The Use of Animal Models for Cancer Chemoprevention Drug Development

Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
Seminars in Oncology (Impact Factor: 3.9). 08/2010; 37(4):327-38. DOI: 10.1053/j.seminoncol.2010.05.010
Source: PubMed


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.

Download full-text


Available from: Vernon E Steele, Sep 08, 2014
  • Source
    • "In addition, the model must be consistent in generating tumors in a significant number of animals in a reasonable period. Finally, the model must be predictive in terms of clinical efficacy, i.e. that the positive or negative results obtained in the animal model should later correlate with positive and negative results in human trials (Steele et al., 2010). One of most useful models is the induction of bladder cancer in mice and rats with hydroxybutyl(butyl)nitrosamine (OH-BBN). "

    Full-text · Chapter · Feb 2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is one of the most important avoidable causes of death around the world, the most widespread carcinoma, with a very poor prognosis, and is the leading cause of cancer death in both developed and developing countries. We report morphological and biological behavior characteristics of a tumor that arose in only one BALB/c mouse of an experimental group treated with urethane, a chemical lung-tumorigenic agent. Morphological and immunochemical analysis indicated phenotypic compatibility with a lung adenocarcinoma. The tumor was named LAC1 (lung adenocarcinoma 1). Implant success in eight LAC1-bearing mice generations was 100%, with a fast evolution (58 survival days) and good metastatic capacity (41% of animals with metastases). The tumor induced a paraneoplastic syndrome characterized by anemia, neutrophilia, cachexia, splenomegaly and thymic atrophy. The lymphoproliferation to Con A was altered in tumor-bearing mice. This lung adenocarcinoma may be a useful experimental model for studying tumor progression, paraneoplastic syndromes and immunology in carcinogenic studies.
    Full-text · Article · Jan 2011 · Journal of Experimental Therapeutics and Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the in vivo efficacy of a novel polybisphosphonate (ODX) in the treatment of bone metastasis from prostate cancer. A rat prostatic carcinoma model was used. Forty-two rats (21 control, 21 treatment) had induction of bone lesions through injection of AT6.1 cells into the distal medullar cavity of long bones (right femur). At day 21 post injection, radiographs were taken and tumor score (severity of lesions, 0-4) and tumor incidence (score >0) were determined. Treatment started at day 23 and lasted until day 49 (four i.v. administrations of ODX during four weeks). ODX reduced the severity of the lesions compared to the control group. Forty-seven percent of the treated rats had regression of their lesions at the study end, including four rats showing disappearance of the lesions i.e. score 0. Osteocondensation at the growth plate was only observed in the treatment group, indicating osteoclast inhibition. In spite of a relatively short treatment period with only four administrations, ODX showed significant efficacy (p=0.0023), with inhibition of tumor progression and osteolysis. The results are encouraging, confirming previous in vitro studies. Clinical research is pending on patients with bone metastasis from castration-resistant prostate cancer.
    No preview · Article · Dec 2011 · Anticancer research
Show more