Abstract
The simple multistage model of carcinogenesis is outlined. It provides a satisfactory explanation of the power law for the age incidence of many forms of epithelial carcinoma, for the effects in human populations of changing exposures to supposed carcinogenic agents, and for many of the observed effects of applied carcinogens in animal experiments. In particular, the evidence on the effects of starting and stopping cigarette smoking suggests that both an early and a late stage may be affected. In the absence of direct evidence on the nature of the cellular changes there is some reluctance to accept a model with more than two stages, and several forms of two-stage models provide good general explanations of observed phenomena. Such a model has recently been applied to breast cancer; another approach to this disease, effectively involving transformations of the time scale, is discussed.
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Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- ARMITAGE P., DOLL R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer. 1957 Jun;11(2):161–169. doi: 10.1038/bjc.1957.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- ARMITAGE P., DOLL R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954 Mar;8(1):1–12. doi: 10.1038/bjc.1954.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armitage P. The assessment of low-dose carcinogenicity. Biometrics. 1982 Mar;38 (Suppl):119–139. [PubMed] [Google Scholar]
- Brown C. C. Statistical aspects of extrapolation of dichotomous dose-response data. J Natl Cancer Inst. 1978 Jan;60(1):101–108. doi: 10.1093/jnci/60.1.101. [DOI] [PubMed] [Google Scholar]
- Cook P. J., Doll R., Fellingham S. A. A mathematical model for the age distribution of cancer in man. Int J Cancer. 1969 Jan 15;4(1):93–112. doi: 10.1002/ijc.2910040113. [DOI] [PubMed] [Google Scholar]
- Cooper G. M. Cellular transforming genes. Science. 1982 Aug 27;217(4562):801–806. doi: 10.1126/science.6285471. [DOI] [PubMed] [Google Scholar]
- Cornfield J., Rai K., Van Ryzin J. Procedures for assessing risk at low levels of exposure. Arch Toxicol Suppl. 1980;3:295–303. doi: 10.1007/978-3-642-67389-4_22. [DOI] [PubMed] [Google Scholar]
- Crump K. S., Guess H. A., Deal K. L. Confidence intervals and test of hypotheses concerning dose response relations inferred from animal carcinogenicity data. Biometrics. 1977 Sep;33(3):437–451. [PubMed] [Google Scholar]
- Crump K. S., Hoel D. G., Langley C. H., Peto R. Fundamental carcinogenic processes and their implications for low dose risk assessment. Cancer Res. 1976 Sep;36(9 PT1):2973–2979. [PubMed] [Google Scholar]
- Day N. E., Brown C. C. Multistage models and primary prevention of cancer. J Natl Cancer Inst. 1980 Apr;64(4):977–989. [PubMed] [Google Scholar]
- Doll R. An epidemiological perspective of the biology of cancer. Cancer Res. 1978 Nov;38(11 Pt 1):3573–3583. [PubMed] [Google Scholar]
- Doll R., Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidemiol Community Health. 1978 Dec;32(4):303–313. doi: 10.1136/jech.32.4.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doll R., Peto R. Mortality in relation to smoking: 20 years' observations on male British doctors. Br Med J. 1976 Dec 25;2(6051):1525–1536. doi: 10.1136/bmj.2.6051.1525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Evans C. H., DiPaolo J. A. Independent expression of chemical carcinogen-induced phenotypic properties frequently associated with the neoplastic state in a cultured guinea pig cell line. J Natl Cancer Inst. 1982 Nov;69(5):1175–1182. [PubMed] [Google Scholar]
- Evans C. H., DiPaolo J. A. Neoplastic transformation of guinea pig fetal cells in culture induced by chemical carcinogens. Cancer Res. 1975 Apr;35(4):1035–1044. [PubMed] [Google Scholar]
- FISHER J. C., HOLLOMON J. H. A hypothesis for the origin of cancer foci. Cancer. 1951 Sep;4(5):916–918. doi: 10.1002/1097-0142(195109)4:5<916::aid-cncr2820040504>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
- Guess H., Crump K., Peto R. Uncertainty estimates for low-dose-rate extrapolations of animal carcinogenicity data. Cancer Res. 1977 Oct;37(10):3475–3483. [PubMed] [Google Scholar]
- Hartley H. O., Sielken R. L., Jr Estimation of "safe doses" in carcinogenic experiments. Biometrics. 1977 Mar;33(1):1–30. [PubMed] [Google Scholar]
- Hoel D. G., Gaylor D. W., Kirschstein R. L., Saffiotti U., Schneiderman M. A. Estimation of risks of irreversible, delayed toxicity. J Toxicol Environ Health. 1975 Sep;1(1):133–151. doi: 10.1080/15287397509529314. [DOI] [PubMed] [Google Scholar]
- Kennedy A. R., Cairns J., Little J. B. Timing of the steps in transformation of C3H 10T 1/2 cells by X-irradiation. Nature. 1984 Jan 5;307(5946):85–86. doi: 10.1038/307085a0. [DOI] [PubMed] [Google Scholar]
- Knudson A. G., Jr, Hethcote H. W., Brown B. W. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci U S A. 1975 Dec;72(12):5116–5120. doi: 10.1073/pnas.72.12.5116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee P. N., O'Neill J. A. The effect both of time and dose applied on tumour incidence rate in benzopyrene skin painting experiments. Br J Cancer. 1971 Dec;25(4):759–770. doi: 10.1038/bjc.1971.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MANTEL N., BRYAN W. R. "Safety" testing of carcinogenic agents. J Natl Cancer Inst. 1961 Aug;27:455–470. [PubMed] [Google Scholar]
- Moolgavkar S. H., Day N. E., Stevens R. G. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J Natl Cancer Inst. 1980 Sep;65(3):559–569. [PubMed] [Google Scholar]
- Moolgavkar S. H. The multistage theory of carcinogenesis and the age distribution of cancer in man. J Natl Cancer Inst. 1978 Jul;61(1):49–52. doi: 10.1093/jnci/61.1.49. [DOI] [PubMed] [Google Scholar]
- NORDLING C. O. A new theory on cancer-inducing mechanism. Br J Cancer. 1953 Mar;7(1):68–72. doi: 10.1038/bjc.1953.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peto R., Lee P. Weibull distributions for continuous-carcinogenesis experiments. Biometrics. 1973 Sep;29(3):457–470. [PubMed] [Google Scholar]
- Peto R., Roe F. J., Lee P. N., Levy L., Clack J. Cancer and ageing in mice and men. Br J Cancer. 1975 Oct;32(4):411–426. doi: 10.1038/bjc.1975.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pike M. C. A method of analysis of a certain class of experiments in carcinogenesis. Biometrics. 1966 Mar;22(1):142–161. [PubMed] [Google Scholar]
- Pike M. C., Krailo M. D., Henderson B. E., Casagrande J. T., Hoel D. G. 'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer. Nature. 1983 Jun 30;303(5920):767–770. doi: 10.1038/303767a0. [DOI] [PubMed] [Google Scholar]
- STOCKS P. A study of the age curve for cancer of the stomach in connection with a theory of the cancer producing mechanism. Br J Cancer. 1953 Dec;7(4):407–417. doi: 10.1038/bjc.1953.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stenbäck F., Peto R., Shubik P. Initiation and promotion at different ages and doses in 2200 mice. I. Methods, and the apparent persistence of initiated cells. Br J Cancer. 1981 Jul;44(1):1–14. doi: 10.1038/bjc.1981.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Whittemore A. S. Quantitative theories of oncogenesis. Adv Cancer Res. 1978;27:55–88. doi: 10.1016/s0065-230x(08)60930-6. [DOI] [PubMed] [Google Scholar]
- Whittemore A., Altshuller B. Lung cancer incidence in cigarette smokers: further analysis of Doll and Hill's data for British physicians. Biometrics. 1976 Dec;32(4):805–816. [PubMed] [Google Scholar]