to summaries list
The Role of Glutathione
Antioxidants in the Therapy of Chemoradiotherapy Induced Mucositis
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
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
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.
to summaries list