Radiosensitization by Nitric Oxide at Low Radiation Doses

Wardman, P., Rothkamm, K., Folkes, L. K., Woodcock, M. and Johnston, P. J. Radiosensitization by Nitric Oxide at Low Radiation Doses. Radiat. Res. 167, 475–484 (2007). Nitric oxide was shown to radiosensitize anoxic V79 and CHO hamster cells and MCF7 and UT-SCC-14 human cells, measuring clonogenic survival and/or DNA damage in vitro at low radiation doses (0.1–5 Gy). Radiosensitization was easily detected after 2 Gy in anoxic V79 cells exposed to 40 ppm (∼70 nM) nitric oxide, indicating that nitric oxide is a significantly more efficient radiosensitizer than oxygen. The yield of double-strand breaks (as γ-H2AX foci) in V79 and MCF7 cells was doubled by irradiation in 1% v/v nitric oxide/N2, and there was a longer repair time in cells irradiated in nitric oxide than in air or anoxia; single-strand breaks (“comet” assay) also appeared to be enhanced. Potent radiosensitization by nitric oxide is consistent with near diffusion-controlled reaction of nitric oxide with purine and pyrimidine radicals observed by pulse radiolysis, with nitric oxide reacting two to three times faster than oxygen with the 5-hydroxy-uracil-6-yl radical. Stable NO/base adducts were formed with uracil radicals. Effects on the radiosensitivity of cells exposed to as low as 40 ppm v/v nitric oxide after doses of 1–2 Gy suggest that variations in radiosensitivity in individual patients after radiotherapy might include a component reflecting differing levels of nitric oxide in tumors.