>Prove, factually, that smoking causes cancer. It's still not a fact. I
>think it does, don't get me wrong. Just playing devils advocate.
>
>Timothy Heald
>Information Systems Specialist
>Overseas Security Advisory Council
>U.S. Department of State
>571.345.2235
From:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12619108&dopt=Abstract
1: Hum Mutat. 2003 Mar;21(3):229-39. Related Articles, Links
The TP53 gene, tobacco exposure, and lung cancer.
Toyooka S, Tsuda T, Gazdar AF.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern
Medical Center, Dallas, Texas 75390-8593, USA.
Of the various genetic alterations in lung cancer, the abnormalities of the TP53
gene (p53) are among the most frequent and important events. Because of its
importance, many aspects of TP53 have been studied, including preneoplastic lesions
and TP53as a marker for early detection and prognosis and as a therapeutic option. We
summarize recent knowledge of TP53 in lung cancer with a special emphasis on the
relationship between smoking exposure (e.g, cigarette, etc.) and specific mutational
pattern of TP53by analyzing the latest version of the International Agency for
Research on Cancer (IARC) database on TP53 mutations in human cancer. Our analysis
confirmed several other studies showing significant differences in the frequencies of
G:C to T:A transversions between ever-smokers and never-smokers. Furthermore, when
comparing the mutational spectrum by gender, important differences were noted between
male and female never-smokers. We concluded that the previously noted G:C to T:A
transversions were mainly due to female smokers having a high frequency of these
changes compared to female never-smokers. There was no relationship between
adenocarcinomas and squamous cell carcinomas independent of gender. We also examined
the seven codons which have been previously identified as hot spots, that is, the
sites of frequent G:C to T:A transversions in smoking-related lung cancers. However,
there was no specific codon which was strongly related to smoke exposure despite a
moderate relationship. We considered the term "warmspot" may be more appropriate.
While mutations of TP53 are frequent in lung cancers, further investigation is
necessary to understand their role for lung carcinogenesis, especially as they relate
to gender differences, and to translate our laboratory knowledge to clinical
applications. Copyright 2003 Wiley-Liss, Inc.
Publication Types:
* Review
* Review, Tutorial
PMID: 12619108 [PubMed - indexed for MEDLINE]
There are several thousand other studies, most of which show some form of link in
terms of mutations, cigarette smoking and lung cancer.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12640684&dopt=Abstract
Int J Cancer. 2003 May 10;104(6):758-63. Related Articles, Links
Association between self-reported environmental tobacco smoke exposure and lung
cancer: modification by GSTP1 polymorphism.
Miller DP, De Vivo I, Neuberg D, Wain JC, Lynch TJ, Su L, Christiani DC.
Department of Environmental Heath, Occupational Health Program, Harvard School of
Public Health, Boston, MA 02115, USA.
Environmental Tobacco Smoke (ETS) exposure has been associated with lung cancer
risk. ETS is composed of emissions from cigarette smoke and contains a higher
concentration of tobacco smoke carcinogens than mainstream smoke. Polymorphisms in
genes that metabolize tobacco smoke carcinogens have been studied as effect modifiers
of the association between active smoking and lung cancer risk. GSTP1 is a polymorphic
gene that encodes for GST pi, a detoxification enzyme and has a high expression in the
lung. We investigated the association between ETS and lung cancer risk and the
modification of this association by the GSTP1 polymorphism. Using a case-control
design, individuals were genotyped for GSTP1 using PCR-RFLP techniques. All analyses
were carried out using multiple logistic regression. The association between ETS
exposure and lung cancer risk was evaluated in different strata based on smoking
habits to evaluate the consistency of results. The effect of the GSTP1 polymorphisms
on lung cancer risk was evaluated by considering the joint effect of having both an
ETS exposure and the GSTP1 GG genotype compared to the absence of ETS exposure and the
GSTP1 AA genotype as a reference group as well as doing stratified analysis by
genotype. ETS exposure was associated consistently with higher lung cancer risk in all
the strata considered. The adjusted odds ratios (AOR) evaluating the association
between ETS and lung cancer risk for the different strata were: nonsmokers
(Cases/Controls 66/413; AOR = 1.38; 95% CI = 0.78-2.43), ex-smokers (Cases/Controls
560/527; AOR = 1.66; 95% CI = 1.22-2.25), current smokers (Cases/Controls 415/219; AOR
= 1.56; 95% CI = 1.00-2.41). The AORs for ex-smokers and light smoking subgroups were:
ex-smokers who quit for 19 years or more (Cases/Controls 144/244; AOR = 2.64; 95% CI =
1.55-4.50), ex-smokers who quit for 10-19 years (Cases/Controls 141/128; AOR = 1.16;
95% CI = 0.66-2.04), ex-smokers who quit for 10 years or less (Cases/Controls 247/122;
AOR = 1.45; 95% CI = 0.83-2.55) and participants who had <15 packyears and nonsmokers
combined (Cases/Controls 143/640; AOR = 1.52; 95% CI = 1.02-2.28). Among those with
the GSTP1 GG genotype the ETS-lung cancer risk association was greater than those with
the GSTP1 AA genotype: nonsmokers (GSTP1 GG AOR = 7.84; 95% CI = 0.80-76.68; GSTP1 AA
AOR = 1.15; 95% CI = 0.46-2.90), ex-smokers (GSTP1 GG AOR = 2.32; 95% CI = 0.90-5.96;
GSTP1 AA AOR = 2.15; 95% CI = 1.34-3.44), current smokers (GSTP1 GG AOR = 1.75; 95% CI
= 0.42-7.32; GSTP1 AA AOR = 1.32; 95% CI = 0.67-2.58) and participants who had <15
packyears and nonsmokers (GSTP1 GG AOR = 1.93; 95% CI = 0.54-6.97; GSTP1 AA AOR =
1.58; 95% CI = 0.83-3.01). We found that ETS exposure is associated with higher lung
cancer risk. Furthermore, the presence of the GSTP1 GG genotype appears to enhance the
magnitude of the association between ETS exposure and lung cancer. Larger studies will
be needed to confirm these preliminary findings. Copyright 2003 Wiley-Liss, Inc.
PMID: 12640684 [PubMed - indexed for MEDLINE]
1: Mutat Res. 2003 Feb-Mar;523-524:237-52. Related Articles, Links
Modulation of cigarette smoke-related end-points in mutagenesis and carcinogenesis.
De Flora S, D'Agostini F, Balansky R, Camoirano A, Bennicelli C, Bagnasco M,
Cartiglia C, Tampa E, Longobardi MG, Lubet RA, Izzotti A.
Department of Health Sciences, University of Genoa, Via A Pastore 1, I-16132
Genoa, Italy. [EMAIL PROTECTED]
The epidemic of lung cancer and the increase of other tumours and chronic
degenerative diseases associated with tobacco smoking have represented one of the most
dramatic catastrophes of the 20th century. The control of this plague is one of the
major challenges of preventive medicine for the next decades. The imperative goal is
to refrain from smoking. However, chemoprevention by dietary and/or pharmacological
agents provides a complementary strategy, which can be targeted not only to current
smokers but also to former smokers and passive smokers. This article summarises the
results of studies performed in our laboratories during the last 10 years, and
provides new data generated in vitro, in experimental animals and in humans. We
compared the ability of 63 putative chemopreventive agents to inhibit the bacterial
mutagenicity of mainstream cigarette smoke. Modulation by ethanol and the mechanisms
involved were also investigated both in vitro and in vivo. Several studies evaluated
the effects of dietary chemopreventive agents towards smoke-related intermediate
biomarkers in various cells, tissues and organs of rodents. The investigated
end-points included metabolic parameters, adducts to haemoglobin, bulky adducts to
nuclear DNA, oxidative DNA damage, adducts to mitochondrial DNA, apoptosis,
cytogenetic damage in alveolar macrophages, bone marrow and peripheral blood
erytrocytes, proliferation markers, and histopathological alterations. The agents
tested in vivo included N-acetyl-L-cysteine, 1,2-dithiole-3-thione, oltipraz,
phenethyl isothiocyanate, 5,6-benzoflavone, and sulindac. We started applying
multigene expression analysis to chemoprevention research, and postulated that an
optimal agent should not excessively alter per se the physiological background of gene
expression but should be able to attenuate the alterations produced by cigarette smoke
or other carcinogens. We are working to develop an animal model for the induction of
lung tumours following exposure to cigarette smoke. The most encouraging results were
so far obtained in models using A/J mice and Swiss albino mice. The same smoke-related
biomarkers used in animal studies can conveniently be applied to human chemoprevention
studies. We participated in trials evaluating the effects of N-acetyl-L-cysteine and
oltipraz in smokers from Italy, The Netherlands, and the People's Republic of China.
We are trying to develop a pharmacogenomic approach, e.g. based on genetic metabolic
polymorphisms, aimed at predicting not only the risk of developing cancer but also the
individual responsiveness to chemopreventive agents. Copyright 2002 Elsevier Science
B.V.
Publication Types:
* Review
* Review, Tutorial
PMID: 12628522 [PubMed - indexed for MEDLINE]
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