Camptothecin, a plant alkaloid isolated from Camptotheca acuminata, was identified in the late 1950's. Due to severe and unpredictable toxic side effects in early clinical studies, the clinical development of this drug was halted in the 1970's. In the early 1980's several important events occurred that resulted in renewed interest in this agent. The molecular target of camptothecin, the nuclear enzyme topoisomerase I, was identified. This topoisomerase I was described as an enzyme involved in transient scission and relegation of DNA during the replication and transcription phases. Binding of carnptothecin to the topoisomerase I-DNA complex (cleavable complex) and interference with the relegation step of this process was recognized as the primary mechanism of action of camptothecin, finally leading to a double stranded DNA break and, ultimately, cell death. At the same time, it was shown that the failures encountered in the clinical development of camptothecin were related, at least partially, to the drug's poor water solubility, which necessitated pharmaceutical formulation in alkaline solutions for i.v. administration. This not only led to chemical modification of the original structure into an entity lacking antitumor activity, but also induced profound alterations in the toxicological behavior of the agent. These two key fmdings then boosted drug-research efforts aimed at identifYing and developing new analogues with improved water solubility while maintaining the unique mechanism of action.

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J. Verweij (Jaap)
Erasmus University Rotterdam
Gilead Science Inc., Amgen, Astra-Zencca, Aventis, Bristol Meijers Squibb. Glaxo Wellcome, Novartis, Ortho Biotech, Pierre Fabre, Roche
Erasmus MC: University Medical Center Rotterdam

Kehrer, D.F.S. (2001, November 16). Pharmacologic Modulation of Topoisomerase I Inhibitors. Erasmus University Rotterdam. Retrieved from