The term “DNA Repair” normally evokes consideration of DNA repair enzymes and their mechanisms of action. However non-enzymic chemical repair also plays a role in ameliorating the impact of a hostile environment on cellular DNA. This reality is reflected by the prominence of functional groups such as thiols and tyrosine in nuclear proteins.
We have developed a new class of radioprotecting drugs, with the view to their use as topical radioprotectors to selectively protect normal tissues “at risk” in cancer radiotherapy patients, for example oral and rectal mucosa. These agents can be described as DNA-binding antioxidants, which act by repairing transient radiation-induced lesions in DNA, by electron transfer from the DNA-bound ligand.
The lead drug of this series, methylproamine, shares the bibenzimidazole structural feature with the commercially-available fluorescent DNA dyes Hoechst 33342 and 33258. As well as protection against the radiation-induced decrease in clonogenic survival in vitro, the drugs also reduce the level of radiation-induced g-H2AX foci, consistent with the proposal that the mechanism of radioprotection involves attenuation of initial radiation-induced DNA damage.
The clinical potential of methylproamine is limited by its cytotoxicity, but an extensive lead optimisation program (> 100 new analogues) has identified several new analogues with reduced cytoxicity, without compromise of radioprotective activity. Topical formulations have been developed to optimise delivery of the drugs to mouse oral mucosa. The best of the new drug/formulation combinations have been shown to confer topical radioprotection of mouse oral mucosa. This radiobiological model involves irradiation of a small area (3mm x 3mm) of the ventral surface of mouse tongue with low energy (25keV) X-rays. Ulceration about 10 days post-irradiation is confined to the ventral surface, so feeding is not impeded.
We are now in the closing stages of selecting a final lead for clinical studies.