Carcinogenesis; a comprehensive survey最新文献

Phorbol ester tumor promoters enhance the ability of primary normal rat tracheal epithelial cells to form colonies in a time-dependent fashion. The potency of phorbol derivatives in inducing this effect is relative to their potency as tumor promoters in mouse epidermis. Agents which do not interact with the putative TPA receptor are not effective. In contrast, both hamster tracheal and human bronchial epithelial cells are inhibited from forming colonies by phorbol esters. The sensitivity of human cells varied among individuals but could not be related to age, smoking history, or presence of a cancerous condition. These results bear some similarity to those of Harris et al. where levels of BP-DNA binding were measured in organ cultures of human bronchus. An interindividual variation of 120-fold was observed in 37 specimens of human bronchus, however, no correlation was apparent between levels of binding and whether the specimens were from patients with cancer. It would be of interest to determine if there is a relationship between carcinogen metabolism or binding and the ability to respond to promoters in specimens from normal and lung cancer patients. It is conceivable that lung cancer arises in individuals that have rare peculiarities in carcinogen metabolism combined with peculiarities in their responses to promoters present in cigarette smoke. Several conclusions can be drawn from these data. Species vary in response to tumor promoting agents, and the type of response may be a result of the biochemical events which are triggered by interaction with protein kinase C or another cellular receptor. Both responses, that of enhanced growth of epithelial cells observed in the rat, or that of inhibition of growth (induction of terminal differentiation) seen in human and hamster epithelial cells are consistent with proposed mechanisms by which tumor promoters may function. A general enhancement of cell proliferation may lead to fixation or expansion of genetic damage in initiated cells, while induction of terminal differentiation in normal cells could lead to expanded cell proliferation in initiated cells resistant to differentiation controls. This indicates that both responses may be useful in detecting environmental promoting agents. In light of these studies perhaps the hamster trachea may more closely mimic the responses of the human bronchus than does the rat. This is consistent with observations of the difficulty in transforming hamster tracheal epithelium (Dr. Brooke Mossman, personal communication) and human bronchial epithelium compared with rat tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

In tobacco smoke, catechols represent a major group of cocarcinogens. Model studies have indicated that polyphenols and polysaccharides are two major groups of precursors for the catechol formation during smoking. Results from the application of BP together with catechol on mouse skin indicate that the detoxification path of BP metabolism is decreased and the formation of the BP-7,8-diol is increased in comparison to the metabolism pattern observed when BP is applied alone. It remains to be demonstrated that the increased BP-7,8-diol formation leads also to increased formation of BP-DNA adducts in epithelial tissues. The nicotine-derived N-nitrosamines represent a major group of carcinogens in chewing tobacco, snuff, and tobacco smoke. Their concentrations in processed tobacco and smoke exceed by far those of carcinogenic nitrosamines in other environmental materials. Whereas it has been shown that nicotine gives rise to NNN and NNK during tobacco chewing, the endogenous formation of these potent carcinogens upon smoke inhalation has so far not been demonstrated. However, the formation of N-nitrosoproline in cigarette smokers and snuff dippers proves that smoke and snuff have a measurable potential for the endogenous formation of carcinogenic nitrosamines. Finally, the data presented here indicate that the individuals subjected to passive smoke exposure under controlled conditions take up measurable amounts of particulate matter. The nicotine level in the saliva of nonsmokers reflect recent passive smoke exposure and levels of nicotine and cotinine in urine reflect the long-term exposure to smoke particulates. The indicators, measured in saliva and serum, make it clear that uptake of particulates due to passive smoke exposure corresponds only to a low percentage (less than 2%) of the particulates that represent the uptake of a 1 pack-a-day adult smoker. However, in special settings, such as in the exposure of infants to the smoke pollutants generated by their mothers, uptake of smoke constituents can reach levels which raise concerns as to possible long range toxic effects. A broader base of subjects and a wider range of pollution situations need to be tested in order to substantiate the significance of the dosimetry of uptake executed to date. Such measurements constitute an attempt at more accurate risk assessment for nonsmokers in smoke polluted environments.

Substantial interindividual differences occur for the metabolism of drugs, carcinogens, and steroid hormones, and these person-to-person differences are caused by genetic and environmental factors. It is likely that interindividual differences in the metabolism of xenobiotics and steroid hormones play a role in explaining interindividual differences in the initiation and progression of some human cancers. Factors that influence the metabolism and action of xenobiotics in human beings include age, disease states, hormonal changes in the body, ingestion of medicinal agents, exposure to environmental chemicals, and changes in life style, including factors such as cigarette smoking, alcohol consumption, and diet. Some individuals have a much larger response to environmental perturbations than do other individuals, and further research is needed to elucidate the reasons for differences in the responsiveness of people to modulators of chemical biotransformations. Immigration to a new country can represent a substantial change in a person's diet, life style, and environment, and these changes may alter the metabolism of xenobiotics and endogenous hormones that play a role in the carcinogenic response.

The concepts of tumor promotion discussed in this chapter demonstrate the complexity of the tumor promotion process, and illustrate the difficulty of determining which events are mechanistically important to promotion, and which ones are the result, or by-product of promotion. A number of possible mechanisms of promotion, both epigenetic and genetic, have been described on a molecular level. However, it should be stressed that none of these mechanisms is mutually exclusive; indeed, the enormous complexity of tumor promotion suggests that several of the mechanisms discussed above may very well be interrelated. The effects on epidermal differentiation, for example, may turn out to be the result of altered expression of particular oncogene whose product is actually a growth factor able to select for and amplify certain subpopulations of cells. Furthermore, the multiple steps which may occur at the molecular level, perhaps by way of sequential gene activation, serve to mirror the multiple stages which now delineate carcinogenesis in mouse skin.