The Stable Nitroxide Tempol Facilitates Salivary Gland Protection during Head and Neck Irradiation in a Mouse Model

Vitolo, Joseph M.; Cotrim, Ana P.; Sowers, Anastasia L.; Russo, Angelo; Wellner, Robert B.; Pillemer, Stanley R.; Mitchell, James B.; Baum, Bruce J.

doi:10.1158/1078-0432.ccr-03-0194

Cited by 75 publications

(61 citation statements)

References 44 publications

(54 reference statements)

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“…This represents an average reduction in salivary flow of 58%. In our previous study (12), we found a similar reduction in salivary output after 15 Gy.…”

Section: Resultssupporting

confidence: 77%

“…Single irradiation doses at 15 Gy were delivered to only the animal's head by a Therapax DXT300 X-ray irradiator (Pantak, Inc., East Haven, CT) using 2.0-mm Al filtration (300 kVp) at a dose rate of 1.9 Gy/min. This irradiation dose leads to significant (60%) loss of salivary flow (12). Immediately after irradiation, animals were removed from the Lucite jig and housed (five animals per cage) in a climate and light-controlled environment and allowed free access to food and water.…”

Section: Methodsmentioning

confidence: 99%

“…To determine salivary flow rate, saliva samples were collected 8 weeks after irradiation (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, St. Joseph, MO) in sterile water, given i.p.…”

Section: Methodsmentioning

confidence: 99%

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

Cotrim¹,

Sowers

Lodde³

et al. 2005

Clinical Cancer Research

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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.

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“…This represents an average reduction in salivary flow of 58%. In our previous study (12), we found a similar reduction in salivary output after 15 Gy.…”

Section: Resultssupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

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

Cotrim¹,

Sowers

Lodde³

et al. 2005

Clinical Cancer Research

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“…One such consequence of radiotherapy is the occurrence of xerostomia, decreased saliva production, in the treated area which can result in dental caries, infection, dysphagia and significant discomfort. Since the radioprotective effects of nitroxides appear to be selective for normal tissues, the ability of Tempol to prevent damage to the salivary glands from irradiation was studied [35]. Pilocarpine-induced salivary gland output eight weeks after a single dose of radiation was compared between C3H mice treated with Tempol and controls.…”

Section: Radioprotectionmentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

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Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

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“…Tempol treatment alone significantly reduced radiation-induced salivary hypofunction in a mouse model [67].…”

Section: Therapy For Childhood Thyroid Cancermentioning

confidence: 94%

Childhood Thyroid Cancers and Radioactive Iodine Therapy: Necessity of Precautious Radiation Health Risk Management

et al. 2007

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Abstract. One of the lessons from Chernobyl's legacy on health impact beyond 20 years is not only how to detect and treat the patients with radiation-associated thyroid cancers but how to follow up those who received radioactive iodine treatment repetitively after surgery in order to monitor any recurrence/worsening and also how to predict the risk of secondary primary cancers for their lifetime period. To evaluate the possibility of second primary tumors after radioactive iodine treatment, we reviewed the reports on risks from both external and internal radiation exposure, especially at high doses during childhood through an internet service of the National Library of Medicine and the National Institutes of Health, PubMed by the end of June, 2007, together with our own experience of Chernobyl childhood thyroid cancers. Children who were internally exposed after Chernobyl accident have a long-term risk of well differentiated thyroid cancers. Once they have disease, ironically radioactive iodine ablation is one of the useful therapies after surgical treatment. Elevated risks of solid cancers and leukemia have been found in radioiodine-treated patients, however, so far precious few reports from Chernobyl thyroid cancer patient were published. To reduce the adverse effects of radioactive iodine therapy on non-target tissues, recombinant human TSH has been applied and proved effective. Period of latency of second primary cancers may be very long. Therefore patients treated with high activities of radioactive iodine, especially children cases, should be carefully followed up during their whole lifespan.

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The Stable Nitroxide Tempol Facilitates Salivary Gland Protection during Head and Neck Irradiation in a Mouse Model

Cited by 75 publications

References 44 publications

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

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

The chemistry and biology of nitroxide compounds

Childhood Thyroid Cancers and Radioactive Iodine Therapy: Necessity of Precautious Radiation Health Risk Management

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