PRECLINICAL AND CLINICAL-RESULTS WITH IRINOTECAN - EXTENDING PRINCIPLES LEARNED IN MODEL SYSTEMS TO CLINICAL-TRIALS DESIGN

Clinical results with irinotecan (CPT-II [Camptosar]) and other campto thecin derivatives in various cancers, although encouraging have falle n short of the expectations predicted by preclinical models. One propo sed explanation for this is that preclinical xenograft models do not p redict for the sensitivity of human cancer. In this article, we descri be the results of several studies suggesting that this explanation is incorrect. instead our results indicate that the discrepancy between c linical response rates and findings in preclinical models may be due t o a failure to incorporate the principles learned from preclinical stu dies into the design of clinical trials. Our analysis suggests that if differences in host tolerance are taken into account the xenograft mo dels are quite accurate predictors of clinical response. Moreover, app lication of the principles derived from preclinical models to the desi gn of clinical trials may significantly enchance clinical response rat es. Thus, the camptothecin analogs provide a paradigm for better integ rated, pharmacokinetically driven, preclinical and clinical developmen t of new drugs.