Experimental Carcinogenesis Modeling

In spite of these genetic changes, the initiated cell is not phenotypi-cally different from the normal cell. Furthermore, the altered cell can remain dormant for the lifetime of the animal unless it is exposed to a selective proliferative stimulus (Pitot and Sirica, 1980 Peraino et al, 1973 Solt et al, 1977). The genotypic change confers on the initiated cells an advantage such that, under the influence of adverse or otherwise selective environmental conditions, they can proliferate while the growth of the normal cell is inhibited (Farber, 1973, 1980). 

Under repeated stimulation, the foci develop into nodules, a small number of which persists even in the absence of the environmental influences necessary for the initial proliferation. Although the evidence is largely indirect, it has been hypothesized that within these persistent nodules, a rare event of unknown etiology occurs in, at most, a few cells, which become malignant and develop into tumors (Solt et al, 1911 Farber, 1980). The majority of these nodules, however, mature and remodel into normal-appearing tissue that is, they lose selected phenotypic characteristics even though the cells of these remodeled foci retain their ability to respond to post-initiation modifiers. 

Due to the resources required, the carcinogenicity of ethanol has been examined in only a few lifetime feeding studies in experimental animals. Ketcham et al (1963) found no increased incidence of cancer in mice fed ethanol in a 20% w/v solution offered in place of the drinking water for up to 15 months. However, the ethanol intake was low when compared to the levels which human alcoholics are able to consume (Scheig, 1970 Patek et al, 1975). For example, no more than 20% of total caloric intake could be obtained from ethanol when provided in the drinking water of experimental rats (Missibeck, 1983). In contrast, alcoholics can consume as much as 50% of their calories from ethanol (Mills et al., 1983). In another study, Schmahl et al. (1965) administered either brandy (38% of caloric intake) or a 25% ethanol solution to rats until their natural death. They found no increase in the incidence of cancer and 

Another factor which could contribute to the elevated incidence of upper gastrointestinal tract cancers in alcoholics is the presence of carci- 

A third factor which has not been carefully explored is the incidence of nutritional deficiencies in alcoholics. Alcoholics tend to have marginal intakes of fruits and vegetables, and their diets may be particularly lacking in P-carotene and folacin. These vitamins are essential for maintaining normal epithelial cell regeneration and integrity (P-carotene after conversion to retinol), and a deficiency could contribute to the cocarcinogenic potential of ethanol. 

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Human exposure to complex mixtures of polycyclic aromatic hydrocarbons (PAH) occurs through inhalation of tobacco smoke and polluted indoor or outdoor air, through ingestion of certain foods and polluted water, and by dermal contact with soots, tars, and oils CO. Methylated PAH are always components of these mixtures and in some cases, as in tobacco smoke and in emissions from certain fuel processes, their concentrations can be in the same range as some unsubstituted PAH. The estimated emission of methylated PAH from mobile sources in the U.S. in 1979 was approximately 1700 metric tons (2). The occurrence of methylated and unsubstituted PAH has been recently reviewed (1, 2). In addition to their environmental occurrence, methylated PAH are among the most important model compounds in experimental carcinogenesis. 7,12-Dimethylbenz[a]anthracene, one of... 

Long-chain ester derivatives of phorbol, a tetracyclic diterpene from the seed oil of Croton tiglium L., including its most abundant representative, 12-0-tetradecanoylphorbol-13-acetate (65), are potent activators of protein kinase G (PKG) and are used as standard tumor promoters for the study of experimental carcinogenesis in animal models." ... 

Palytoxin was identified as a skin tnmor two decades ago. Palytoxin is a potent tumor promoter in the monse skin carcinogenesis model. The biochemical mechanism of action of palytoxin as a tnmor promoter differs significantly from that of the prototypical phorbol ester tumor promoters. In contrast to the skin tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA), palytoxin does not activate protein kinase C or increase ornithine decarboxilase activity in the mouse skin. " There are several interesting stndies on the cellnlar mechanisms activated by palytoxin as a tumor promoter however, the biochemical mechanisms by which palytoxin-stimnlated signaling contribntes to tnmor promotion are cnrrently elncidated, and it seems that they conld depend on the experimental... 

As mentioned pievionsly, eaidnogen metabolism has been one of the drivers for the P450 field. There is strong evidenee that the P450 composition can strongly inflnence chemical carcinogenesis in experimental animal models [2762], reinforced with transgenie monse models [1441]. 

The simplest experimental model of carcinogenesis is the three-stage model (Pitot and Dragan, 1994) consisting of ... 

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