DNA topoisomerase I (TOP-I) is a ubiquitous nuclear enzyme, which plays a key 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 programs. Irinotecan is enzymatically converted by carboxylesterase to its most active cytotoxic metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38), which is inactivated by hepatic biotransformation in a sequential metabolism. SN-38 establishes an equilibrium between the pharmacologically active closed lactone ring and the inactive hydroxy acid form by reversible pH-dependent hydrolysis. SN-38 exerts its cytotoxic mechanism by generating intermediate 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 TOP-I gene. Based on promising preclinical data on synergistic cytotoxic drug interactions, a variety of irinotecan-based combinations are currently under 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.

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