Identification of mode of action of camptothecin
Preliminary works of Moore BG, Kessel D, Bosmann HB, Horwitz, SB and others have established that the synthesis of macromolecules such as RNA, DNA and protein are inhibited by camptothecin in tumor or dividing mammalian cells. The inhibition over DNA synthesis was transient when the drug is removed. But prolonged incubation could lead to irreversible suppression of DNA synthesis. Also camptothecin was not able to bind with isolated DNA when incubate them together. But, when intact cells were incubated with camptothecin for a short term, it induced rapid but reversible fragmentation of cellular DNA. The longer the incubation, more the damage of DNA that leads to cell death. However camptothecin was found to be ineffective to block the effects of purified RNA and DNA polymerases. Later studies by Hsiang confirmed topoisomerase, not topoisomerase, is the molecular target of camptothecin.