Nitric oxide as a radiosensitizer:: Evidence for an intrinsic role in addition to its effect on oxygen delivery and consumption

Different nitric oxide (NO)-mediated treatments (e.g., isosorbide dinitrate, insulin and electrical stimulation of the host tissue) have been investigated for their effects on tumor oxygenation and radiation sensitivity. We further address the issue of the role played by modulation of the NO-pathway in tumor radiosensitivity. For this purpose, the local concentration of NO was monitored after treatment in FSall tumors and a comparison between the sensitivity of LLC tumors implanted both on eNOS(-/-) and wild-type (WT) mice was carried out. First, we demonstrate the central role played by eNOS in the radiosensitizing effect after application of insulin treatment and electrical stimulation: a significant increase in tumor NO content is induced by these treatments and the increase in tumor oxygenation, as well as the radiosensitizing effect are abolished in eNOS knock-out mice, in contrast to WT mice. Second, by comparing the level of oxygen and NO achieved in tumors after NO-mediated treatments and carbogen, we provide evidence that these NO-mediated treatments are not simply acting by a single oxygen effect. These treatments induced significant regrowth delays compared to carbogen, despite a smaller increase in tumor oxygenation. For the NO-mediated treatments, there was a direct correlation between the NO content and the radiosensitizing effect. These data strongly suggest that NO is a complementary factor additive to oxygen in determining the sensitivity to irradiation and we therefore propose that NO acts as an intrinsic radiosensitizer in vivo. (C) 2004 Wiley-Liss, Inc.