Preclinical toxicology of anticancer agents.

The use of animal toxicology as a potential predictive system for drug toxicity in man is particularly important to the field of cancer chemotherapy because of several major clinical considerations (11). The nature of the growth characteristics of tumors in man requires that repeated courses of treatment be given oven extended periods of time; this approach carries with it an increased risk for the development of drug toxicity. Cancer chemotherapy agents, as a group, fail in varying degrees to discriminate efficiently between normal and target tissues. A wide range of qualitative toxicities are encountered; with many compounds, administration of moderately toxic doses may be required in order to achieve a maximum therapeutic response. In addition, a proportion of patients to whom new compounds are to be given are debilitated by disease and/or previous therapy and thus are potentially less tolerant of drug toxicity. Many of the drugs act upon DNA as their principal mechanism for cytotoxic action. This derangement of genetic information has been correlated with tematogenesis, mutagenesis, and carcinogenesis in lower animals and probably in man. The principal objective of animal toxicology is the generation of information about the new agent that may forewarn the physician about potential drug hazards that may be encountered during the initial trial. In this process, toxicity data are extrapolated from one species to another. This involves 2 implicit assumptions: toxicity tests in a particular animal species have significant predictive value for man; important toxicity will not go unpredicted. The scientific community has remained somewhat skeptical of this basic assumption of pnedictivity, and the overall value of animal toxicological studies has been seriously questioned. Nevertheless, this problem has necieved remarkably little systematic study. The pharmaceutical industry continued to generate extensive descriptive information relating to the toxicity of a new compound in animals as required by federal regulatory agencies, without an apparent attempt by either party to analyze these data for the larger question of its overall usefulness. In recognition of the potential importance of animal toxicological testing as a predictive system, the Laboratory of Toxicology of the NCI2 has developed an extensive protocol for use by its contractors (9). The Food and Drug