Toxicity issues in cancer drug development.

Cancer chemotherapy has evolved from the use of cytotoxic drugs that are accompanied by highly deleterious and often life-threatening side effects, to the application of hormone antagonists that are more specific for hormone-mediated tumor growth and that are generally substantially less toxic and, most recently, to the use of targeted therapies including humanized mAbs and drugs such as imatinib (Gleevec) that have been developed for the treatment of malignancies induced by a unique chromosomal rearrangement. While these newer agents should theoretically prove to be more efficacious than the conventional drugs that have been the foundation of cancer treatment for decades, such improvement has not always been demonstrated either with the use of single agents or when these agents are combined with established therapies. Furthermore, neither cell culture nor animal model systems have provided reliable predictions of drug efficacy or toxicity. Consequently, despite advancing knowledge relating to signaling pathways and potential druggable targets involved in cancer, the use of newer agents will ultimately be dependent on empirical clinical trials, many of which will likely fail to demonstrate efficacy because of pharmacokinetic limitations or undesirable and limiting patient toxicities.