Radiation Nephropathy is not Mitigated by Antagonists of Oxidative Stress

Abstract

Persistent, chronic oxidative injury may play a mechanistic role in late radiation injury. Thus antioxidants may be useful as mitigators of radiation injury. The antioxidants deferiprone, genistein and apocynin were tested in a rat radiation nephropathy model that uses single-fraction total-body irradiation (TBI) followed by syngeneic bone marrow transplant. Deferiprone was added to the drinking water at 1.0 or 2.5 g/liter, starting 3 days after the TBI. Urinary bleomycin-detectable iron, which could enhance production of oxygen radicals, was reduced in the rats on deferiprone compared to untreated rats, but deferiprone did not mitigate radiation nephropathy. Genistein added to the chow at 750 mg/kg starting immediately after TBI did not mitigate radiation nephropathy. Apocynin added to the drinking water at 250 mg/liter immediately after TBI did not mitigate radiation nephropathy. Thus three different types of antioxidants, when used at doses consistent with an antioxidant effect, had no mitigation efficacy against radiation nephropathy.

Evaluation of Genomic Evidence for Oxidative Stress in Experimental Radiation Nephropathy

“…We also tested three anti-oxidant drugs as mitigators of radiation nephropathy in this model and found them ineffective [4]. Together with the present gene expression data, we conclude that there is no evidence for a role for chronic oxidative stress in radiation nephropathy.…”

“…Using an experimental radiation nephropathy model, we have not been able to confirm this hypothesis. Biochemical and histological markers of oxidative stress were absent after irradiation and anti-oxidants were ineffective in the mitigation of radiation nephropathy [2–4]. But it remained possible that the assays were not sensitive enough, and that the anti-oxidants chosen were not appropriate for the model.…”

Mitigation of normal tissue radiation injury: evidence from rat radiation nephropathy models

“…We found neither genomic nor biochemical nor histochemical evidence for chronic oxidative stress [17,41]. We also tested deferiprone, genistein, and apocynin, which all have anti-oxidant activity, but none of these were mitigators of radiation nephropathy [31]. Despite previous evidence for deficient nitric oxide production in radiation nephropathy, post-irradiation use of nitrite was deleterious ( Table 2).…”

Radioprotective Agents for Radiation Therapy: Future Trends

“…Calveley et al [14] also demonstrated that genistein treatment could provide partial mitigation of the effects of lung irradiation as evidenced by an improvement in breathing rate and a delay of lethality. In contrast, genistein did not show any antifibrotic effects when given as a mitigator for late radiation-induced renal toxicities [70]. Limitations to the use of genistein include its rapid elimination from the circulation and a narrow time window for administration.…”