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The Role of Glutathione Antioxidants in the Therapy of Chemoradiotherapy Induced Mucositis (Stomatitis)

Theodore Hersh, MD, MACG
Professor of Medicine, Emeritus,
Emory University School of Medicine

Glutathione, the body’s key antioxidant, is composed of three amino acids, glycine, cysteine, and glutamine as the glutamate. Chemoradiotherapy generates countless reactive oxygen and other free radical species, which requires the endogenous antioxidants, led by glutathione, to scavenge and neutralize these injurious free radicals. Inflammation with the innumerable white blood cell infiltration causes further free radical reaction through the mechanism called respiratory burst reaction. These cells also release enzymes like elastase that destroy connective tissues and blood vessels. Thus it is important to support the endogenous cellular antioxidants by enhancing the body’s antioxidant stores and by topically applying glutathione and its synergistic antioxidant partners to the affected areas of the body, notably, the skin from radiotherapy and the lining mucosa, such as in the mouth and throat, from chemotherapy.

Because radio and chemotherapy are associated with significant toxicities, a search for chemoprotective agents is vital but one which should not interfere with the intended use of chemoradiotherapy for malignancy. Thiol antioxidants, particularly glutathione, by neutralizing free radical species, are targeted chemoprotectants. Glutathione and the aminothiol prodrug, WR-2721 are being studied with preliminary results showing protection from developing mucositis and other organ toxicities, including reduction in cisplatin induced nephrotoxicity. Administration of glutathione in these cases had no side effects, yet its chemoprotecting activity requires further elucidation.

The role of plasma glutathione (GSH) levels on acute radiation mucositis during therapeutic irradiation was evaluated in 13 patients with squamous cell carcinoma of the oral cavity. The results indicate that those patients who developed severe changes of mucositis in the mouth had the lowest levels pre-therapy of GSH. The investigators postulate that plasma GSH may be a predictor of an individual’s sensitivity to acute radiation mucositis. This protective effect of GSH may be related to its ability of scavenging free radicals in the mouth induced by radiotherapy.

Since one of the dose limiting adverse effects of chemoradiotherapy is oral mucositis, Osaki and co-workers in Japan studied the value of antioxidants as prophylaxis for this location of mucositis (stomatitis). They studied a regimen of oral administration of vitamins C and E, glutathione, and the drug Azelastine which has antioxidant properties. The study was done in 53 patients with oral cancer undergoing chemoradiotherapy. Thirty-seven received the full regimen and 26 the same regimen minus the drug. Azelastine was independently shown to suppress the free radical production from neutrophil respiratory burst reaction and suppressed cytokine release from lymphocytes. The investigators evaluated the degree of stomatitis at the end of treatment period by grading the stomatitis:

Grade I: Redness of the oral mucosa
Grade II: Erosions with mild irritation
Grade III: Ulcerations with contact pain
Grade IV: Ulcerations with pain and dysphagia (difficulty swallowing)

Their conclusion was that an oral regimen of antioxidants which includes Azelastine, all of which suppress reactive oxygen/free radical production, is useful in the prophylaxis of mucositis due to chemoradiotherapy.

Glutathione, the body’s main antioxidant, protects cells from free radical damage caused by irradiation. Navarro and co-workers studied blood glutathione as an index of radiation induced oxidative stress in mice and humans.4 They found that blood reduced glutathione was decreased after irradiation while the oxidized form (the disulfide GSSG) increased. The latter indicated that glutathione is neutralizing the free radicals and thus being oxidized in this reaction. This reaction may even be more exaggerated in tissues like skin which is receiving irradiation administered for a deep lesion and augurs well for localized glutathione repletion topically to affected skin. Likewise, glutathione levels in the oral cavity may be reduced not only by the radiotherapy for head and neck and oral cancers but also from the marked inflammatory reaction which occurs in mucositis. Herein lies the value of topical (intra-oral spray, suckable antioxidant tablets) glutathione and its synergistic antioxidant partners. Finally, these investigators suggest using the ratio of reduced to oxidized glutathione (GSH/GSSG) as an overall index of oxidative stress to the body frame irradiation.

Glutamine, as one of the three amino acid precursors of glutathione and for its other biochemical properties, has been used topically to help heal lesions of mucositis, particularly in the oral cavity. Although oral administration of glutamine has not been found to be of benefit in some patients on 5-FU or after the chemoradiotherapy for bone marrow transplantation, others have found “swish and swallow” glutamine suspensions to help ameliorate the signs and symptoms of stomatitis. Glutamine, in these cases, may act by enhancing cellular glutathione synthesis. In one controlled double blind, cross-over study, Anderson and co-workers treated 24 cancer patients with either glutamine or glycine as the placebo. They reported significant amelioration of oral pain and trouble swallowing in those on the glutamine suspension. These findings confirmed their earlier reported study where glutamine was used as a nutritional supplement.

In summary, topical antioxidants reportedly are of benefit in helping prevent and in ameliorating the symptoms in the mouth (stomatitis) resulting from chemoradiotherapy. Glutathione with its synergistic partners, selenium and vitamins C and E, plus its amino acid precursor and a known thiol antioxidant, L-cysteine, both enhance the body’s endogenous antioxidants and provide further defenses to scavenge and neutralize these toxic free radicals. The results not only confer symptomatic improvement in these ill patients but also permit the uninterrupted course of therapy by diminishing the toxicity of chemoradiotherapy.

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