Abstract
Historically our knowledge about the direct carcinogenic activity of cigarette smoke and its constituents grew from painting experiments on the skin of mice to produce papillomas and carcinomas. The neutral fraction of cigarette smoke condensate had most of the carcinogenic activity in this test and was rich in carcinogenic polycyclic aromatic hydrocarbons (PAHs), the most abundant by far being BP. However, the concentration of BP in the condensate was only about 2% the amount of pure BP required to cause skin tumors. In other fractions there were non-carcinogenic constituents that promoted tumor formation when applied repeatedly to mouse skin that had been initiated by a single subcarcinogenic application of BP. There were also constituents of cigarette smoke that acted as co-carcinogens when applied simultaneously with repeated applications of BP. BP was effective as an initiator at lower concentrations than as a complete carcinogen, and some non-carcinogenic PAHs in the condensate were also active initiators. It was concluded from these studies that cigarette smoke condensate is primarily a tumor-promoting and co-carcinogenic agent with weak activity as a complete carcinogen. A major effect of promoters, and possibly of co-carcinogens, is a diffuse hyperplasia which includes selective expansion of clones carrying endogenous mutations and/or mutations induced by PAHs and other carcinogens such as NNK. The induced mutations as well as damaged cells would occur throughout the exposed region and, along with the hyperplasia, increase the permissiveness of the cellular microenvironment for neoplastic expression of any potential tumor cell in its midst. Since neither the promoters nor co-carcinogens in tobacco smoke are known to interact directly with DNA, their effects can be considered epigenetic processes that act upon genetically altered cells. Examples are cited from studies of experimental skin carcinogenesis, smoking-induced histopathological changes in human lung and spontaneous transformation in cell culture to illustrate the genetic and epigenetic interactions of neoplastic development in general and their significance for smoking-induced lung cancer in particular. Certain dietary modifications that appear to be effective in moderating the promotional phase of animal and human carcinogenesis are suggested for trial in managing lung cancer.
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Notes
It is noteworthy that the skin of p53-null mice initiated with DMBA and promoted with TPA developed only one-fifth as many papillomas as p53 heterozygous and wild type mice (Kemp et al., 1993). However, the papillomas of the p53 null mice progressed to carcinomas much faster than those of the other two strains, while the final percentage of carcinomas was much higher in both p53-null and heterozygous mice than the wild type mice. There is also evidence that clonal expansion of p53 mutant cells is associated with progression of human brain tumors (Sidransky et al., 1992).
It is of interest that Auerbach's histopathological studies of smokers' lungs at autopsy played a powerful role in widespread acceptance of smoking as the major cause of lung cancer and were prominently cited in the 1964 Surgeon General's report about the dangers of smoking (Burkhart, 1997). This resulted in the requirement that cigarette packages carry a warning that cigarettes could be harmful to health, and it was estimated that in the next 25 years 750 000 lives had been saved by people's decisions not to smoke (ibid.). The decrease in cigarette smoking in men that began in the 1960's was followed, after 1980, in a decreasing mortality for lung cancer. A further finding of Auerbach and colleagues that influenced public opinion about the dangers of smoking came from an experiment in which dogs were taught to smoke cigarettes through a tracheostoma. Eight of 12 dogs that were killed after 2.4 years of smoking seven unfiltered cigarettes per day developed invasive bronchiolo-alveolar tumors while none of the eight non-smoking controls developed invasive tumors (Auerbach et al., 1970).
Abbreviations
- BA:
-
benzanthracene
- BP:
-
benzo(a)pyrene
- B(e)P:
-
benzo(e)pyrene
- BPDE:
-
7,8-dihydrodiol-9,10-epoxide
- BPDE-1:
-
syn or cis isomer of BPDE also BPDE-II
- BPDE-2:
-
anti or trans isomer of BPDE also BPDE-I
- CS:
-
calf serum
- DB(a,c)A:
-
dibenz(a,c)anthracene
- DB(a,h)A:
-
dibenzo(a,h)anthracene
- DB(a,l)P:
-
dibenzo(a,l)pyrene
- DMBA:
-
7,12-dimethylbenzanthracene
- MCA:
-
3-methylcholanthrene
- NNK:
-
nicotine-derived nitrosamine ketone
- PAHs:
-
polycyclic aromatic hydrocarbons
- RPA:
-
phorbol-12-retinoate-13-acetate
- RSV:
-
Rous sarcoma virus
- TPA:
-
12-0-tetradecanoylphorbol-13-acetate
- TPNH:
-
reduced form of triphosphopyridine nucleotide
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Acknowledgements
The comments of David Sidransky helped to improve the balance and clarity of the paper. Many thanks are due to Dorothy Rubin for care in transcribing several drafts of the manuscript. Support for the work came from the Elsasser Family Fund and the National Institutes of Health grant G13LM07483.
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Rubin, H. Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis. Oncogene 21, 7392–7411 (2002). https://doi.org/10.1038/sj.onc.1205800
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