PubMed · 6694609
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E Papadopulos-Eleopulos. 1984-02-04. Carcinogenesis.. https://pubmed.ncbi.nlm.nih.gov/6694609/
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Lung cancer is the single most common cause of death, and almost all of it is due to tobacco smoking. Before the widespread use of cigarettes in this century, lung cancer was a rare illness. Tobacco smoke is a complex mixture of numerous mutagens and carcinogens. Over the last 40 years, the type of cigarettes most frequently used has been changing, namely the increased use of low tar and nicotine cigarettes. This has been accompanied by an increased risk of lung cancer due to a smokers' need to maintain blood nicotine levels, which in turn causes the need for smoking more cigarettes per day and deeper inhalation. This phenomena has led to the increasing rates of lung adenocarcinoma, compared to squamous cell carcinoma. It also probably explains, in part, the greater risk of lung cancer in women compared to men (in addition to some biological differences). The study of lung cancer involves many types of biomarkers, including those that measure exposure, the biologically effective dose and harm. The use of these has allowed us to understand many parts of lung carcinogenesis. Genetic susceptibilities play a large role in lung cancer risk. They govern smoking behavior (affecting dopamine reward mechanisms due to nicotine and nicotine metabolism), carcinogen metabolism and detoxification, DNA repair, cell cycle control and other cellular responses. The need for the study of lung cancer is highlighted by the need to improve cessation rates and reduce exposure among persons who cannot quit smoking, for better prevention strategies for former smokers and an understanding of environmental tobacco smoke risk.
OBJECTIVE: To study the dynamic change of glutathione S- transferase pi (GST-pi) in normal gastric mucosa, gastric mucosa with intestinal metaplasia (IM) and gastric cancer and to investigate the relationship between human carcinogen detoxification system and the virulence of Helicobacter pylori(H.pylori) in the stage of IM. METHODS: Two hundred and nineteen biopsy specimens of gastric mucosa, including 30 cases with normal gastric mucosa, 171 cases with IM and 18 cases with gastric cancer, were examined. The expression of GST-pi was detected by S-P immunohistochemical method. High-iron diamine /alcian blue pH2.5/periodic acid -Schiff (HID-ABpH 2.5-PAS) method was used to classify IM. H.pylori infection was confirmed or excluded by hematoxylin-eosin (HE) staining, of H.pylori-DNA PCR and ELISA. The 80 cases with H.pylori infection were treated by bismuthate + amoxicillin + metronidazole for three months and then biopsy specimens were taken again from the original sites. RESULTS: The GST-pi expression rate was 69.6% in gastric mucosa with IM, significantly higher than that in gastric cancer (44.4%, P < 0.05) and that in normal gastric mucosa (0%, P <0.01). The GST-pi expression rate in IM II, IM III, and IM I decreased in sequence (83.3%, 71.1%, and 48.9%). The GST-pi expression rate in IM without H.pylori infection was 79.0%, significantly higher than that in IM with HP infection (64.2%, P <0.05). The positive rate of GST-pi expression in H.pylori eradicated group was 81.9%, significantly higher than that before H.pylori eradication (63.8%, P < 0.01). The GST-pi expression rate decreased from normal gastric mucous to IM and to gastric cancer, and from IM I -->II-->III too. CONCLUSION: IM III with low or no expression of GST-pi is a high-risk condition of gastric cancer. The risk of gastric cancer increases when low or no expression of GST-pi is combined with H.pylori infection. The carcinogen detoxification role of GST-pi and the virulence of H.pylori might interact each other in the stage of intestinal metaplasia, the precancerous condition of gastric cancer.
A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4- dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A*, are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.