Topoisomerases induce transient protein linked DNA breaks which modulate the structure of DNA. Topoisomerase I (topo I) induces single strand DNA breaks that allow for conformational changes required during chromatic organization, mitosis, replication, and transcription. Topo I levels remain constant throughout the cell cycle. However, topoisomerase levels differ between normal and neoplastic tissues. In human lymphoma specimens, the concentrations of topo I have been found to be 5-15 fold higher than in normal tissues. This suggests that there may be a therapeutic window to exploit using Topo I inhibitors. The cytotoxicity of campothecins (and the analogue 9-AC) (Topo I inhibitors) is highly correlated with the ability to form DNA-protein adducts. Drug binding is reversible, and cytotoxicity cell cycle dependent. Drug resistance may be mediated through alterations in drug accumulation, altered cell cycle duration, or changes in the target enzyme. Pre-clinical data suggests that prolonged maintenance of drug levels above a threshold is beneficial, and that continuous infusion schedules may be preferable to bolus administration. Neoplasms such as mycosis fungoides with slow growth rates similarly may be best treated by continuous infusions of agents. Toxicity in phase I studies was primarily myelosuppression when a 72 hour infusion schedule was utilized. This could be ameliorated by growth factor support.
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