Kinetics of Tempol for Prevention of Xerostomia Following Head and Neck Irradiation in a Mouse Model

Abstract

Purpose: Radiotherapy is commonly used to treat the majority of patients with head and neck cancers. Salivary glands in the radiation field are dramatically affected by this procedure. The purpose of this study was to examine pharmacokinetic characteristics of the stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) with respect to radioprotection of the salivary glands. Experimental Design:To evaluate the effect of different doses and times of administration, the heads of C3H mice were exposed to a single irradiation dose of 15 Gy, with i.p. tempol injection. To analyze other routes of administration, we injected 275 mg/kg tempol by an i.m., i.v., or s.c. route, 10 minutes before irradiation. We also tested whether oral administration of tempol in a topical form (either in a mouthwash or gel) provided any salivary gland protection. Results:Tempol treatment (137.5 or 275 mg/kg, i.p., 10 minutes before irradiation) significantly reduced irradiation-induced salivary hypofunction (f50-60%). I.v. or s.c. administration of tempol also showed significant radioprotection, whereas i.m. administration proved to be ineffective. Topical use of tempol, either as a mouthwash or gel, also was radioprotective. Conclusions: Our results strongly suggest that tempol is a promising candidate for clinical application to protect salivary glands in patients undergoing radiotherapy for head and neck cancers.

Adenoviral delivery of Tousled kinase for the protection of salivary glands against ionizing radiation damage

“…Salivary function was evaluated 8 weeks after radiation, a time period at which a true decline in radiation-dependent salivary flow occurs. 37,38 Similar to previous results, 37,38 an exposure to single dose of 16 Gy radiation precipitated a 67% drop in salivary flow in control animals. Alternatively, pretreatment with TLK1B successfully mitigated the effects of radiation on saliva production.…”

Differential Radiation Protection of Salivary Glands versus Tumor by Tempol with Accompanying Tissue Assessment of Tempol by Magnetic Resonance Imaging

“…To determine salivary flow rate, saliva samples were collected 8 weeks after ionizing radiation (12). Mice were weighed and mild anesthesia was induced with a solution of ketamine (100 mg/mL; Fort Dodge Animal Health, Fort Dodge, IA) and xylazine (20 mg/mL; Phoenix) in sterile water, given i.p.…”

“…and s.c. administration of Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), a stable nitroxide, protected single-dose radiation-induced damage to murine salivary glands (11,12). Our preclinical studies to date have used a single radiation dose.…”

The chemistry and biology of nitroxide compounds

“…The radiation dose dependent decrease in saliva production in the untreated cohort, was significantly ameliorated in the Tempol treated group. The effect of different administration routes on the observed pharmacokinetics of Tempol was tested by administering the agent via several routes and evaluating development of xerostomia [36]. The efficacy of intraperitoneal injection of Tempol was compared to administration by intramuscular, intravenous or subcutaneous injection and topical administration using a gel and mouthwash in C3H mice.…”