The use of animal models for cancer chemoprevention drug development.
Animal models currently are used to assess the efficacy of potential chemopreventive agents, including synthetic chemicals, chemical agents obtained from natural products, and natural product mixtures. The observations made in these models as well as other data are then used to prioritize agents to determine which are qualified to progress to clinical chemoprevention trials. Organ-specific animal models are employed to determine which agents or classes of agents are likely to be the most effective at nontoxic doses to prevent organ-specific forms of cancer. These results are then used to target specific organs in high-risk populations in clinical trials. The animal models used are either carcinogen-induced with carcinogens specific for particular organ sites or they are transgenic/mutant animals with insertions, deletions, or mutations at targeted gene sites known to enhance cancers in a specific organ. Animal tumor models with characteristics favorable to chemoprevention studies are available for cancers of the lung, colon, skin, bladder, mammary, prostate, head and neck, esophagus, ovary, and pancreas. In addition to single-agent dose-response testing, such models are frequently used for testing combinations of agents, testing different routes of administration, evaluating surrogate endpoint biomarkers, and generating initial pharmacokinetics and toxicology data. For some of the more standard animal models there is significant correlation with human chemopreventive trial results. There are a growing number of positive human chemoprevention trials that have used agents or combinations that were positive in animal testing. There have been fewer negative human clinical trials, but their results again correlate with negative animal results. Clearly the validation of animal models to predict the efficacy of agents in human clinical trials will await further human data on positive and negative outcomes with chemopreventive agents. Whether validated or not, animal efficacy data remain central to the clinical trial decision-making process.
Steele
Vernon E
VE
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA. vs1y@nih.gov
Lubet
Ronald A
RA
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents
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