Preclinical evaluation of irinotecan

DNA topoisomerase I (TOP-I) is a ubiquitous nuclear enzyme, which plays a k ey role in cellular processes like DNA replication and transcription. With the realization that TOP-I is an important target in cancer therapy, TOP-I interactive agents entered intensive preclinical and clinical evaluation pr ograms. Irinotecan is enzymatically converted by carboxylesterase to its mo st active cytotoxic metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38), whi ch is inactivated by hepatic biotransformation in a sequential metabolism. SN-38 establishes an equilibrium between the pharmacologically active close d lactone ring and the inactive hydroxy acid form by reversible pH-dependen t hydrolysis. SN-38 exerts its cytotoxic mechanism by generating intermedia te forms of drug-stabilized covalent DNA/TOP-I complexes, which may lead by collision with the moving replication complexes to arrest and disassembly of the replication machinery. In preclinical models, acquired resistance to camptothecin derivatives has been mainly related to down-regulation of TOP -I expression as well as to alterations in structure and function of the TO P-I gene. Based on promising preclinical data on synergistic cytotoxic drug interactions, a variety of irinotecan-based combinations are currently und er clinical evaluation (e.g., cisplatin, oxaliplatin, raltitrexed, taxanes) . The task of future investigations will be to identify molecular markers, which are predictive for tumor response to irinotecan-based chemotherapy.