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- W2102751818 abstract "textabstractCamptothecin, a plant alkaloid isolated from Camptotheca acuminata, was identified inthe late 1950's. Due to severe and unpredictable toxic side effects in early clinical studies, theclinical development of this drug was halted in the 1970's. In the early 1980's severalimportant events occurred that resulted in renewed interest in this agent. The molecular targetof camptothecin, the nuclear enzyme topoisomerase I, was identified. This topoisomerase Iwas described as an enzyme involved in transient scission and relegation of DNA during thereplication and transcription phases. Binding of carnptothecin to the topoisomerase I-DNAcomplex (cleavable complex) and interference with the relegation step of this process wasrecognized as the primary mechanism of action of camptothecin, finally leading to a doublestranded DNA break and, ultimately, cell death. At the same time, it was shown that thefailures encountered in the clinical development of camptothecin were related, at leastpartially, to the drug's poor water solubility, which necessitated pharmaceutical formulationin alkaline solutions for i.v. administration. This not only led to chemical modification of theoriginal structure into an entity lacking antitumor activity, but also induced profoundalterations in the toxicological behavior of the agent.These two key fmdings then boosted drug-research efforts aimed at identifYing anddeveloping new analogues with improved water solubility while maintaining the uniquemechanism of action." @default.
- W2102751818 created "2016-06-24" @default.
- W2102751818 creator A5031452664 @default.
- W2102751818 date "2001-11-16" @default.
- W2102751818 modified "2023-09-26" @default.
- W2102751818 title "Pharmacologic Modulation of Topoisomerase I Inhibitors" @default.
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