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Toxicologic Pathology
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Cell Death and Cell Proliferation in the Control of Normal and Neoplastic Tissue Growth

John R. Foster

Pathology Section, Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, United Kingdom

The development of reliable methodology for the assessment of rates of cell replication and cell death has enabled the study of how these 2 fundamentally opposed processes work to form and maintain tissue and to remodel tissue following diseases resulting in cell loss. The balance between these 2 processes and the consequences of an imbalance are fundamental to a clearer understanding of how hyperplasia and neoplasia develop in tissues under the influence of chemicals and drugs. An understanding of the changes that occur in target organs and tissues following chemical or drug exposure has enabled a better understanding of the mechanism by which these chemicals are able to induce cancer after prolonged exposure. Studies of the control of cell replication and the changes that occur following drug exposure have defined 2 types of response, 1 in which the cell replicative response is sustained and the other in which the cell replicative response is transient and occurs during the first few days of exposure. Although regulatory and scientific opinion appears ready to accept sustained cell replicative processes as an increased risk factor in the development of cancer, the role played by transient increases in cell replication remains unclear. Concurrent events in target organs following treatment with chemicals that induce transient increases in cell replication have revealed that the rates of apoptosis are suppressed at the same time as the cell replication levels are induced. Additional evidence suggests that growth and antigrowth factors are central in controlling these responses. Escape from the regulatory action of these factors is postulated to be one of the ways in which nongenotoxic carcinogenic chemicals, such as the peroxisome proliferators and sodium phenobarbitone, may induce cancer, with apoptosis playing a key role in the process.

Key Words: Cell death • cell replication • cancer • transient • sustained • growth control

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Toxicologic Pathology, Vol. 28, No. 3, 441-446 (2000)
DOI: 10.1177/019262330002800314
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