Camptothecins and Topoisomerase I; A Foot in the Door. Targeting the Genome Beyond Topoisomerase I with Camptothecins and Novel Anticancer Drugs; Importance of DNA Replication, Repair and Cell Cycle Checkpoints
Affiliation: Bldg. 37, Room 5068, NIH, Bethesda, MD 20892-4255, USA.
Camptothecins selectively target topoisomerase I (Top1) by trapping the catalytic intermediate of the Top1- DNA reaction, the cleavage complex. Hence, camptothecins represent a paradigm for targeting macromolecular interactions. Instead of preventing the binding of the two macromolecules they target (Top1 and DNA), camptothecins slow down the dissociation of these macromolecules. The activity of camptothecins underlines the usefulness of screening for drugs that inhibit the dissociation of macromolecules. Camptothecins and non-CPT Top1 inhibitors are being developed to improve the pharmacodynamics, pharmacokinetics and clinical pharmacology of camptothecins, and it is likely that drugs with improved anticancer activity will be discovered. Although Top1 is the only primary target of camptothecins, the mechanisms of camptothecins anticancer activity rest beyond the formation of cleavage complexes. Indeed, Top1 cleavage complexes lead to replication- (and transcription-) mediated DNA damage. It is likely that DNA damage can be repaired more efficiently in normal than in cancer cells that are intrinsically deficient for DNA repair and cell cycle checkpoints. Evaluating such deficiencies in clinical samples is becoming possible. If specific deficiencies are associated with clinical responses, their detection should guide therapeutic decisions. Furthermore, targeting DNA repair (Tdp1) and checkpoints (ATM, Chk1 and Chk2) might increase the selectivity of Top1 inhibitors for tumors, thereby increasing the antitumor activity while reducing the side effects of Top1 inhibitors.