The evaluation of potential human carcinogens: a histopathologist's point of view.
Over 100 marketed drugs induce neoplasia when administered at high doses to rats and mice for periods of up to two years. Despite their diverse chemical structures and biological activities, these compounds produce a relatively limited range of tumour types in rodents, most commonly in the liver. Tumours usually develop only after long periods of time following high exposure to drug. The main exceptions are DNA-reactive anticancer drugs such as alkylating agents which produce tumours rapidly in rodents in several organs. In this laboratory, mouse carcinogenicity studies are performed using the C57BL/10J strain. This strain infrequently develops hepatic tumours spontaneously but it is sensitive to the effects of DNA-reactive carcinogens. Moreover, hepatic neoplasms regularly develop in male but not female C57BL/10J mice following long-term treatment with nongenotoxic drugs that produce hepatic enlargement associated with diverse hepatocellular effects. Studies in this strain with the tumorigenic liver enlarger, phenobarbitone, have shown that although such liver enlargement is characterised by a brief burst of hepatocyte replication, this is associated with persistent regional modulation of hepatic growth stimulatory and inhibitory factors and their associated receptors. These findings indicate that there is a sustained alteration to the internal hepatic environment characterised by regional alterations to the balance of hepatocyte mitogens and inhibitors of replication and their respective receptors. Thus, the development of hepatocellular tumours in C57BL/10J mice following two-year treatment with nongenotoxic drugs appears to be a regular response of an organ to an exaggerated and long-term disruption of its homeostasis. Agents that produce tumours in rodents in this way seem likely to pose little or no risk to humans if administered under appropriate clinical circumstances at doses which show no significant disruption of organ homeostasis. However, drugs that produce this type of response need to be distinguished from those that induce unusual and rapid patterns of tumour development because these agents may have high tumorigenic potency of potential hazard to humans.
Greaves
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Safety of Medicines Group, ZENECA Pharmaceuticals, Cheshire, UK.
D000818:Animals; D015197:Carcinogenicity Tests / Q000706:statistics & numerical data; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D008107:Liver Diseases / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL