Gimatecan.: DNA-intercalating drug, DNA topoisomerase I inhibitor, Oncolytic

Topoisomerase I is recognized as an important anticancer target and dramatic antitumor activity has been observed with camptothecin, which inhibits the enzyme by stabilizing the topoisomerase I-DNA complex, thereby inducing DNA breakage by preventing DNA religation. Camptothecin was unfortunately unsuccessful in clinical trials due to unpredictable pharmacological activity and severe adverse events. Researchers have focused on modifying camptothecin to synthesize agents with improved pharmacological and toxicological profiles. Gimatecan (ST-1481, LBQ-707) was identified from a series of lipophilic 7-oxyiminomethyl-substituted derivatives and is a particularly promising camptothecin analogue. The lipophilicity of the agent allows for oral administration and increased cellular accumulation, and it exerts potent activity against tumor cell growth in preclinical models. The antitumor efficacy and safety of gimatecan have also been demonstrated clinically in phase I and II trials in patients with advanced cancer.