Phosphorothioate DNTP Radioprotector Medical Countermeasures

Nanohmics proposes to incorporate phosphorothioate antioxidants into the backbones of stem cell DNA by polymerase-driven synthesis using alpha-thiol deoxynucleotide triphosphates (S-dNTPs) so that free radical attacks will be minimized by the intrinsic antioxidant nature of the modified DNA backbones to prevent DNA cleavage. The approach mimics the binding of the protective antioxidant WR-2721 (amifostine), but unlike WR-2721, the covalently incorporated thiol-dNTPs cannot diffuse away, because they are part of the DNA backbone until diluted out in nascent DNA over several cell cycles when the S-dNTP dose is terminated. In Phase I, Nanohmics will investigate the ability of HL-60 cells to incorporate S-dNTPs during S phase and assess any impacts on viability, proliferation, differentiation induction, and potential mutations or apoptosis. If the S-dNTPs incorporate and are well tolerated, the treated HL-60 and other cell lines (HMECs and MM6) will be exposed to various doses of H2O2 to emulate radiation-induced free radical attacks at Nanohmics. Finally all three cell types will be S-dNTP-treated with various doses of S-dNTPs and exposed to LD70/30 ionizing X-ray radiation at the University of Texas Health Sciences Center in San Antonio to determine if a protective effect significantly greater than that of WR-2721 is produced.