Role of nitric oxide radicals in cancer therapy with heavy ion-beams

The purpose of this study was to investigate whether the bystander effect mediated nitric oxide (NO) radicals excreted from the tumor irradiated with accelerated carbon ion beams modulates growth of the unirradiated tumor at an opposite side in the same mouse. Also, to investigate whether NO generating agents can sensitize the tumoricidal effect by accelerated carbon ion beams. Human non-small cell lung carcinoma (H1299) with identical genotype except for p53 status was used as an in vivo model for cancer radiotherapy. Tumor growth delay assay were performed in mice bearing tumors after irradiation with accelerated carbon ion beams (7.5 Gy, 290 MeV/u, 70 KeV/μm, 6 cm-spread-out Bragg peak (SOBP)) or X-rays (10 Gy, 150 KVp). An NO generating agent, isosorbide dinitrate (ISDN) was administered at 0.3 mM to tumors just before irradiation and 2 days after irradiation. A significant inhibition of H1299 tumor growth was observed by irradiation with accelerated carbon ion beams at 7.5 Gy. At the same time, a significant inhibition of tumor growth was observed in the unirradiated wild-type p53 (wtp53) tumor at an opposite thigh, when the mutant p53 (mp53) tumor was irradiated with accelerated carbon ion beams as is in the case of SAS tumors. This inhibition of tumor growth in the unirradiated tumor was abolished by administration of NO-specific scavenger, c-PTIO, prior to irradiation. On the other hand, a significant stimulation of tumor growth was observed in the unirradiated mp53 tumor at an opposite thigh, when the wtp53 tumor was irradiated with accelerated carbon ion beams as is in the case of SAS tumors. This stimulation of tumor growth in the unirradiated tumor was suppressed by administration of c-PTIO prior to irradiation. In addition, the sensitization of the tumoricidal effect by X-rays by ISDN was observed, which was independent on the p53 status. NO at the relatively low concentrations, which excreted from the irradiated donor tumors with accelerated carbon ion beams induced both inhibition and stimulation of tumor regrowth. These findings indicate the importance of an intercellular signal transduction pathway initiated by NO in cellular response to radiation. On the other hand, NO at the relatively high concentrations (0.3 mM) sensitized the tumoricidal effect of X-rays in the p53-independent manner. (author)