excision repair (BER), non-
homologous end joining (NHEJ), homologous recombi-
nation repair (HRR), transcription coupled repair (TCR).
Several studies have shown that polymorphisms of certain
genes of NER increase the efficiency of repair [42].
Four known polymorphism — 4G/A substitution in XPA
(xeroderma pigmentosum, complementation group A)
gene, C8092A in ERCC1 (excision repair cross-comple-
mentation group 1) gene, Lys751Gln in XPD (xeroderma
pigmentosum group D, ERCC2) gene and Ser835Ser
in XPF (xeroderma pigmentosum group F, ERCC4) gene
are associated with reduced DNA repair capacity and
increased incidence of tumors of various types [43].
Recent studies have shown that BER plays a special role
in the repair of damage produced by the action of PAHs.
It was found that the CHO (Chinese hamster ovary) cell
line deficient in BER genes more sensitive to 11,12-dihy-
droxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]
pyrene (DBPDE), resulting in an increase in the frequency
of chromosome aberrations [44]. Polymorphic variants
of BER genes are associated with an increased incidence
of DNA damage. Thus, the product of the XRCC1 (X-ray re-
pair cross-complementing protein 1) gene has 4 functional
polymorphic variants — T77C, Arg194Trp, Arg280His and
Arg399Gln [45], which are associated with altered ability
to repair DNA damage caused by PAH action [46].
Polymorphisms of proteins involved in HRR, is probably
able to protect the effects of PAHs. One of these proteins,
XRCC3, is involved in homologous recombination repair
of double strand breaks and removing of double bonds
(cross-linking) between guanine bases belonging to diffe-
rent chains. According to Shen et al. (2003), polymor-
phism of XRCC3 codon 241 is protective for bladder can-
cer, especially for long-term smokers [47]. Considering
that tobacco smoke contains a large number of PAH, this
fact allows making sure that HRR involved in repair of DNA
lesions induced by exposure to PAHs. Furthermore, it has
been shown in vitro that CHO cell line deficient in HR genes
are more susceptible to the adverse effects of PAHs, which
also confirms the data of the important role of homologous
recombination in DNA repair [44].
DNA ADDUCTS AS MARKERS OF LUNG
CANCER RISK
Polycyclic aromatic hydrocarbons. Initially PAHs
are absolutely inert substances and acquire their biologi-
cal activity only after metabolic activation. Among PAHs,
benzo[a]pyrene is the well-studied compound and its
ability to induce lung tumors when administered topically
and inhaled well described [48].
Benzo[a]pyrene forms at least nine different DNA
adducts which have been characterized and isolated
from body fluids (saliva, urine, blood), lung, liver and
cells of human and animals. Different types of adducts
were determined by mass spectrometry and were
shown specific sites of DNA damage. There are three
metabolic pathways of benzo[a]pyrene activation —
formation of a radical cation, diol epoxide and ortho-
quinone [49]. The third pathway leads to the formation
of reactive metabolite — benzo[a]pyrene-7,8-dione
by oxidation of benzo[a]pyrene-7,8-trans-dihydrodiol
catalyzed by aldo-keto reductases. Thus, it was shown that
H358 cells produce large amount of benzopyrene-7,8-
dione under exposure to benzo[a]pyrene. In subsequent
experiments it was found that 7,8-benzopyrene-dione
DNA-adducts detected in immortalized HBEC-KT cells
and in human lung adenocarcinoma cells A549. Wherein
A549 cells mainly produce adducts of 2’-deoxyguanosine
(dGuo), while HBEC-KT cell lines — 2’-deoxyadenosine
(dAde). Mass spectrometric study allowed to identify
several stable benzo[a]pyrene-7,8-dione adducts: hy-
drated forms of benzo[a]pyrene 7,8-dione-N2-dGuo
and benzo[a]pyrene-7,8-dione-N1-dGuo in A549 cells;
hydrated and unhydrated forms of benzo[a]pyrene-7,8-
dione-N1-dAde and benzo[a]pyrene-7,8-dione-N3-dAde
in HBEC-KT cells.
Another product of benzo[a]pyrene metabolic ac-
tivation is benzopyrene-7,8-diol-9,10-epoxide. All diol
epoxides exist as diasteromers, i.e. stereoisomers that are
not mirror images of each other, and referred to as anti-
BPDE and syn-BPDE, each of which at one time may
be represented by two (+/−) enantiomers. The experiment
conducted by Buening et al. showed that isomer (+) —
anti-BPDE has the greatest tumorigenicity in vivo [50].
It is known that indicated isomer interacts with N2-atom
of deoxyguanosine forming (+)-trans, (+)-cis-BPDE-N2-
dG, and (−)-trans and (−)-cis-BPDE-N2-dG adducts.
Of these four adducts (+)-cis-BPDE- N2-dG is the most
common and its presence is registered in 45% of smokers.
Presence of BPDE-DNA adducts in human tissues has
been reliably established [51] and shown to be the highest
concentration in the bronchial epithelium, indicating a di-
rect role in the initiation of LC [52].
Aromatic amines. Aromatic amines contained
in the tobacco smoke can also be sources for DNA adduct
formation. The most studied aromatic amine in tobacco
smoke is a 4-aminobiphenyl (4-ABP) [53]. A recent study
Experimental Oncology 37, 5–12, 2015 (March) 9
authored by Lee et al. found that 4-ABP-adducts are
formed mainly in the mutational hot spots of TP53 gene
(codons 280 and 285) in a human bladder cancer cell
line [53]. These results confirm pathogenic role of 4-ABP-
adducts in the development of bladder cancer. Using
of sensitive immunobiological and mass spectrometric
methods allows detecting the presence of DNA and pro-
tein 4-ABP-adducts in various human tissues resulting
from exposure to tobacco smoke.
It is interesting that in intact breast tissue adjacent
to the tumor, level of 4-ABP-adducts correlated with smo-
king status. In biopsies obtained from patients with bladder
cancer quantity of DNA adducts were also associated with
smoking and the tumor size. However, the results ob-
tained in studies of different groups of patients are rather
contradictory. Thus, using of HPLC (high-performance
liquid chromatography) method, followed by tandem
mass spectrometry does not allowed the identification
of 4-ABP-adducts in biopsies of 70 breast cancer patients.
Perhaps this may be due to incorrect grouping of patients,
as a systema tic survey and detection of patient’s smoking
status has not been established. The few studies of aro-
matic amines DNA adducts in the tissues of smokers and
non-smokers LC patients are also characteri zed as a highly
controversial [54].
Aldehydes. Acrolein (2-propenal) — highly reactive
unsaturated aldehyde contained in thermally processed
foods and in the environment, as the pro duct of incom-
plete combustion of gasoline, plastic and wood. Tobacco
smoke contains approximately 180 mg of acrolein per
cigarette, which is 1000 times greater than the PAHs
content. In this case, unlike PAHs, acrolein is initially ac-
tive component capable of providing a damaging effect.
Acrolein has a mutagenic effect toward bacterial and
mammalian cells. Acrolein binds deoxyguanosine forming
one of two stereoisomers, 1,N2-propanodeoxyguanosine
(Acr-dGuo) — α-OH-Acr-dGuo and γ-OH-Acr-dGuo.
Highest mutagenic effect has α-isomer which induce
G>T substitutions in CpG-islands, mainly, in TP53 codons
249 and 273 [55].
One of the first studies authored by Nath et al. (1998)
demonstrated a significant increase of Acr-dGuo adducts
in epithelial cells of the oral mucosa in smokers [56].
Based on the similarity of the mechanisms of acrolein and
PAHs action, many authors have suggested that indicated
major component of tobacco smoke may be responsible
for the TP53 gene mutations in lung cancer associated
with smoking. To detect the presence of acrolein ad-
ducts in the lung tissue and to evaluate their contribu-
tion in the pathogenesis of LC, Zhang et al. developed
a methodo logical approach based on liquid chromatogra-
phy and tandem mass spectrometry to quantify Acr-dGuo
in biological samples [57]. They analyzed 30 samples
of normal lung tissue and detected the presence of both
stereoisomers in all samples irrespective of smoking status.
In the next study, the presence of Acr-dGuo adducts was
evaluated in peripheral blood lymphocytes of 25 smokers
and 25 non-smokers. Predominant presence γ-isomer
was detected in all samples except three patients.
However, significant differences between smokers and
non-smo kers were not found. Paradoxically, the average
content of γ-OH-Acr-dGuo was statistically higher in non-
smokers. Based on these results, the authors conclude
that acrolein probably undergoes detoxification with a very
high efficiency by conjugation with glutathione. Obviously,
the most damaging effect of acrolein adducts, promoting
malignant transformation of epithelial cells of the lung,
is the inhibition of NER, which is responsible for the removal
of DNA damage caused by the action of PAHs [55].
Acetaldehyde is the one of the most common carcino-
gens in tobacco smoke, may also be present in foods and
in products of combustion. A certain amount of acetal-
dehyde is formed endogenously in threonine catabolism
and metabolism of ethanol. Acetaldehyde binds DNA
forming N2-ethylidene-dGuo. After enzymatic hydrolysis
of DNA in the pre sence of NaBH3CN indicated metabo-
lite forms N2-ethyl-dGuo, which can be detect by mass
spectrometry [58]. Theoretically, N2-ethylidene-dGuo
may undergo a subsequent transformation forming 1,N2-
propanodeoxyguanosine (the same adduct formation
occurs under the exposure of acrolein). The proof of this
hypothesis serves an experiment in vivo conducted
by Wang et al. (2006) [58]. 1,N2-propanodeoxyguanosine
can be detected in the cells after exposure to micromolar
concentrations of acetaldehyde. Probably acetaldehyde
adducts play a role in the carcinogenic effect of tobacco
smoke, but the contribution of this component to the over-
all genotoxicity should be clarified in further studies.
The evidence exists that, among other components
there are some ethylating agents in a tobacco smoke
whose structure has not yet been established [59]. When
studying normal lung epithelium obtained from patients
with LC, O4-etiltimidin was detected in 10 of 13 smokers
and only 3 out of 11 non-smoking subjects. Another study
on a small group of patients de monstrated the presence
of the O4-ethyltimidine in sputum from two of four smokers
and was not detected in either of the samples obtained
from nonsmokers [60].
Nitrosamines. Significant contribution to the study
of nitrosamines metabolism contained in tobacco smoke
was made by Hecht and co-authors [61]. For metabolite
identification the authors used the HPLC-electrospray
ionization-MS-MS analysis in vitro and in vivo studies.
It was found that these chemicals act as bidentate (ligand
that binds through two sites) carcinogens. Contained
in cigarette smoke nitrosamine 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK) undergoes metabolic
activation, forming 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol (NNAL). The further reaction consists of con-
version of intermediate metabolite to methanediazo-
hydroxid, which in its turn interacts with DNA and forms
O6-methyl-dGuo, 7-methyl-dGuo and O6-methyl-dThd.
O6-methyl-dGuo has the highest mutagenic effect [62].
In addition to the well-studied pathway of activation,
leading to the formation of a methylating agent, there
is another mechanism which results in the formation
of pyridyloxobutyla ting agent. Another nitrosamine —
N-nitrosonornicotine (NNN) also produces two types
of reactive agents. Both compounds have a pronounced
carcinogenic effect in animal models, forming tumors with
10 Experimental Oncology 37, 5–12, 2015 (March)
similar localization to smokers with LC [63]. Pathway which
associated with pyridyloxobutylation leads to the formation
of a large number of adducts: 7-[4-(3-pyridyl)-4-oxobut-
1-yl]-2´-deoxyguanosine (7-pobdG), O2-[4-(3-pyridyl)-
4-oxobut-1-yl]-2´-deoxycytosine(O2-pobdC), O2-[4-(3-
pyridyl)-4-oxobut-1-yl]-2´-deoxythymidine(O2-pobdT),
O6-[4-(3-Pyridyl)-4-Oxobut-1-yl]-2´-Dexoyguanosine
(O6-pobdG). Two of these adducts — 7-pobdG and O2-
pobdC release appropriate nitrogenous base, forming
7-[4-(3-pyridyl)-4-oxobut-1-yl]-guanine ( 7-pobG)
and O2-[4-(3-pyridyl)-4-oxobut-1-yl]-cytosine (O2-
pobC). The presence of all these adducts was detected
in the tissues of rodents after admini stration of NNN
and NNK. Moreover, the maximum concentration was
detected in lung, liver and then, in mucosa of the nasal
cavity and pancreas. If one considers the ratio of different
adducts their distribution in the lung tissue, was as follows:
O2-pobdT≥7-pobG>O2-pobC>> O6-pobdG.
Interestingly, the study of the content of these adducts
in tissues of patients with LC have not been conducted.
These data could clarify the role of nitrosamines in the
pathogenesis of LC associated with smoking. Study of Bes-
sette et al. [64] demonstrated that N-(deoxyguanosine-
8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]
pyridine was detected in saliva samples of 13 out
of 29 smokers and only in 2 out of 8 samples of non-
smokers, while а N-(deoxyguanosin-8-yl)-2-amino-9H-
pyrido[2,3-b]indole and N-(deoxyguanosin-8-yl)-
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline were
detected in saliva samples only in three smokers and
N-(deoxyguanosin-8-yl)-4–4-aminobiphenyl was de-
tected in saliva of two smokers. The levels of these various
adducts ranged from 1 to 9 adducts per 108 base pairs.
Formaldehyde. Recent mass-spectrometric stu-
dies comparing the level of formaldehyde DNA adduct
in smokers and non-smokers showed that the level
of N6-hydroxymethyldeoxyadenosine (N6-HOMe-dAdo)
in smokers was higher than in non-smokers [65], that
may indicate a role of formaldehyde in the pathogenesis
of LC induced by smoking.
Formaldehyde is also a component of tobacco
smoke, which is classified as carcinogenic and genotoxic
agent, forming DNA adducts. Meta-analysis conducted
by US researchers of more than 25 thousand manufactu-
ring workers who are exposed to formal dehyde, showed
a significant increase in the risk of leukemia. In the study
held by Wang et al. quantity of N6-HOME-dAdo was
measured using mass spectrometry in leukocyte DNA
from 32 smo kers and 30 non-smokers [65]. The presence
of this adduct was detected in 21 out of 29 smokers (179 ±
205 fmol/μmol dAdo) and only in 7 out of 30 non-smokers
(15.5 ± 33.8 fmol/μmol dAdo). However, the study
of Lu et al. [66] showed that formaldehyde metabolites
form DNA adducts, preferably binding to deoxyguano-
sine and forms unstable N2-hydroxymethyl-dGuo, which
is converted in N2 -methyl-dGuo in the presence of so-
dium cyanoborohydride. At the same time, the presence
of formaldehyde adducts detected mainly in the mucosa
of the nasal cavity, lung tissue, but not in distant organs
such as liver, spleen, bone marrow.
Estimation of the contribution of formaldehyde adducts
inhaled with tobacco smoke, complicated by the fact that
all cells of the organism contain endogenous formalde-
hyde and, accordingly, its adducts. Therefore, while stu-
dying the biological effects of exo genous formaldehyde
it is necessary to carry out its radioactive labeling.
CONCLUSION
Analysis of recent data has demonstrated that DNA-
adducts may be potential markers of LC risk. The appear-
ance of DNA adducts in blood or tissues is the result of the
interaction of carcinogenic factors, such as tobacco constitu-
ents, and the body reaction which is determined by individual
characteristics of me tabolic and repair systems. An important
fact is that initially most carcinogens of tobacco smoke are
inert substances and acquire their genotoxic activity only
after metabolic activation. Thus, the ultimate carcinogenic
effect of tobacco constituents (initiation of malignancy)
manifests as a result of their genotoxic action which can
be considerably modified by the functioning of the repair
systems. So, DNA adducts may be consi dered as a cu-
mulative mirror of heterogeneous response of different
individuals to smoking carcinogens, which finally could
provide the risk for LC.
At the current moment, there are some difficulties
impeding the widespread use of DNA adducts as cancer
biomarkers. Firstly, there are no analytical standards
of substance for quantitative determination of DNA ad-
ducts, except for the most common 8-oxo-dG. For the rest
of the substances it is necessary to develop commercially
available standards, including deuterated forms. Third,
in order to detect the increased level of DNA-adducts,
it is required to establish background values, because
some adducts may be formed endogenous. The level
of background DNA damage formed as a result of some
endogenous processes may reach 1 to 105 according
to some reports [67]. Furthermore, the same DNA-ad-
ducts can be formed by several pathways, so 8-oxo-dG,
may be produced by exposure to benzo[a]pyrene, as well
as to carbon tetrachloride [68, 69]. In our opinion, further
studies are needed to establish the laws of the content
of individual adducts in tissues and biological fluids of pa-
tients, as well as their concentration.
Using of common research method of mass spectro-
metry as a routine method in clinical laboratory is economi-
cally unjustified. Therefore, for the realization of the early
detection of LC it is necessary to develop an appropriate
method. It is known that all DNA adducts are immuno-
genic, their accumulation to some threshold concentration
leads to the appe arance of long-living autoantibodies [70,
71]. Over the past year, incre asing attention has focused
on the possibility to detect autoantibodies against DNA
adducts, in particular adducts of benzo[a]pyrene [72–74].
Thus, identification of autoantibodies to DNA adducts may
be a promising approach for early diagnosis of LC in high-
risk groups (smo kers, manufacturing workers, urban
dwellers). The use of high effective multiplex ELISA im-
munoassay will allow the numerous autoantibodies against
different DNA adducts to be detected in order to increase
the method sensitivity.
Experimental Oncology 37, 5–12, 2015 (March) 11
ACKNOWLEDGEMENT
This Research was supported by Federal Targeted
Programme for Research and Development in Prio rity
Areas of Development of the Russian Scientific and
Technological Complex for 2014–2020, “Development
of molecular signatures for early detection of lung cancer”
(№ 14.575.21.0064 from 05.08.2014).
REFERENCES
1. GLOBOCAN 2012: Estimated Cancer Incidence, Morta-
lity and Prevalence Worldwide in 2012. International Agency for
Research on Cancer (IARC) (http://globocan.iarc.fr).
2. Chissov VI, Starinsky VV. The course of implementation
of measures to improve oncological care to the population of Russia.
Ros Onkol Zhurnal 2011; 4: 4–8 (in Russian).
3. Mutti A. Molecular diagnosis of lung cancer: an overview
of recent development. Acta Biomed 2008; 79: 11–23.
4. Evangelista L, Cervino AR, Ghiotto C, et al. Tumor marker-
guided PET in breast cancer patients: a recipe for a perfect wed-
ding: a systematic literature review and meta-analysis. Clin Nucl
Med 2012; 37: 467–74.
5. Mirabelli P, Incoronato M. Usefulness of traditional serum
biomarkers for management of breast cancer patients. BioMed
Research Int 2013; Article ID 685641: 9.
6. Molina R, Auge JM, Filella X, et al. Pro-gastrin-rele asing
peptide (ProGRP) in patients with benign and malignant disea-
ses: comparison with CEA, SCC, CYFRA 21-1 and NSE in pa-
tients with lung cancer. Anticancer Res 2005; 25: 1773–8.
7. Rykova EY, Morozkin ES, Ponomaryova AA, et al. Cell-free
and cell-bound circulating nucleic acid complexes: mechanisms
of generation, concentration and content. Expert Opin Biol Ther
2012; 12: S141–53.
8. Ignatiadis M, Dawson SJ. Circulating tumor cells and
circulating tumor DNA for precision medicine: dream or reali ty?
Ann Oncol 2014; 25: 2304–13.
9. Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA
as a liquid biopsy for cancer. Clin Chem 2015; 61: 112–23.
doi: 10.1373/clinchem.2014.222679.
10. Garaguso I, Halter R, Krzeminski J, et al. Method for
the rapid detection and molecular characterization of DNA al-
kylating agents by MALDI-TOF mass spectrometry. Anal Chem
2010; 82: 8573–82.
11. Hoffmann D, Hecht SS. Advances in tobacco carcinogene-
sis. In: CS Cooper, PL Grover, eds. Handbook of experimental phar-
macology. Heidelberg (Germany): Springer-Verlag, 1990: 63–102.
12. IARC Monographs on evaluation of the carcinogenic risk
of chemicals to humans: tobacco smoke and involuntary smoking.
Lyon, 2002; 83: 1452.
13. Hecht SS. Tobacco smoke carcinogens and lung cancer.
J Natl Cancer Inst 1991; 91: 1194–210.
14. Pfeifer GP, Hainaut P. On the origin of G –> T transver-
sions in lung cancer. Mutat Res 2003; 526: 39–43.
15. Le Calvez F, Mukeria A, Hunt JD, et al. TP53 and KRAS
mutation load and types in lung cancers in relation to tobacco
smoke: distinct patterns in never, former, and current smokers.
Cancer Res 2005; 65: 5076–83.
16. Hainaut P, Pfeifer GP. Patterns of p53 G–>T transversions
in lung cancers reflect the primary mutagenic signature of DNA-
damage by tobacco smoke. Carcinogenesis 2001; 22: 367–74.
17. Hussain SP, Amstad P, Raja K, et al. Mutability
of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and
the frequency of p53 mutations in nontumorous human. Cancer
Res 2001; 61: 6350–5.
18. Bowman RV, Yang IA, Semmler AB, et al. Epigenetics
of lung. Respirology 2006; 11: 355–65.
19. Belinsky SA, Grimes MJ, Casas E, et al. Predicting gene
promoter methylation in non-small cell lung cancer by evalu ating
sputum and serum. Brit J Cancer 2007; 96: 1278–83.
20. Palmisano WA, Crume KP, Grimes MJ, et al. Aberrant
promoter methylation of the transcription factor genes PAX5 alpha
and beta in human cancers. Cancer Res 2003; 63: 4620–5.
21. Ponomaryova AA, Rykova EY, Cherdyntseva NV, et al.
RARβ2 gene methylation level in the circulating DNA from blood
of patients with lung cancer. Eur J Cancer Prev 2011; 20: 453–5.
22. Ponomaryova AA, Rykova EYu, Cherdyntseva NV, et al.
Molecular genetic markers in diagnostic of lung cancer. Mol Biol
2011; 45: 175–89 (in Russian).
23. Valko M, Leibfritz D, Moncol J, et al. Free radicals and
antioxidants in normal physiological functions and human disease.
Int J Biochem Cell Biol 2007; 39: 44–84.
24. Chekhun VF. Inflammation and cancer. Onkologiya 2009;
11: 244–5 (in Russian).
25. van der Vaart H, Postma DS, Timens W, et al. Acute effects
of cigarette smoke on inflammation and oxidative stress: a review.
Thorax 2004; 59: 713–21.
26. Hanahan D, Weinberg RA. Hallmarks of cancer: the next
generation. Cell 2011; 144: 646–74.
27. Wang XC, Tian LL, Wu HL, et al. Expression of miRNA-
130a in nonsmall cell lung cancer. Am J Med Sci 2010; 340: 385–8.
28. Gao W, Yu Y, Cao H, et al. Deregulated expression
of miR-21, miR-143 and miR-181a in non small cell lung cancer
is related to clinicopathologic characteristics or patient prognosis.
Biomed Pharmacother 2010; 64: 399–408.
29. Landi MT, Zhao Y, Rotunno M, et al. MicroRNA ex-
pression differentiates histology and predicts survival of lung. Clin
Cancer Res 2010; 16: 430–41.
30. Imyanitov E.N. Molecular pathology of lung cancer. Pract
Oncol 2006; 7: 131–7 (in Russian).
31. Tunali NE, Tiryakioğlu NO. Polymorphisms in the xeno-
biotic genes and susceptibility to bladder cancer. J Cell Mol Biol
2011; 9: 5–13.
32. Reszka E, Wasowicz W, Gromadzinska J. Genetic poly-
morphism of xenobiotic metabolising enzymes, diet and cancer
susceptibility. Br J Nutr 2006; 96: 609–19.
33. Shimada T. Xenobiotic-metabolizing enzymes involved
in activation and detoxification of carcinogenic polycyclic aromatic
hydrocarbons. Drug Metabol Pharmacokin 2006; 21: 257–76.
34. Williams JA, Phillips DH. Mammary expression of xenobi-
otic metabolizing enzymes and their potential role in breast cancer.
Cancer Res 2000; 60: 4667–77.
35. Rojas M, Cascorbi I, Alexandrov K, et al. Modulation
of benzo[a]pyrene diolepoxide-DNA adduct levels in human white
blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism.
Carcinogenesis 2000; 21: 35–41.
36. Tang D, Rundle A, Mooney L, et al. Sulfotransferase
1A1 (SULT1A1) polymorphism, PAH-DNA adduct levels in breast
tissue and breast cancer risk in a case-control study. Breast Cancer
Res Treatment 2003; 78: 217–22.
37. Strickland PT, Kang D, Bowman ED, et al. Identification
of 1-hydroxypyrene glucuronide as a major pyrene metabolite in hu-
man urine by synchronous fluorescence spectroscopy and gas chro-
matography-mass spectrometry. Carcinogenesis 1994; 15: 483–7.
38. Obolenskaya MY, Teplyuk NM, Divi, RL, et al. Human
placental glutathione S-transferase activity and polycyclic aromatic
hydrocarbon DNA adducts as biomarkers for environmental oxida-
tive stress in placentas from pregnant women living in radioactivity-
and chemically-polluted regions. Toxicol Letters 2010; 196: 80–6.
39. Binkova B, Chvatalova I, Lnenickova Z, et al. PAH-DNA
adducts in environmentally exposed population in relation to meta-
bolic and DNA repair gene polymorphisms. Mutat Res/Fund Mol
Mech Mutagen 2007; 620: 49–61.
12 Experimental Oncology 37, 5–12, 2015 (March)
40. Hung RJ, Boffetta P, Brockmoller J, et al. CYP1A1 and
GSTM genetic polymorphisms and lung cancer risk in Caucasian
nonsmokers: a pooled analysis. Carcinogenesis 2003; 24: 875–82.
41. Imyanitov EN, Togo AV, Hanson KP. Searching for cancer-
associated gene polymorphisms: promises and obstacles. Cancer
Lett 2004; 204: 3–14.
42. Shen J, Desai M, Agrawal M, et al. Polymorphisms in nu-
cleotide excision repair genes and DNA repair capa city phenotype
in sisters discordant for breast cancer. Cancer Epidemiol Biomark
Prev 2006; 15: 1614–9.
43. Monzo M, Moreno I, Navarro A, et al. Single nucleotide
polymorphisms in nucleotide excision repair genes XPA, XPD,
XPG and ERCC1 in advanced colorectal cancer patients treated
with first-line oxaliplatin/fluoropyrimidine. Oncology 2007;
72: 364–70.
44. Meschini R, Berni A, Marotta E, et al. DNA repair mecha-
nisms involved in the removal of DBPDE induced lesions leading
to chromosomal alterations in CHO cells. Cytogen Genome Res
2010; 128: 124–30.
45. Cherdyntseva NV, Sevostjanova NV, Urazova LN, et al.
Genetic and epigenetic risk factors for lung cancer. Mol Med 2005;
3: 49–55 (in Russian).
46. Ji G, Gu A, Zhou Y, et al. Interactions between exposure
to environmental polycyclic aromatic hydrocarbons and DNA
repair gene polymorphisms on bulky DNA adducts in human
sperm. PLoS ONE 2010; 5: e13145.
47. Shen M, Hung RJ, Brennan P, et al. Polymorphisms
of the DNA repair genes XRCC1, XRCC3, XPD, interaction with
environmental exposures, and bladder cancer risk in a case-control
study in northern Italy. Cancer Epidemiol Biomark Prev 2003;
12: 1234–40.
48. Wolterbeek AP, Schoevers EJ, Rutten AA, et al. A critical
appraisal of intratracheal instillation of benzo[a]pyrene to Syrian
golden hamsters as a model in respiratory tract carcinogenesis.
Cancer Lett 1995; 89: 107–16.
49. Huang M, Blair IA, Penning TM. Identification of stable
benzo[a]pyrene-7,8-dione-DNA adducts in human lung cells.
Chem Res Toxicol 2013; 26: 685–92.
50. Buening MK, Wislocki PG, Levin H, et al. Tumorigenicity
of the optical enantiomers of the diastereomeric benzo[a]pyrene
7,8-diol-9,10-epoxides in newborn mice: exceptional activity of
(+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9, 10-tetrahydrobenzo[a]
pyrene. Proc Nat Acad Sci USA 1978; 75: 5358–61.
51. Boysen G, Hecht SS. Analysis of DNA and protein ad-
ducts of benzo[a]pyrene in human tissues using structure-specific
methods. Mut Res/Rev Mut Res 2003; 543: 17–30.
52. Rojas M, Marie B, Vignaud JM, et al. High DNA damage
by benzo[a]pyrene 7,8-diol-9,10-epoxide in bronchial epithelial
cells from patients with lung cancer: comparison with lung paren-
chyma. Cancer Lett 2004; 207: 157–63.
53. Lee HW, Wang HT, Weng MW, et al. Acrolein- and
4-Aminobiphenyl-DNA adducts in human bladder mucosa and
tumor tissue and their mutagenicity in human urothelial cells.
Oncotarget 2014; 5: 3526–40.
54. Arif JM, Dresler C, Clapper ML, et al. Lung DNA adducts
detected in human smokers are unrelated to typical polyaromatic
carcinogens. Chem Res Toxicol 2006; 19: 295–9.
55. Feng Z, Hu W, Hu Y, et al. Acrolein is a major cigarette-
related lung cancer agent: Preferential binding at p53 mutational
hotspots and inhibition of DNA repair. Proc Natl Acad Sci USA
2006; 103: 15404–9.
56. Nath RG, Ocando JE, Guttenplan JB, et al. 1,N2-
propano deoxyguanosine adducts: potential new biomarkers
of smoking-inducedDNA damage in human oral tissue. Cancer
Res 1998; 58: 581–4.
57. Zhang S, Villalta PW, Wang M, et al. Detection and quan-
titation of acrolein-derived 1,N2-propanodeoxyguanosine adducts
in human lung by liquid chromatography-electrospray ionization-
tandem mass. Chem Res Toxicol 2007; 20: 565–71.
58. Wang M, Yu N, Chen L, et al. Identification
of an acetaldehyde adduct in human liver DNA and quantitation
as N2-ethyldeoxyguanosine. Chem Res Toxicol 2006; 19: 319–24.
59. Singh R, Kaur B, Farmer PB. Detection of DNA damage
derived from a direct acting ethylating agent present in cigarette
smoke by use of liquid chromatography-tandem mass spectrometry.
Chem Res Toxicol 2005; 18: 249–56.
60. Godschalk R, Nair J, Kliem HC, et al. Modified immunoen-
riched (32)P-HPLC assay for the detection of O(4)-ethylthymidine
in human biomonitoring studies. Chem Res Toxicol 2002; 15: 433–7.
61. Hecht SS, Yuan JM, Hatsukami D. Applying tobacco car-
cinogen and toxicant biomarkers in product regulation and cancer
prevention. Chem Res Toxicol 2010; 23: 1001–8.
62. Phillips DH, Venitt S. DNA and protein adducts in human
tissues resulting from exposure to tobacco smoke. Int J Cancer
2012; 131: 2733–53.
63. Hecht SS. Biochemistry, biology, and carcinogenicity
of tobacco-specific N-nitrosamines. Chem Res Toxicol 1998;
11: 559–603.
64. Bessette EE, Spivack SD, Goodenough AK. Identification
of carcinogen DNA adducts in human saliva by linear quadrupole
ion trap/multistage tandem mass spectrometry. Chem Res Toxicol
2010; 23: 1234–44.
65. Wang M, Cheng G, Balbo S, et al. Clear diffe rences in lev-
els of a formaldehyde-DNA adduct in leukocytes of smokers and
nonsmokers. Cancer Res 2009; 69: 7170.
66. Lu K, Collins LB, Ru H, et al. Distribution of DNA ad-
ducts caused by inhaled formaldehyde is consistent with induction
of nasal carcinoma but not leukemia. Toxicol Sci 2010; 116: 441–51.
67. Gupta RC, Lutz WK. Background DNA damage for
endogenous and unavoidable exogenous carcinogens: a basis for
spontaneous cancer incidence? Mutat Res 1999; 424: 1–8.
68. Marie-Desvergne C, Maitre A, Bouchard M, et al.
Evaluation of DNA adducts, DNA and RNA oxidative lesions, and
3-hydroxybenzo(a)pyrene as biomarkers of DNA damage in lung
following intravenous injection of the parent compound in rats.
Chem Res Toxicol 2010; 23: 1207–14.
69. Tarantini A, Maitre A, Lefebvre E, et al. Relative contribu-
tion of DNA strand breaks and DNA adducts to the genotoxicity
of benzo[a]pyrene as a pure compound and in complex mixtures.
Mutat Res 2009; 671: 67–75.
70. Singh R, Teichert F, Verschoyle RD, et al. Simultane-
ous determination of 8-oxo-2’-deoxyguanosine and 8-oxo-2’-
deoxyadenosine in DNA using online column-switching liquid
chromatography/tandem mass spectrometry. Rapid Commun
Mass Spectrom 2009; 23: 151–60.
71. Petruzzelli S, Celi A, Pulerà N, et al. Serum antibodies
to benzo(a)pyrene diol epoxide-DNA adducts in the general
population: effects of air pollution, tobacco smoking, and family
history of lung diseases. Cancer Res 1998; 58: 4122–6.
72. Pulerà N, Petruzzelli S, Celi A, et al. Presence and per-
sistence of serum anti-benzo[a]pyrene diolepoxide-DNA adduct
antibodies in smokers: effects of smoking reduction and cessation.
Int J Cancer 1997; 70: 145–9.
73. Ustinov VA, Matveeva VA, Kostyanko MA, et al. Antibod-
ies against benzo[a]pyrene in immunized mouse and in lung cancer
patients. Exp Oncol 2013; 35: 207–10.
74. Borska L, Andrys C, Krejsek J, et al. Serum level of an-
tibody against benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA ad-
ducts in people dermally exposed to PAHs. J Immunol Res 2014;
2014: 834389. doi: 10.1155/2014/834389.
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