Many chemicals present in our environment and many antitumor drugs induce DNA damage which, depending on the level of DNA lesions, triggers complex cellular responses. These include reversible growth arrest and repair of DNA lesions or, if DNA damage is too severe or not fully repaired, cells undergo cell death by apoptosis or become growth-arrested due to cellular senescence. Which of the pathways is activated by DNA lesions depends on different intracellular signalling pathways, regulated by p53 and pRb tumor suppressor proteins or oncogenes such as ras or c-myc. Induction of cell death or senescence in cells with damaged genomes are basic mechanisms which prevent the development of cancer by eliminating cells with potentially deleterious DNA mutations or genetically unstable genomes.

It has now become apparent that cell death by apoptosis is induced at relatively high doses of genotoxic agents. At low doses, a dominant process observed in many types of cells exposed to DNA damaging agents is induction of permanent growth arrest due to senescence. Cellular senescence can be regarded as 'proliferative death' since it does not lead to cell killing but rather it prevents clonal expansion of mutated cells or drug-treated tumor cells.

We have only begun to understand the mechanisms which are decisive for induction of cellular senescence as a result of DNA damage in normal and tumor cells. However, there is a wealth of information concerning molecular mechanisms involved in carcinogenesis and mechanisms by which specific agents exert their chemopreventive effect. It seems that we can now use this knowledge to propose new approaches in cancer chemoprevention or cancer treatment which will force normal cells with DNA lesions or tumor cells treated with DNA damaging agents into premature senescence. If we consider that cancer usually develops over a 10- to 20-year period, it should give us sufficient time to apply modulators which could delay or stop the process of carcinogenesis by induction of accelerated senescence. However, in chemoprevention a problem of treatment protocols exists, as it may be necessary for some chemopreventive agents to be provided before or early in the initiation steps of carcinogenesis to have beneficial effects. On the other hand, some agents may be more suitable for cancer prevention if provided at a later stage of carcinogenesis. Finally, some agents can still be applied during cancer treatment to potentiate the antitumor effect of standard drugs or at least to lower undesirable toxic effects of anticancer chemotherapy. In drug-induced senescence in tumor cells, it is critical to establish if this is a truly irreversible process. Most recent data show that a small fraction of cells treated with DNA damaging agents, after initial growth arrest, resume cell proliferation. It is particularly important given that induction of premature senescence by antitumor drugs may represent an alternative approach to treat human cancers.

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