The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes--mechanisms that are reasonably well understood--and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer--an approach that has not yet reached its full potential--are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.

/pdf/tobacco-smoke-carcinogens-and-lung-cancer-151e8tf0fh.pdf

Tobacco Smoke Carcinogens and Lung Cancer

Publisher Summary This chapter discusses the role of glutathione (GSH) and glutathione s-transferases in metabolism of chemical carcinogens and other electrophilic agents. GSH is a tripeptide (I) that is present in nearly all living cells and is the most abundant sulfhydryl compound present in animal tissues, mainly in the cytosol. The chapter illustrates the wide range of electrophilic agents, including several known mutagens and carcinogens, which conjugate with GSH, a process usually catalyzed by the GSH S-transferases. This conjugation is probably a protective mechanism and is the initial stage in mercapturic acid biosynthesis for the elimination of foreign compounds from the body. GSH S-transferases provide protection not only by catalyzing the conjugation of a potential toxicant with GSH, but also by preferentially binding, even covalently, that toxicant. The reactive electrophiles that conjugate with GSH also bind to DNA, RNA, and protein and identification of GSH conjugates provide information on the nature of these biologically active intermediates or even their immediate precursors. Thus, the knowledge of the way in which mutagens and carcinogens are metabolized is essential to a better understanding of their mode of action and of the processes for their detoxication.

The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents.

Guidelines for Canadian Drinking Water Quality

Angiogenesis, or the formation of new blood vessels out of pre-existing capillaries, is a sequence of events that is fundamental to many physiologic and pathologic processes such as cancer, ischemic diseases, and chronic inflammation. With the identification of several proangiogenic molecules such as the vascular endothelial cell growth factor, the fibroblast growth factors (like in FGFs), and the angiopoietins, and the recent description of specific inhibitors of angiogenesis such as platelet factor-4, angiostatin, endostatin, and vasostatin, it is recognized that therapeutic interference with vasculature formation offers a tool for clinical applications in various pathologies. Whereas inhibition of angiogenesis can prevent diseases with excessive vessel growth such as cancer, diabetes retinopathy, and arthritis, stimulation of angiogenesis would be beneficial in the treatment of diseases such as coronary artery disease and critical limb ischemia in diabetes. In this review we highlight the current knowledge on angiogenesis regulation and report on the recent findings in angiogenesis research and clinical studies. We also discuss the potentials, limitations, and challenges within this field of research, in light of the development of new therapeutic strategies for diseases in which angiogenesis plays an important role.

/pdf/angiogenesis-potentials-for-pharmacologic-intervention-in-3ch7srytb3.pdf

Angiogenesis: Potentials for Pharmacologic Intervention in the Treatment of Cancer, Cardiovascular Diseases, and Chronic Inflammation

Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC.

The formation of carcinogenic N-nitroso compounds by the chemical reaction between nitrous acid and oxytetracycline, morpholine, piperazine, N-methylaniline, methylurea, and (in some experiments) dimethylamine was blocked by ascorbic acid. The extent of blocking depended on the compound nitrosated and on the experimental conditions. Urea and ammonium sulfamate were less effective as blocking agents. The possibility of in vivo formation of carcinogenic N-nitroso compounds from drugs could be lessened by the combination of such drugs with the ascorbic acid.

http://science.sciencemag.org/content/sci/177/4043/65.full.pdf

Ascorbate-Nitrite Reaction: Possible Means of Blocking the Formation of Carcinogenic N-Nitroso Compounds

Induction of Lung Tumors and Malignant Lymphomas in Mice by Metronidazole

Hexachlorobenzene (HCB) is a fungicide and a by-product in the manufacture of many chlorinated solvents and pesticides. In Turkey, between 1955 and 1959 HCB was the causative agent of an epidemic of toxic porphyria, which involved more than 3,000 people, predominantly children. HCB was studied in long-term experiments for carcinogenicity in mice. Outbred Swiss mice were given HCB in the diet at dose levels of 50, 100 and 200 parts per million (ppm), for 101–120 weeks. Survival rates in females and males of group HCB 200 were markedly affected by deaths due to toxic manifestations of HCB. All survivors were killed at 120 weeks. Exposure to HCB resulted in an increased incidence of liver-cell tumors in groups HCB 100 and HCB 200. No liver-cell tumors were observed in the controls and in the group fed HCB 50. The incidence of mouse lympho-mas was 35% in controls and 11% in HCB 200. The decrease reflects probably the shortest life-span of HCB-treated animals. The incidence of lung tumors was higher in controls than in the treated groups, but the multiplicity (nodule/mouse) was approximately the same in all groups. In a separate experiment 30 female and 30 male mice were administered 300 ppm HCB in the diet for only 15 weeks. Most of the males died early. The survival rate at 110 weeks of age was 10% and comparable to that of controls. Two mice in the HCB 300 group developed liver-cell tumors. The proportion of tumor-bearing animals and the incidence of lymphomas, lung adenomas and other tumor types in HCB 300 mice were similar to those reported in control animals. The present results indicate the carcinogenicity effect of HCB in mice.

Philippe Shubik

Papers

Ascorbate-Nitrite Reaction: Possible Means of Blocking the Formation of Carcinogenic N-Nitroso Compounds

Induction of Lung Tumors and Malignant Lymphomas in Mice by Metronidazole

Carcinogenesis of hexachlorobenzene in mice.

Skin tumorigenesis in mice by petroleum asphalts and coal-tar pitches of known polynuclear aromatic hydrocarbon content

Transplacental effects of diethylstilbestrol on the genital tract of hamster offspring