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

Abstract

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 FSaII 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. © 2004 Wiley-Liss, Inc. Key words: tumor; radiation sensitivity; eNOS Ϫ/Ϫ ; nitric oxide; oxygenTumor oxygenation and blood flow are of fundamental importance to many forms of cancer therapy. The partial pressure of oxygen (pO 2 ) plays an important role in the response of tumors to cytotoxic treatments such as chemotherapy, radiotherapy and photodynamic therapy. Both oxygen diffusion and oxygen consumption by tumor cell metabolism contribute to the occurrence of hypoxia. Oxygen deficiency is caused by an insufficient oxygen supply as a result of inadequate tumor perfusion (diffusion limited hypoxia) and fluctuations in red cell flux (acute hypoxia). 1 A promising approach in cancer therapy consists of the manipulation of tumor blood oxygen delivery and oxygen consumption to improve either radio-or chemotherapeutic response. Vasoactive agents, 2 modifiers of tumor cell oxygen consumption 3 or carbogen breathing 4 that is already being tested in Phase III clinical studies, are currently being evaluated for their potential therapeutic interest.We documented recently that nitric oxide (NO)-dependent modifiers of tumor hemodynamics were able to radiosensitize experimental tumors in vivo. Three strategies were considered for that purpose: (i) administration of a NO donor (isosorbide dinitrate), 5,6 (ii) slow infusion of insulin, 7 and (iii) electrical stimulation of the host tissue. 8 The first treatment acted by a direct release of exogenous NO whereas the others were actua...

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

“…68 Strong support for the involvement of a nitric oxide pathway came from experiments carried out using eNOS À/À mice. 228 The increase in tumor oxygenation, as well the radiosensitizing effect, was abolished when using eNOS knock-out mice compared with wild type mice. Moreover, by a complete analysis of all nitric oxidemediated treatments, it appeared that it was unlikely that oxygen alone was responsible for the radiosensitizing effect in specific conditions.…”

“…Moreover, by a complete analysis of all nitric oxidemediated treatments, it appeared that it was unlikely that oxygen alone was responsible for the radiosensitizing effect in specific conditions. 228 Using spin trapping studies that allowed the quantification of the release of nitric oxide in tumors, we showed that nitric oxide possesses an intrinsic radiosensitizing effect, additive to the effect on oxygen delivery and consumption. 228 There are only a few examples so far that have used in vivo EPR oximetry in which the applied treatment leads to a reduction in tumor pO 2 .…”

“…228 Using spin trapping studies that allowed the quantification of the release of nitric oxide in tumors, we showed that nitric oxide possesses an intrinsic radiosensitizing effect, additive to the effect on oxygen delivery and consumption. 228 There are only a few examples so far that have used in vivo EPR oximetry in which the applied treatment leads to a reduction in tumor pO 2 . Sersa et al described the decrease of tumor oxygenation and blood flow after treatment with vinblastin 229 and after electrochemotherapy with cisplatin.…”

Bystander signaling between glioma cells and fibroblasts targeted with counted particles

“…52,53 On the other hand, it has been reported that NO can act as an intrinsic radiosensitizer in vivo. 54 Mechanistic control of the bystander effect could either reduce radiation damage and potential carcinogenesis in normal tissues by reducing bystander signaling or maximize cell sterilization during radiotherapy by amplifying bystander responses in tumors.…”

A novel chenodeoxycholic derivative HS-1200 enhances radiation-induced apoptosis in MCF-7 cells

“…Furthermore, nitric oxide has been proposed as an intrinsic radiosensitizer in vivo. (27). It has been reported that the adenoviral gene transfer of the iNOS gene enhances the radiation response of human colorectal cancer associated with alterations in tumor vascularity (28).…”