Radiosensitization by High Affinity Programmable Minor Groove Binders

Non-genotoxic small molecules of low systemic toxicity that can potentiate the effects of radiation could be valuable adjuvant therapeutics for solid tumors. Pyrrole-imidazole (Py-Im) polyamides are synthetic oligomers that bind the minor groove of DNA non-covalently with programmable sequence recognition and high affinity. We reported that a polyamide targeted to the DNA sequence 5'-WGWWCW-3' (W = A/T) suppressed growth of prostate tumor xenografts. In cell culture, this polyamide interferes with RNA Polymerase II activity and results in a dose-dependent depletion of the RNA Polymerase II large subunit. We hypothesized that high-affinity DNA binding Py-Im polyamides may enhance the effects of ionizing radiation.