Cell Proliferation and Carcinogenesis

Abstract

Cancer is due to multiple inherited or acquired mutations occurring in a single cell. DNA replication, although incredibly precise, results in spontaneous errors. A chemical can increase the number of errors per DNA replication by increasing damage to DNA, or it can increase the probability for spontaneous errors by increasing the number of DNA replications. A model has been developed which takes into account the role of DNA reactivity and increased DNA replication in the pluripotential cell population of a tissue on the development of cancer. This model can be used to assess the mode of action of chemicals which are carcinogenic in animal models and to access the relevance of that mode of action to human risk. By using this mode of action-based model, it may then be possible to replace the 2-year cancer bioassay with shorter-term assays which assess DNA reactivity, immunosuppression and estrogenic activity of the chemical and the effects of the chemical on toxicity and cell proliferation. (J Toxicol Pathol 2008; 21: 1-7)

Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide

“…In the current experiment, we demonstrated that urothelial hyperplasia induced by repeated-dose CP is accompanied by increased proliferation activity of urothelial cells. Cohen et al assumed that, every time a cell undergoes a cell division, there is a low probability, but not zero, of a genetic error occurring [4,6]. It is, in general, accepted that at least two irreversible genetic events must occur for tumour formation.…”

“…It is therefore not surprising that, in the present experiment, melatonin significantly decreased the proliferation activity of urothelial cells and therefore prevented hyperplasia from developing. Since the rapid proliferation of urothelial cells seen after repeated doses of CP could increase the likelihood of bladder carcinogenesis [4][5][6][7], melatonin might prevent the development of bladder tumours by decreasing the proliferation activity of urothelial cells.…”

“…Hicks and Chowaniec [2] and our unpublished data showed that repeated intraperitoneal doses of cyclophosphamide (CP) cause persistent urothelial hyperplasia. Cohen et al have developed a model of carcinogenesis which incorporates several basic principles: cancer results from genetic errors within normal cells; carcinogenesis is a multi-stage process, requiring more than one genetic event; and a chance of a genetic event occurring per cell division is a finite quantity and, therefore, that increased cell division increases the chance for a genetic event [4]. Based on this model, they then postulate that changes which lead to increased cell proliferation in the urothelium should be carefully evaluated as a possible contributing factor to carcinogenesis [5][6][7].…”

“…In the rat, it then progresses to nodular and papillary hyperplasia, while in the mouse nodular hyperplasia is considerably more common than papillary proliferations [4]. The rat model then progress to papillomas and strongly resembles low-grade papillary urothelial neoplasia in humans, whereas the mouse model resembles the highgrade, highly malignant disease of humans [15].…”

Phototoxicity and Photocarcinogenicity

“…Modelling analyses demonstrate that induced cell proliferation is sufficient to account for the increase in bladder tumour prevalence after exposure to sodium saccharin (NaS). If sufficient numbers of initiated cells are generated spontaneously, the increased and sustained proliferative activity induced by NaS generates tumors (Cohen and Ellwein, 1990). The authors conclude that, as the mechanisms of carcinogenesis become more thoroughly understood, a more rational approach can be taken for extrapolation from high-dose experimental data in animals to low-dose natural exposure and assessment of the risk faced by human populations exposed to chemical agents.…”