Agent Identification and Preclinical Testing

  • James A. Crowell
  • Cathy J. Holmes
Part of the Cancer Treatment and Research book series (CTAR, volume 106)

Abstract

This chapter provides an overview of the preclinical screening assays and animal efficacy testing models currently utilized by the drug discovery and development program of the Division of Cancer Prevention (DCP), National Cancer Institute (NCI) to identify chemical agents or natural biological products which may be efficacious in preventing human cancers. The first step of the drug discovery process involves subjecting candidate agents to a sequential series of mechanism-based assays which target specific biochemical and molecular pathways known to be involved in carcinogenesis. Thesein vitromechanistic assays provide quantitative data used to establish chemopreventive efficacy and also to assist in classifying and prioritizing agents for further evaluation in whole animal models. Major classes of chemopreventive agents identified thus far include, for example, signal transduction modulators, such as Ras farnesyl transferase inhibitors; retinoids; protein tyrosine kinase inhibitors (PTK), such as epidermal growth factor receptor (EGFR) inhibitors; peroxisome proliferator-activated receptor (PPAR) modulators; hormone modulatory agents, such as anti-androgens, anti-estrogens, and aromatase inhibitors; antiinflammatories including NSAIDs, cyclooxygenase (COX-2), and lipoxygenase (LOX) inhibitors; antimutagens, such as phase II enzyme inducers; antioxidants, such as selenium and vitamin E; and angiogenesis inhibitors, including collagenase and matrix metalloproteinase blocking agents. In the second step promising chemopreventive compounds or combinations of agents possessing pleiotropic activities are subsequently developed both in carcinogen-induced and genetically manipulated animal tumor models, including models of colon, lung, bladder, mammary, prostate, and skin cancer, as well as in batteries of toxicity and pharmacokinetic tests. Development of chemopreventive drugs using this targeted approach affords a strategic framework for evaluating agents according to defined criteria and not only provides evidence of agent efficacy but also serves to generate dose-response, toxicity, and pharmacokinetic data needed to consider Phase 1 clinical safety and pharmacokinetic evaluations.

Keywords

Toxicity Adenocarcinoma Glutathione Oncol Prostaglandin 

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© Springer Science+Business Media New York 2001

Authors and Affiliations

  • James A. Crowell
  • Cathy J. Holmes

There are no affiliations available

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