Radioprotectors and mitigators of radiation-induced normal tissue injury

Abstract

Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissue to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in quality of life. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. Herein, we review agents in clinical use or in development as radioprotectors and mitigators of radiation-induced normal tissue injury. Few agents are approved for clinical use, but many new compounds show promising results in preclinical testing.

Figure 1.

Sequence of events following radiation exposure. The chart is divided into three parts by dashed lines suggesting events and reactions that might be modified by radiation protectors (top), radiation mitigators, and treatment (bottom).

Figure 2.

Schematic diagram of nitroxide radical conversion to hydroxylamine and chemical properties associated with both forms. Abbreviations: MRI, magnetic resonance imaging; SOD, superoxide dismutase.

Figure 3.

Mice were exposed to local fractionated radiation treatment to the salivary glands (A) or tumor-bearing leg (B) with and without systemic tempol (TP) administration (275 mg/kg given 10 minutes prior to each radiation fraction). Note that the same TP dose and timing were used in each study. (A): Saliva production 2 months postradiation for mice exposed to 5 daily fractions of 6 Gy. In addition to systemic delivery of TP, mice were also treated topically for 20 minutes prior to radiation with a TP gel formulation. (B): Radiation tumor (SCCVII) regrowth study for local fractionated radiation treatment with and without systemic TP administration. Tumors received 5 daily fractions (Monday to Friday) of 3 Gy. Adapted from Cotrim AP, Hyodo F, Matsumoto K et al. Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue assessment of Tempol by magnetic resonance imaging. Clin Cancer Res 2007;13:4928–4933, with permission.

Figure 4.

T₁-weighted MRI images using tempol. (A): Schematic diagram of the placement of a tumor-bearing mouse in a resonator and the MRI slice selected that includes normal muscle tissue, the salivary gland region, and the tumor in the contralateral leg. (B): T₂-weighted MR image of the selected slice before injecting tempol to ensure that the target tissues were in the field of view. (C): T₁-weighted images of the selected slice before injection of tempol and as a function of time after i.v. tempol injection. (D): Tempol reduction rates for the selected regions of interest shown in (B). Abbreviations: MRI, magnetic resonance imaging; SCC, squamous cell carcinoma. Adapted from Cotrim AP, Hyodo F, Matsumoto K et al. Differential radiation protection of salivary glands versus tumor by Tempol with accompanying tissue assessment of Tempol by magnetic resonance imaging. Clin Cancer Res 2007;13:4928–4933, with permission.