Previous studies have shown that the DNA repair component Metnase (SETMAR) 
mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease 
domain that shares homology with the Transposase family. We therefore virtually 
screened the tertiary Metnase structure against the 550,000 compound ChemDiv 
library to identify small molecules that might dock in the active site of the 
transposase nuclease domain of Metnase. We identified eight compounds as 
possible Metnase inhibitors. Interestingly, among these candidate inhibitors 
were quinolone antibiotics and HIV integrase inhibitors, which share common 
structural features. Previous reports have described possible activity of 
quinolones as antineoplastic agents. Therefore, we chose the quinolone 
ciprofloxacin for further study, based on its wide clinical availability and low 
toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave 
DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not 
induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. 
Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft 
tumor model to clinically relevant chemotherapy. These studies provide a 
mechanism for the previously postulated antineoplastic activity of quinolones, 
and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer 
chemotherapy.