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Department of Medicine, Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA 30322
3To whom correspondence should be addressed. E-mail: tzieg01{at}emory.edu
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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KEY WORDS: • glutamine • bone marrow transplantation • chemotherapy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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,
Saba et al. 2000
, Mogul 2000
). Patients
with leukemias or lymphomas now routinely receive high dose
chemotherapy ± total body irradiation (TBI) to eradicate
malignant cells, followed by BMT to support the ablated host
hematopoietic system. BMT is also being increasingly studied in
patients with testicular cancer and other solid tumors, multiple
myeloma, sickle cell disease, genetic disorders and even as adjunctive
treatment in solid organ transplantation (Slavin 2000
,
Saba et al. 2000
, Mogul 2000
). BMT may be
allogeneic, in which cells for transplant are derived from human
leukocyte antigen-matched donors, or autologous, in which cells for
transplant are obtained from the patient. Some centers obtain cells for
transplant directly from bone marrow biopsies, but the most commonly
used method is ex vivo mobilization of stem cells from peripheral blood
using growth factors, such as granulocyte/macrophage colony stimulating
factor (Slavin 2000
, Saba et al. 2000
,
Mogul 2000
). Colony stimulating factors are now
routinely used to increase neutrophil recovery in BMT regimens
(Slavin 2000
).
A feature of most BMT protocols for malignancy is administration of
very high doses of chemotherapy (usually including cyclophosphamide,
bulsulfan and epoposide) with or without TBI. These ablative regimens
commonly cause gastrointestinal complications, including nausea,
vomiting, inflammation of the oral and esophageal mucosa (mucositis),
abdominal pain and diarrhea (Blijlevens et al. 2000
).
Recently, nonmyeloablative stem cell allogeneic transplantation (NST)
has become a popular form of BMT (Slavin 2000
). In these
protocols, relatively low doses of chemotherapy and TBI are used in a
strategy of adoptive immunotherapy involving induction of
host-vs.-graft transplantation tolerance with infusion of donor T
lymphocytes. The low doses of cytotoxic therapy are associated with
much lower rates of infectious, gastrointestinal and other adverse
effects. NST will likely be increasingly used to treat nonmalignant
diseases in which replacement of host hematopoietic cells is indicated
(e.g., genetic and autoimmune disorders, induction of organ allograft
tolerance) (Slavin 2000
). However, in malignant disease,
the efficacy of NST remains to be defined and high dose cytotoxic
therapy remains the standard of care for BMT in such patients.
The adverse gastrointestinal effects with BMT regimens often markedly
decrease ad libitum oral food intake for up to several weeks
(Biron et al. 2000
, Blijlevens et al. 2000
, Ziegler et al. 1992
, Jonas et al. 2000
). High dose
chemotherapy and TBI also induce protein catabolism, disruption of the
gastrointestinal mucosa, marked immunosuppression and oxidative stress
(Blijlevens et al. 2000
, Ziegler et al. 1992
,
Jonas et al. 2000
, Szeluga et al. 1987
,
Durken et al. 1995
). Frequent infections and
graft-vs.-host disease may directly cause gut mucosal inflammation and
ulceration and, thus, interfere with spontaneous nutrient intake and/or
increase nutrient requirements and losses (Iqbal et al. 2000
). These observations provide the basis for the common
prescription of parenteral nutrition (PN) or oral nutrient supplements
in patients undergoing BMT. Unfortunately, the efficacy of nutrition
therapy to support BMT patients remains unclear (Blijlevens et al. 2000
, Ziegler et al. 1992
, Weisdorf et al. 1987
, Klein and Koretz 1994
), due in part to a
paucity of well-designed, randomized clinical trials in this field
and the rapid evolution of chemotherapy and growth factor regimens in
BMT. This latter fact has made controlled clinical trials of nutrition
support in BMT difficult to perform and often impractical in many
academic medical centers. Furthermore, clinical nutrition studies
performed several years ago may not be applicable to present BMT
treatment regimes. Thus, it is not surprising that policies for
administration of specialized nutrition vary widely among BMT centers
worldwide.
In a recent study, we found that use of conventional PN in patients
undergoing BMT for hematologic malignancies did not prevent a serial
decline in systemic antioxidant status [plasma glutathione (GSH) redox
capacity and 
-tocopherol concentrations] (Jonas et al. 2000
). In fact, patients receiving standard PN demonstrated
lower plasma GSH and -tocopherol levels than those receiving
intravenous micronutrients alone (Jonas et al. 2000
).
These and other data (Klein and Koretz 1994
) strongly
suggest that new strategies are needed to improve the efficacy of
conventional nutrition support in cancer patients undergoing BMT or
high dose chemotherapy for hematologic or solid tumors. Use of
glutamine-supplemented nutrition has received increasing attention
in basic, translational and clinical research (Souba 1993
, Ziegler et al. 1997
, 2000a
and 2000b
, Darmaun 2000
, Griffiths 1999
).
This review will summarize the available clinical literature on
adjunctive use of glutamine supplementation in patients undergoing BMT
and high dose chemotherapy.
|
Glutamine supplementation in animal models and clinical trials in noncancer patients |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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, Ziegler et al. 1997
) (Table 1
). Glutamine is a critical substrate in many key metabolic processes,
including interorgan nitrogen transfer, protein and nucleic acid
synthesis, gluconeogenesis and acid-base homeostasis. Glutamine is
also used as a major fuel and/or substrate by intestinal mucosal cells
and by lymphocytes and other immune cells (Souba 1993
,
Ziegler et al. 1997
).
|
). Glutamine-enriched nutrition attenuates depletion
of the key antioxidant GSH in plasma, liver and gut after chemotherapy,
sepsis, and gut ischemia/reperfusion and upregulates systemic and
tissue immune function in animals (Souba 1993
,
Ziegler et al. 1997
, 2000a
,
Darmaun 2000
).
Glutamine has become one of the most intensively studied nutrients in
clinical nutrition trials. At least 20 randomized, blinded, controlled
clinical studies of glutamine-enriched enteral nutrition or PN have
been published in adult and pediatric patients; most, but not all, of
these studies indicate beneficial metabolic and/or clinical effects
(Ziegler et al. 2000a
, 2000b
,
Darmaun 2000
, Griffiths 1999
). Clinical benefits
demonstrated in noncancer intensive care unit and postoperative
patients include improved nitrogen balance, decreased length of
hospital stay, improved immune functions and reduced hospital costs,
while decreased infection rates in trauma patients and in neonates
requiring intensive care have been demonstrated (Ziegler et al. 2000a
, 2000b
, Darmaun 2000
, Griffiths 1999
). Glutamine-induced regulation of human immune cell
number and function has been summarized recently (Wilmore and Shabert 1998
, Ziegler and Daignault 2000
)
(Table 2
).
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Administration of intravenous glutamine in bmt |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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, 1990
,
Scheltinga et al. 1991
, Young et al. 1993
, McBurney et al. 1994
). In the first trial,
the clinical safety and dose response of glutamine-containing PN
was performed in healthy adults and patients undergoing allogenic BMT
(Ziegler et al. 1990
). This pilot study was followed by
a double-blind, randomized, controlled trial in a group of 45
clinically patients undergoing allogeneic BMT for hematologic
malignancies (leukemia and lymphomas) (Ziegler et al. 1992
). Patients received standard glutamine-free PN per
usual protocols (n = 21) or isocaloric, isonitrogenous,
glutamine-supplemented PN (n = 24) designed to
provide estimated requirements for energy and protein and supplemented
with L-glutamine (0.57 g·kg·d).
L-glutamine provided 
40% of total amino acid
intake in the trial.
After multidrug chemotherapy and TBI, PN was started on the day after
BMT. Plasma glutamine levels rose 
40% with glutamine-enriched
PN, but plasma glutamate, ammonia and pyroglutamic acid levels were
unaltered; no adverse clinical or significant biochemical effects were
noted. Daily nitrogen balance performed in the initial 23 patients
between d 4 and 11 post-BMT was significantly improved with
glutamine supplementation (glutamine, -1.4 ± 0.5 g/d vs.
control, -4.2 ± 1.2 g/d; P = 0.002)
(Ziegler et al. 1992
). A significant reduction in 7-d
net nitrogen loss and in urinary excretion of 3-methylhistidine
occurred with glutamine administration (Fig. 1
). This later finding suggests that L-glutamine
diminished the rate of skeletal muscle myofibrillar protein breakdown
as a mechanism for the protein-anabolic effect (Ziegler et al. 1992
).
|
) (Ziegler et al. 1992
). In a subgroup of these study
patients, physiological benefits from the use of glutamine
supplementation were demonstrated. These included the attenuation of
extracellular fluid expansion (Scheltinga et al. 1991
),
improvement in mood scores (Young et al. 1993
) and
enhanced recovery of circulating lymphocytes (Ziegler et al. 1998
). The number of circulating total lymphocytes, T
lymphocytes, T helper (CD-4), and T suppressor (CD-8) cells was
increased with glutamine supplementation. No change was observed in
total leukocyte or neutrophil engraftment; thus, glutamine seemed to
predominantly influence lymphocyte metabolism in the postallogeneic BMT
period (Ziegler et al. 1998
). The decrease in hospital
length of stay and in-hospital medical care costs in this trial
translated to a reduction in hospital charges of $21,095 per patient in
glutamine-supplemented subjects compared with patients who received
standard PN therapy (McBurney et al. 1994
). This
reduction in the cost of hospital care is consistent with results of
subsequent studies on glutamine-enriched nutrition in postoperative
adults and critically ill adult and pediatric patients (Ziegler et al. 2000b
, Mertes et al. 2000
, Jones et al. 1999
, Dallas et al. 1998
, Griffiths et al. 1997
).
|
) studied 29 patients receiving similar
glutamine-free or glutamine-supplemented PN after allogeneic or
autologous BMT for hematologic cancer or solid tumors. PN was given for
30 d in each group and no adverse effects related to glutamine
administration were noted. Glutamine-supplemented PN did not affect
the incidence of mucositis, fever, neutrophil engraftment, clinical
infections or microbial colonization; antibiotic requirements and
mortality were also similar between groups. In the subset of patients
receiving allogeneic BMT, significantly more control subjects than
glutamine subjects had bacteremia (P < 0.05). In
addition, the change in total body water during hospitalization was
significantly less with glutamine (control + 3.1 ± 1.5 vs.
glutamine -3.4 ± 1.3 L; P < 0.05). As
demonstrated in the previous trial (Ziegler et al. 1992
), administration of glutamine-supplemented PN
significantly decreased the length of hospital stay in this more
heterogeneous group of BMT patients (33 ± 2 d vs. 27 ± 1 d, P < 0.05) (Schloerb and Amare 1993
). The patient populations investigated, clinical
conditions and cancer treatment protocols were different in these
initial studies (Ziegler et al. 1992
, Schloerb and Amare 1993
), which may have influenced the effect of
glutamine on infection rates. Although glutamine supplementation seems
to upregulate lymphocyte recovery after BMT (Ziegler et al. 1998
), the incidence of acute graft-vs.-host disease was not
increased in these studies. Importantly, both investigations were
carried out in patients before the advent of routine growth factor use;
the current use of granulocyte/macrophage colony stimulating factor in
the post-transplant period has significantly decreased neutropenia
and the incidence of infection in BMT patients.
A third double-blind, randomized trial has been reported, but only
in abstract form (Poynton et al. 1995
). Fifty unselected
BMT patients received 50 g/d of dipeptide glycyl-glutamine
intravenously vs. parenteral infusion of isonitrogenous mixed
nonessential amino acids in clinically matched patients. The study
solutions were begun 1 d before chemotherapy induction and
continued until hospital discharge or post-BMT d 30. There was a
significant improvement in self-reported lower gastrointestinal
symptoms (e.g., diarrhea and abdominal pain) with glutamine
(P = 0.015). The lactulose: mannitol urinary excretion
ratio, a measure of small intestinal permeability, was also improved
with glutamine (P = 0.04) and there were fewer fever
days (P = 0.01) and less episodes of fever
(P = 0.029) in the glutamine group (Poynton et al. 1995
). Critical review of this latter study will be
possible only after publication of the full manuscript.
|
Glutamine and bmt-associated veno-occlusive disease |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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, Brown et al. 1998
). Veno-occlusive
disease is frequently lethal and seems to be related, at least in part,
to oxygen-free radical-mediated liver injury and depletion of
antioxidants, including GSH (Brown et al. 1998
).
Glutamine seems to be rate limiting for the production of hepatic and
intestinal GSH during catabolic stress (Ziegler et al. 2000a
, Rouse et al. 1995
). Furthermore, standard glutamine-free PN
itself may have prooxidative effects and contribute to GSH depletion by
mechanisms that remain unclear (Jonas et al. 2000
Jonas and Ziegler 1998
). Two reported case studies suggest that the
administration of intravenous + oral L-glutamine
(Nattakom et al. 1995
) or intravenous
alanyl-glutamine dipeptide (Goringe et al. 1998
) in
combination with oral vitamin E diminishes signs and symptoms of
veno-occlusive disease after BMT. In a double-blind prospective
study, clinically matched BMT patients received either 50 g/d of
dipeptide glycyl-glutamine intravenously or infusion of
isonitrogenous mixed nonessential amino acids from the start of
conditioning to discharge from the transplant unit (Brown et al. 1998
). Patients in the glutamine dipeptide group demonstrated
significantly preserved plasma protein C and albumin levels, suggestive
of preserved hepatic function and a decreased risk of
veno-occlusive disease (Brown et al. 1998
).
Additional studies are needed to determine whether glutamine and
vitamin E prophylaxis (or treatment with other antioxidants) reduce the
incidence of post-BMT veno-occlusive disease. |
Use of oral glutamine in bmt |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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) studied a
group of 43 patients with hematologic malignancies receiving either
autologous or allogeneic BMT and 23 with solid malignancies receiving
autologous BMT. Patients were randomized to either oral glutamine
(n = 35) or glycine (n = 31) at a dose
of 10 g three times daily. If PN became necessary, patients in the
oral glutamine group received PN supplemented with
L-glutamine (0.57 g·kg·d) and control
subjects receivied isonitrogeneous, isocaloric glutamine-free PN.
Hospital deaths (n = 14) were unrelated to study group
assignment. Respective comparisons were performed in patients
undergoing allogeneic or autologous BMT for hematologic cancer and
subjects with solid tumors undergoing autologous BMT. There were no
significant differences between study groups in hospital length of
stay, days on PN, neutrophil recovery, incidence of positive blood
cultures and sepsis, diarrhea severity or incidence/severity of
mucositis. In the patients with hematologic malignancy, a possible
reduction in need for PN and a clear suggestion of improved
long-term survival (P = 0.0572) were associated
with glutamine administration. Otherwise, combined oral and parenteral
glutamine seemed to be of limited benefit for patients having
autologous or allogeneic BMT for hematologic or solid malignancies.
In the second recent trial of oral glutamine, Coghlin-Dickson et
al. (2000
) organized a prospective, randomized,
double-blind trial in 58 matched adult patients with leukemia or
lymphoma receiving autologous or allogeneic BMT. Subjects received 30
g/d of L-glutamine or sucrose (placebo) daily, beginning at
the initiation of chemotherapy/TBI and continuing until hospital
discharge or d 28 post-BMT. Mucositis, diarrhea, PN use and
clinical outcomes were major endpoints. Amino acid intake was similar
between groups (control, 0.25 g·kg·d vs. glutamine, 0.29
g·kg·d) and was well tolerated clinically and biochemically. No
significant difference in neutrophil engraftment, oral mucositis,
diarrhea, PN use, length of stay, disease relapse or survival occurred
between groups.
|
Effect of glutamine supplementation on mucositis after high dose chemotherapy |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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, Rosenthal et al. 2000
, Biron et al. 2000
).
In the four randomized, controlled trials outlined above
(Ziegler et al. 1992
, Schloerb and Amare 1993
, Schloerb and Skikne 1999
,
Coghlin-Dickson et al. 2000
), and in an additional
controlled trial (Jebb et al. 1995
), intravenous and/or
oral L-glutamine trials did not influence incidence or
severity of mucositis after BMT. However, additional studies indicate
the potential benefit of oral glutamine as a method to decrease
mucositis after BMT. Anderson et al. (1998a
) published a
large, randomized, double-blind clinical trial that evaluated
effects of oral L-glutamine in 193 pediatric and adult
patients receiving allogeneic or autologous BMT. The subjects were
matched for diagnosis, demographics and BMT regimen; the majority of
study subjects had hematologous malignancies but 32% had solid tumors
and 9% were transplanted for inherited diseases. The patients were
given either oral L-glutamine or glycine at a dose of 1.0
g·m2·dose as a swish-and-swallow mouthwash
four times daily. Subjects were randomized to receive the amino acid
mouthwashes from hospital admission (before conditioning) until 28 d post-BMT.
In patients undergoing autologous BMT (n = 87),
glutamine use was associated with significantly less mouth pain and
less difficulty eating and decreased opiate requirements
(Anderson et al. 1998a
). For example, the number of
patients not requiring morphine for pain was significantly greater in
the glutamine group than in the control group (53% vs. 31%,
P = 0.04). When morphine was given, the duration of
administration was 50% less in the glutamine group than in the
control group (5 vs. 10 d, P = 0.005). Because
these effects were not observed in all subgroups (e.g., matched donors
and unrelated donors), the response to glutamine may have been related
to the different consolidation regimens used. There were no differences
between groups in graft-vs.-host disease or the incidence of
infections; however, seven viral infections developed in placebo
patients vs. none in those receiving glutamine (Anderson et al. 1998a
). Furthermore, in autologous BMT patients, glutamine use
was associated with a significant improvement in the 28-d survival rate
(100.0% vs. 92.6% survival, P = 0.006), but this
difference that was no longer statistically significant at 100 d
post-transplant (87.2% vs. 80.9% survival, P = 0.18) (Anderson et al. 1998a
).
In a recent retrospective analysis of 21 consecutive patients receiving high dose paclitaxel and melphalan as the preparative regimen for autologous BMT for metastatic breast cancer, L-glutamine suspension was given as a swish-and-swallow every 4 h around the clock starting on d -7 before BMT (total dose of 24 g/d) (Cockerham et al. 2000). The group that was given oral glutamine demonstrated significantly fewer days of mucositis, a lower maximum grade of mucositis and required fewer days of parenteral morphine for oral pain relief.
Several studies have been published on effects of oral glutamine in
non-BMT patients receiving chemotherapy alone, with mixed results.
In a crossover study of patients receiving 5-fluorouracil (5-FU) and
folinic acid for intestinal cancer, Jebb et al. (1994
)
found that oral glutamine (16 g/d) had no measurable effect on the
incidence or severity of mucositis. In another study, patients
receiving 5-FU-based chemotherapy regimens for various cancers were
randomized, in a double-blind manner, to receive oral glutamine (4
g swish-and-swallow twice daily) for 14 d beginning on d 1 of
chemotherapy (68 patients per group) (Okuno et al. 1999
). Patients in both groups were also given oral cryotherapy
before chemotherapy and were evaluated for mucositis by standard
physicians’ evaluation and by a self-report instrument. There were
no significant differences or substantial trends in the mucositis
scores between the two study arms (Okuno et al. 1999
).
Bozzetti et al. (1997
) studied 65 patients with advanced
breast cancer being treated with doxifluridine. Subjects received
either L-glutamine orally (30 g/d) or maltodextrine for
eight consecutive days during each interval before chemotherapy. There
were no differences between groups in doxifluridine-induced
diarrhea or tumor response.
In contrast to the results presented above, additional data indicate
that glutamine administration can decrease gastrointestinal toxicity to
chemotherapy in cancer patients (Anderson et al. 1998b
,
Muscaritoli et al. 1997
, Daniele et al. 2001
). In a double-blind, crossover study of 24 pediatric
and adult patients receiving doxorubicine-based chemotherapy for
solid tumors, Anderson et al. (1998b
) found that
twice-daily oral administration of glutamine (2.0
g/m2 per dose) vs. glycine swish-and-swallow
significantly decreased the duration of mucositis by 4.5 d and
also the severity of oral pain. In an unblinded study of 14 patients
with acute leukemia receiving high dose combination chemotherapy, oral
glutamine given at a dose of 18 g/d begun 3 d before chemotherapy
induction significantly decreased the duration and severity of diarrhea
and requirements for antifungal agents (Muscaritoli et al. 1997
). In a recently published study, Daniele et al.
(2001
) investigated 70 chemotherapy-naive patients
with colorectal cancer randomly assigned to oral glutamine (18 g/d) or
placebo before the first cycle of 5-FU and folinic acid, administered
intravenously for 5 d. Treatment was continued for 15 consecutive
days starting 5 d before chemotherapy. Serial urinary excretion
D-xylose and cellobiose-mannitol after oral loads were
measured as indices of intestinal absorption and permeability,
respectively, and patients kept a daily diarrhea diary. Results showed
that patients receiving oral glutamine had a significantly improved
D-xylose absorption and decreased cellobiose-mannitol
urinary excretion, indicating improved gut absorptive and barrier
function compared with controls. Glutamine also significantly decreased
the severity of diarrhea and the need for loperamide therapy for
diarrhea. Thus, oral glutamine in this clinical setting had a
protective effect on 5-FU-induced diarrhea and abnormal intestinal
function after chemotherapy. Trials on effects of glutamine treatment
in chemotherapy-induced mucositis and diarrhea are summarized in
Table 3
.
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|
Effects of glutamine supplementation on outcomes in non-bmt chemotherapy patients |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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). Administration of GLN
dipeptide did not improve clinical outcome, infection rates, use of
antibiotics, mucositis, diarrhea or neutrophil engraftment. In patients
undergoing high dose cispatin and 5-FU chemotherapy with mediastinal
radiotherapy for esophageal cancer, orally administered glutamine (30
g/d) or isonitrogenous, glutamine-free intravenous mixed amino
acids was given for 28 d after the initiation of therapy
(Yoshida et al. 1998
). The patients receiving oral
glutamine demonstrated improved circulating lymphocyte number and
function and decreased gut permeability over time (Yoshida et al. 1998
). Decker-Baumann et al. (1999
)
recently published an unblinded prospective study in 24 patients with
metastatic colon cancer undergoing serial 5-d infusions of high dose
5-FU. Intravenous glycyl-glutamine dipeptide (0.4 g/kg per day) was
given to 12 patients, while the 12 controls received no additional
treatment. Serial endoscopic studies of the gastric and duodenal mucosa
were performed after the first and third course of chemotherapy. There
were no significant differences between groups in the incidence or
severity of clinical adverse effects during the study. However,
endoscopic visual analysis and histomorphology showed that subjects
receiving intravenous glutamine dipeptide demonstrated significantly
decreased inflammation and ulceration of the gastric and duodenal
mucosa after the third course of chemotherapy and an improved duodenal
villus height/crypt depth ratio as an index of gut mucosal integrity. The administration of enteral or parenteral glutamine seems safe and potentially efficacious in patients undergoing BMT and high dose chemotherapy. Given the positive data to date, additional double-blind, controlled clinical trials of glutamine-enriched nutrition in patients receiving BMT and chemotherapy protocols are indicated to define the utility of this amino acid as adjunctive therapy. Studies of glutamine nutrition combined with novel combinations of cytoreductive agents and hematopoietic growth factors in BMT may be particularly pertinent.
The mechanisms of the beneficial glutamine actions observed in some
studies of BMT and chemotherapy patients remain speculative. Glutamine
supplementation exerts a number of effects that may be interrelated
(Ziegler et al. 1992
). For example, reduced protein
breakdown rates may improve patient nitrogen retention. Improved
resistance to colonization and decreased clinical infection may be
related to a protein-sparing effect of glutamine combined with
enhanced number/function of tissue-associated or circulating immune
cells, maintenance of gut mucosal barrier defenses and/or improved
tissue antioxidant GSH status (Ziegler et al. 2000a
).
Decreased mucositis observed in some studies may be related to
cytoprotective or antioxidant effects of glutamine and/or use of this
amino acid as an energy source for epithelial cells. Additional study
is needed to define underlying mechanisms of glutamine action.
It is possible that glutamine is used as a growth factor or fuel for
malignant cells or may alter pharmacokinetic interactions between
malignant tumors and chemotherapeutic drugs (Wilmore et al. 1999
). Thus, carefully planned pharmacological studies may need
to be performed before administering large doses of glutamine that may
have pharmacological effects on the patients receiving cytotoxic drugs.
However, the available clinical data in cancer patients does not
suggest that glutamine-supplemented nutrition enhances or induces
tumor growth or worsens clinical outcomes. In fact, available data
suggest that glutamine may improve clinical outcomes in some patients
undergoing BMT (Ziegler et al. 1992
, Wilmore and Shabert 1998
, Schloerb and Skikne 1999
,
Anderson et al. 1998a
). As noted above, glutamine
treatment may increase plasma or tissue levels of the antioxidant GSH
(Ziegler et al. 2000a
). Antioxidant supplementation as a
modality to protect normal tissue from injurious oxygen-free
radicals has been approached with caution because of potential to
reduce the therapeutic efficacy of cytotoxic regimens by upregulation
of tumor antioxidants (Jonas et al. 2000
). Therefore,
further study of long-term outcomes with glutamine supplementation
in cancer patients seems indicated to complement the primarily
short-term safety data available to date. Although not all studies
demonstrate benefits, sufficient positive data exist to suggest that
glutamine supplementation should be considered in the design of
clinical trials and in metabolic support of many individuals undergoing
BMT for treatment of cancer.
|
FOOTNOTES |
|---|
2 Supported, in part, by National Institutes of
Health Grants R01 DK55850 and M01 RR00039.
4 Abbreviations used: 5-FU, 5-fluorouracil; BMT,
bone marrow transplantation; GSH, plasma glutathione; NST,
nonmyeloablative stem cell allogeneic transplantation; PN, parenteral
nutrition; TBI, total body irradiation.
|
LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONGlutamine supplementation in...Administration of intravenous...Glutamine and bmt-associated...Use of oral glutamine...Effect of glutamine...Effects of glutamine...LITERATURE CITED |
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3. Biron P., Sebban C., Gourmet R., Chvetzoff G., Philip I. & Blay J. Y. (2000) Research controversies in management of oral mucositis. Support Care Cancer 8:68-71.[Medline]
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P < 0.02 control vs.
glutamine-supplemented. Data from Ziegler et al. 1992