Mechanisms of Carcinogenesis

Halogenated hydrocarbons (e.g., vinyl chloride and ethylene dibromide) 

Some agents are complete carcinogens, that is, they act as both initiators and promoters of carcinogenesis. These include 

Many xenobiotic chemicals are not by themselves carcinogenic, but require metabolism to the ultracarcinogens that form DNA adducts. Examples of these include benzene and benzo (a) pyrene, which are metabolized to their hydroquinones, the carcinogenic agents)18 2128 3()l 

It is widely believed that oxidative stress (OS) is critical to carcinogenesis. OS theory states that bioactive agents (or their metabolites) that incorporate 

They show evidence of an ET entity being present in the parent compound or metabolite. 

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KNUDSON A G Jr (1989) The ninth Gordon Hamilton-Fairley memorial lecture. Hereditary cancers clues to mechanisms of carcinogenesis , Br J Cancer, 59, 661-6. 

Both l-nitroso-3,5-dimethylpiperazine and l-nitroso-3,4,5-trimethylpiperazine induced a high incidence of thymic leukemia in rats within 6 months (23). The 4-acetyl derivative of the former induced esophageal tumors in the same time, while the 4-benzoyl derivative was a very much weaker carcinogen, giving rise to only a few tumors of the forestomach after almost 2 years. These contrasting results are difficult to reconcile with any simple mechanism of carcinogenesis. 

The symposium upon which this book is based brought together leading investigators concerned with the mechanisms of carcinogenesis of PAH at the molecular level. The individual chapters in this book are not merely verbatim reports of the symposium proceedings but rather critical reviews of symposium topics with extensive references to investigations in other laboratories. Since the pertinent literature references are scattered in journals... 

The mechanism of carcinogenesis by PAHs is believed to involve alkylation of an informational macromolecule in a critical, but at present unknown, manner. Such an interaction with a protein has been modelled by alkylation of a peptide this showed a conformational change occurred on alkylation. It has not yet been possible to study the structure of DNA alkylated by an activated carcinogen this is because DNA is a fiber and the structural order in it is not sufficient for a crystal structure determination. However the crystal structures of some alkylated portions of nucleic acids are described, particularly some nucleosides alkylated by chloromethyl derivatives of DMBA. In crystals of these alkylation products the PAH portion of the adduct shows a tendency to lie between the bases of other nucleoside... 

Hamadeh, H. K. et al., Arsenic disrupts cellular levels of p53 and mdm2 A potential mechanism of carcinogenesis, Biochem. Biophys. Res. Commun., 263, 446, 1999. 

A review of data from 250 chemicals found an 82% concordance between results of carcinogenicity testing in the mouse and the rat (Purchase, 1980). Haseman et al. (1984a) reported a concordance of 73% for 60 compounds studies in both species. However, 30 to 40% of 186 National Cancer Institute (NCI) chemicals were found to be positive in one species and negative in the other (Gold et al., 1984). It is reasonable to conclude that neither rodent species will always predict the results in the other rodent species or in humans, and that the use of two species will continue until we have a much better understanding of the mechanisms of carcinogenesis. 

Carcinogenesis. No studies were located regarding carcinogenic effects of cyanide exposure in humans or animals following any route of exposure. Therefore, no mechanism of carcinogenesis can be discussed. 

R. G. Harvey, The Molecular Mechanism of Carcinogenesis of Polycyclic Hydrocarbons , in Molecular Mechanisms of Carcinogenicity and Antitumor Activity , Eds. C. Chagas, B. Pullman, Pontifica Academia Scientiarum, The Vatican, and Adenine Press, Schenectady, NY, 1987, p. 95 - 129. 

Van Beneden, R.J., Environmental effects and aquatic organisms investigations of molecular mechanisms of carcinogenesis, Em. Health Perspect., 105 (Suppl. 3), 669, 1997. 

The model was developed when little was known about the genetic and cellnlar mechanisms of carcinogenesis. The two professors drew upon earlier observations regarding the relationship between age and human cancer development and fonnd clear patterns in observed, age-specific mortality rates that conld be modeled mathematically based on a mnlti-step process (described below). That cancer might be initiated... 

Section 3.4 is devoted to organic ion-radical behavior in living organisms. Particularly, the consideration of an ion-radical mechanism of carcinogenesis reflects a point of view, which is new, and, in many respects, promising. 

The ease of formation of PAH cation-radicals is related to their IP. Above a certain IP, activation by one-electron oxidation becomes unlikely because the removal of one electron by the active forms of P450 or peroxidases is more difficult. A cutoff IP above which one-electron oxidation in not likely to occur was tentatively proposed to be about 7.35 eV (Cavalieri and Rogan 1995). For example, 7,12-dimethylbenz[a]-anthracene has an IP of 7.22 eV and is extremely carcinogenic. Benz[a]anthracene has an IP of 7.54 eV and is very weak in this sense. The active carcinogenicity of dibenz[a,h]anthracene (IP 7.61 eV) is not attributable to the one-electron mechanism. It is worth noting that the one-electron transfer is only one of the operating mechanisms of carcinogenesis. 

The biochemical mechanism of CNS depression seen with fuel oils and common to many organic solvents has not been elucidated. The mechanism of carcinogenesis associated with various formulations of fuel oils is unknown. 

W. N. Choy, Genotoxic and nongenotoxic mechanisms of carcinogenesis, in Genetic Toxicology and Cancer Risk Assessment, ed. W. N. Choy, Marcel Dekker, New York, 2001, pp. 47-71. 

IARC s mission is to coordinate and conduct research on the causes of human cancer, the mechanisms of carcinogenesis, and to develop scientific strategies... 

When available, data relevant to mechanisms of carcinogenesis that do not involve structural changes at the level of the gene are also described. 

For the agent, mixture or exposure circumstance being evaluated, the available data on end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in humans, experimental animals and tissue and cell test systems are summarized within one or more of the following descriptive dimensions ... 

Similarly, modulation of hepatocellular proliferation by peroxisome proliferators has been implicated in the mechanism of carcinogenesis. This can theoretically result in increased levels of mutation by increasing the frequency of replicative DNA synthesis as well as increasing the number of hepatocytes at risk. Furthermore, hepatocellular proliferation is probably involved in the promotion of growth of pre-neoplastic hepatocytes. There is clear evidence that di(2-ethylhexyl) phthalate causes acute and sustained hepatocellular proliferation under bioassay conditions which resulted in liver tumours in rats (Marsman et al., 1988). 

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