Tumor models: Assessing toxicity in efficacy studies

Efficacy studies in animal tumor models provide an early opportunity to col lect preliminary information on toxicity. When screening and evaluating cyt otoxic chemotherapeutic agents, efficacy studies usually include at least 1 dosage level that causes severe toxicity and death. Pathologic evaluation in early efficacy studies may reveal major target organs, dosage/schedule r elationships, pharmacokinetic/toxicity relationships, effects of formulatio n and route of administration, maximum tolerated dose, cause of death, and reversibility of changes in normal tissues. Intraperitoneal formulations ar e frequently used to establish proof of concept for promising compounds (hi ts) from in vitro screens; however, these crude formulations may also induc e intraperitoneal inflammation and confound the interpretation of both effi cacy and toxicity. Efficacy studies conducted in the later stages of drug d iscovery may be used to refine the dose and schedule proposed for phase I c linical trials. Efficacy studies in animal tumor models provide useful toxi cologic data for screening potential drug candidates, optimizing the therap eutic index, and designing both preclinical and clinical development progra ms.