Camptothecins

Camptothecins act through DNA topoisomerase I (Top1), an enzyme essential for DNA replication and transcription^[1][2]. Mechanistically, camptothecin, topotecan, and irinotecan stabilize Top1-DNA cleavable complexes, block DNA resealing, and generate replication-associated DNA double-strand breaks^[3][4]. This Top1-focused mechanism distinguishes camptothecins from Top2 inhibitors, which can induce DNA damage in both replicating and non-replicating cells^[3]. In intact cells, topotecan-induced Top1-DNA covalent complexes can be detected by immunoblotting, immunofluorescence, or flow cytometry, supporting mechanism-based pharmacodynamic analysis^[5]. In cancer models, ATR inhibition sensitizes cells to camptothecin-class Top1 inhibitors by disabling DNA replication initiation and fork elongation responses^[6]. Camptothecin derivatives also poison Leishmania DNA topoisomerase IB and reduce parasitic burden in infected splenocytes^[7]. For colorectal cancer research, SN-38 suppresses Nrf2 transcriptional activity and can enhance sensitivity to Nrf2-sensitive anticancer drugs^[8].