The process of discovery in cancer developmental therapeutics may
begin with either empiric screening or rational drug design. In either
case, the necessary steps in drug development that follow the
identification of an interesting lead require appropriate animal model
systems. Just as screening systems and rational drug design have
benefited from recent advances in cell culture technique and molecular
biology, so too has the role of animal model systems in drug
development. Beyond simply predicting dose-limiting toxicity, drug
metabolism, or tissue and compartment distribution, animal models are
increasingly being used to guide dose escalation in phase I trials and
to provide tumor microenvironments that mimic the clinical situation.
The
processes of cancer developmental therapeutics and drug development
have evolved, and will continue to change, since the first successful
use of drugs to treat systemic cancer more than 50 years ago. Basic
research in cancer biology has provided new targets for cancer drug
development and has brought older targets into sharper focus, leading to
new and novel approaches to cancer prevention and treatment. Of the
properties that make a cell malignant (uncontrolled growth, metastasis,
dedifferentiation, genetic plasticity, and drug resistance), only
uncontrolled growth has been exploited as a target for cancer drug
development. Agents that have the potential to interfere with the
metastatic cascade, interrupt autocrine and paracrine growth loops,
differentiate tumors, or reverse drug resistance are now in preclinical
development and early clinical trial. Appropriate and evolving animal
model systems will be needed to discover the next generation of cancer
drugs and bring them to clinical study. This chapter will discuss the
history and future of cancer drug discovery and drug development, with
special emphasis on the role of animal models in the process.