Aspects of Amino Acid and Protein Metabolism in Cancer-

Bearing States
AURORA M. LANDEL, PHD, WILLIAM G. HAMMOND, MD, AND MICHAEL M. MEGUID, MD, PHD

Overt malnutrition is seen in about 40°/o of patients hospitalized for treatment of cancer. In patients
whose primary treatment modality is surgical, morbidity and mortality is twice as high in the malnour-
ished group as in the normally nourished patients. This clinically important malnutrition is a conse-
quence of obligatory parasitism by the tumor, which grows at its own genetically determined rate and
which competes effectively with the host for the limited available nutrients. Administration of extra
nutritional support as total parenteral nutrition (TPN) can alter the tumor- host nutritional balance so
that host repletion may occur. Provision of a significant proportion of TPN calories as fat diminishes the
incidence of glucose intolerance and reduces the incidence of abnormal liver function. I n v i m and in vivo
studies both show that leucine is the significant controlling branched-chain amino acid in the TPN
mixture, and adequate leucine content is a crucial component of effective TPN. Variations in TPN
content of large neutral amino acids have important effects on brain tyrosine and tryptophan availability
and hence may also effect neurotransmitter activity. Although the usefulness of TPN for correcting
malnutrition in cancer patients is clear, the optimal choices of constituents for the TPN mixture continue
to evolve.
Cancer 55230-237,1985.

< 3.5 g/dl, there was a significant increase in postopera-

T HIS REVIEW considers current knowledge of amino
acid and protein metabolism in the cancer-bear-
ing state as related to ( 1 ) significance of malnutrition in
cancer patients, as regards incidence and consequences;
(2) the available evidence bearing on the metabolic
mechanisms involved; and (3) the imperfect state of
therapeutic endeavors directed towards correction of
this malnutrition, especially as they bear on selection of
more appropriate regimens and as they shed light on the
involved metabolic abnormalities. We will draw on data
from clinical studies, as well as from work with experi-
mental animals.
Reported observations noted that 4590 of hospitalized
adult cancer patients had lost 10%or more of their body
weight, while 25% had lost 20% or more.' In patients
with esophageal2and colorecta13 carcinoma, preopera-
tive weight loss of more than 15% to 20%was associated
with a significantly higher postoperative morbidity and
mortality than that encountered in those patients with
less weight loss, while in patients with serum albumin
From the Department of Clinical Nutrition, Division of Surgery,
City of Hope National Medical Center, Duarte, California.
Supported in pan by a City of Hope National Medical Center
Cancer Core Grant #CA 16434.
Address for reprints: Michael M. Meguid, MD, PhD, FACS, Depart-
ment of Surgery, University Hospital, Upstate Medical Center, 750 E.
Adams Street, Syracuse, NY 13210.
tive complications.
During the past 2 years at the City of Hope National
Medical Center, 365 patients with a primary diagnosisof
gastrointestinal intra-abdominal malignancies under-
went major surgical resections. On admission, 44% of
these patients in the aggregate were frankly malnour-
ished by the criteria of premorbid weight loss, body com-
positional changes, and low serum albumin level^.^.^
However, the incidence of malnutrition vaned depend-
ing on the involved organ system and disease stage. A
further 30% had a borderline nutritional status, and were
at risk of becoming malnourished following major surgi-
cal resection if their postoperative course was associated
with a prolonged period of inadequate nutrient intake.
The malnourished patients had a preponderance of
the postoperative complications: 65% occurred in the
malnourished, with a statistically significant decrease to
34%in the normally nourished patients. The mortality
rate was also significantly higher in the malnourished.
Furthermore, a high incidence of complications was
correlated with the higher incidence of malnutrition
found in patients with certain specific disease states.
It seems certain that malnutrition, as defined above, is
both prevalent and problematical in cancer patients.
Viewed simplistically, this malnutrition is caused by an
intake of nutrients inadequate to meet the metabolic

230
No. I AMINOACIDMETABOLISM
IN CANCER-BEARING
STATES
needs of the cancer patient. The usual anorexigenic ef-
fects of cancer and its treatment are well known, but
many cancer patients become malnourished while in-
gesting dietary regimens quite ample for normal individ-
uals ofcomparable size and activity. For possible expla-
nations of this phenomenon, we turn to animal data.
Because of the difficulty of precisely controlling nutri-
tional intake and of utilizing radioisotopes in cancer pa-
tients, aspects of protein metabolism not directly mea-
surable in humans have been studied in tumor-bearing
animal models.
Using isotopically labeled amino a ~ i d s ,tumor-bear-
~,~
ing animals have been shown to have higher liver frac-
tional synthetic rates, higher muscle catabolic rates,
higher whole body protein turnover rates, and lower
skeletal muscle fractional synthetic rates than do normal
controls. These changes were observed before decreased
nitrogen balance, decreased weight and decreased food
intake occurred, suggesting that these metabolic effects
were induced by the tumor.6-11In order to grow, the
tumor requires energy substrates that must be supplied
by the host. When the tumor demands become greater
than the host can supply, especially when decreased host
food intake occurs, host weight loss and malnutrition
result. Several mechanisms have been suggested to ex-
plain the decreased food intake: (1) The tumor acts as a
nitrogen trap.12Tumor cells are more efficient in utiliz-
ing amino acids for gluconeogenesis(thus providing en-
ergy) and for protein synthesis. (2) The host recycles the
lactate produced by the tumor during anaerobic glycoly-
s ~ s . ’ ~From
* * ~ 1 mol of glucose, the tumor produces
2 mols of ATP for its use and also produces lactic acid.
The lactic acid is converted by the host liver to glucose
which the tumor uses, thereby consuming 6 mols of
ATP. This results in a loss to the host of 8 ATP molecules
per mole of glucose. Furthermore, this mole of glucose
used by the tumor is lost to the host, which might have
used it to generate 36 mols of ATP via the Krebs cycle.
(3) The tumor produces peptides and other metabolites
involved in the regulation of certain compounds (e.g.,
serotonin, catecholamines) believed to be responsible for
maintaining nutritional homeostasis in the host.15J6(4)
The host responds to increased tumor load by increased
tissue protein breakdown, as shown by increased uri-
nary-3-methylhistidine (3-MH) excretion; this may re-
flect loss of gut myofibrillar mass, as well as decreased
muscle protein ~ynthesis.~~J* Alanine and glutamine re-
sulting from muscle breakdown are subsequently used
by the liver for gluconeogenesis, further increasing the
host’s metabolic burden. l9
Many studies have relied on the rate of urinary excre-
tion of 3-MH to indicate skeletal muscle degradation.
Recent studies indicate that skeletal muscle contributes
about 25% of the total urinary 3-MH excretion per day.20
Landel et al. 23 1
These studies, done on the adult female rat, suggested
that gastrointestinal (GI) muscle provides approxi-
mately 10%of this excretion. Whether such a difference
also occurs in humans, in whom the skeletal muscle
mass/gut mass proportion is significantly larger than in
the rat, is currently not known. Caution should therefore
be exercised in freely translating rat data to malnour-
ished cancer patients. There is, however, overwhelming
evidence that 3-MH release can be suppressed in cancer
patients by the use of nutritional support.21 Thus, the
tumor acts as an obligatory metabolic parasite upon its
host, the cancer patient. The resulting malnutrition is
aggravated by chemotherapy and radiotherapy.22-231
The anatomic location of the tumor may also contribute
to the inability of the host to take in or absorb nutrients.
With modem pharmaceutical technology, it would seem
fairly simple to provide an adequate nutrient intake so
that the host would not suffer from the effects of its
parasitic tumor. However, one must also consider
whether an increase in nutrient supply to the cancer
patient may augment tumor growth instead of repleting
the host. Again, animal data are relevant to this question.
The provision of nutritional support as total paren-
teral nutrition (TPN) has been carried out in tumor-
bearing animals to investigate its effect on the nutritional
status of the host and on the tumor. Stein et aL6 and
Oram-Smith er aL8 used [15N] glycine in the AC33
tumor-bearing rat to study the effects of four different
+
dietary regimens: (1) 25% glucose 2.5% amino acids;
(2) 2.5% amino acids; (3) 2.5% glucose; and (4) 25%
glucose. Compared to normal controls, muscle protein
synthesis decreased in the tumor-bearing animals on all
the diets. Liver protein synthesis increased on all except
diet “ 1” on which it remained normal. However, tumor
protein synthesis also increased, being slightly inhibited
on only the very restrictive “3” diet.
Using a TPN solution of 27%glucose and 3.9%amino
acid, Cameron et observed increased host weight,
but demonstrated both fluid retention and an increase in
tumor growth rate. Buzby et aL9 observed nutritional
repletion of the host with both carbohydrate-based TPN
(+amino acid) and fat-based TPN (+amino acid).
Tumor growth was stimulated in the former but not in
the latter.
Proteindepleted Morris hepatoma-bearing rats had a
reduced liver protein content that was restored to prede-
pletion levels after repletion with TPN or a normal pro-
tein diet. On the other hand, the protein content of the
hepatoma was not affected by the dietary manipula-
. ~ ~et aLz5 compared the effect of TPN (20%
t i ~ nKishi
+
glucose 2.5% amino acid) to 5% glucose in the Walker
256 tumor-bearing Wistar rat. The TPN group had a
positive N balance, a higher plasma albumin level, and
higher liver, spleen, and tumor weights than the glucose
232 CANCERJanuary 1 Supplement 1985
group, but there was little difference between the tumor
weight-to-body weight ratios. They concluded that TPN
was effective for maintaining the nutritional state of the
tumor-bearing host without producing tumor growth
stimulation.
Daly et a1.2bobserved no significant difference in
tumor weight-to-body weight ratios between previously
protein depleted rats given TPN and those remaining on
a protein-free diet, but the repleted animals looked
healthier.
The enzyme involved in the conversion ofpyruvate to
glucose, fructose-1,6-diphosphatase(FDP), was elevated
in the liver of protein depleted rats, suggesting that liver
protein was being utilized for glucone~genesis.~~ Gluta-
mate-pyruvate transaminase (GPT) and glutamate-ox-
aloacetate transaminase (GOT) in the liver were re-
duced, indicating reduced alanine and aspartic acid de-
grading pathways. On repletion with a normal protein
diet or TPN, the liver levels of these enzymes were re-
stored to normal. However, in the tumor, neither protein
depletion nor repletion had an effect on FDP. Tumor
GPT and GOT increased during protein depletion and
decreased on repletion, indicating that the tumor was
more efficient in competing with the liver for amino
acids to be used as energy and nitrogen sources.
Walker 256 tumor-bearing rats showed increased
plasma alanine, histidine and glycine, and decreased ar-
ginine when fed a casein diet (3.2% N).25 Wu and
Bauer2’ did not note any significant change in plasma
amino acids between normal and Walker 256 tumor-
bearing rats with small tumors. However, with medium
and large tumors, increased aspartic, serine, glutamic
and tyrosine, and decreased glutamine plasma levels
were observed. In the host liver, increased intracellular
free threonine, aspartic, serine, and decreased glutamine
levels were found; in host muscle, these were all de-
creased. Plasma glutamine levels were increased in the
MCA tumor-bearing rat.28 The alterations in these
amino acid plasma levels may be a consequence of
tumor growth, i.e., increased utilization of amino acid
for tumor growth as a cause of the decreased plasma
levels of amino acid. It has been suggested that the in-
crease in plasma glutamic acid indicated increased entry
of other amino acids into cells, as well as indicating im-
paired urea formation.28 Although it therefore seems
highly probable that the proportion of specific amino
acid components in the TPN mixture will prove impor-
tant, very little data are available regarding plasma (or
intracellular) amino acid levels in tumor-bearing rats
given TPN.
Thus, the animal data indicate that nutritional sup-
port enables the host to be maintained in the face of
inexorable parasitism, while the tumor proceeds at its
genetically determined pace, only minimally affected by
Vol. 5 5
the state of its host’s nutrition. Although not studied in a
comparably methodical way, human tumors appear to
be essentially unaffected by changing host nutrition; cer-
tainly the great number of patients who have received
TPN without manifesting clinical signs of altered tumor
growth supports this view.
What then of the host, when given additional nu-
trients? In attempts to influence postoperative outcome
by providing nutritional support, four prospective ran-
domized ~ t u d i e s examined
~ ~ - ~ ~ the effects of preopera-
tive TPN on cancer patients undergoing major surgical
resection for malignant neoplasms. Although 60% were
malnourished at the beginning, the results showed that
(1) 2 to 3 days,29or (2) 5 to 7 days30 of TPN did not
improve outcome; (3) 7 to 10 days of preoperative TPN
resulted in a significant reduction of postoperative
wound infections3’ and of major complications and
mortality .32
However, some caution must be exercised in evaluat-
ing these results. Comparisons were made between ther-
apeutic regimens in subject groups each of which con-
tained both nourished and malnourished patients.
Implicit in the use of such a mixed population is the
hazardous assumption that both subpopulations will ex-
perience the same postoperative complication rates and
will benefit equally from preoperative nutritional sup-
port. (Although a patient’s eventual clinical course
largely reflects the prognosis of the primary disease, con-
comitant malnutrition greatly increases the risk ofa seri-
ous postoperative complication and thereby prejudices
ultimate outcome.) Estimates of the actual benefit from
TPN may thus be underrated when such mixed popula-
tions are studied.
Obviously, it will be desirable to identify high-risk pa-
tients and to study the effects of preoperative TPN on
postoperative morbidity and mortality in comparable
populations.
The arbitrarily fixed repletion times used in these
studies make the assumption that all malnourished pa-
tients require an equal period of repletion. By current
anthropomorphic and biochemical indices, there ap-
pears no consistent relationship between giving TPN for
a fixed number of days and adequacy of nutritional re-
pletion. A rational approach to determining the requisite
length of preoperative TPN would be the use of a stan-
dard measure of repletion prior to operation.
Since severe malnutrition is associated with muscle
wasting, changes in the function of the adductor pollicis
muscle (as assessed via electrical stimulation ofthe ulnar
nerve) have been successfully used to assess extent of
repletion. In patients with malnutrition, changes in ad-
ductor pollicis contractility, relaxation rate, and endur-
ance precede biochemical changes or detectable alter-
ations in body composition. In mildly and severely
No. 1 AMINOACIDMETABOLISM
IN CANCER-BEARING
STATES
malnourished patients, studies have shown that abnor-
malities of skeletal muscle function became normal after
varying periods of nutritional support (ranging from 7 to
14 days) at a time when conventional measurements of
nutritional status did not significantly ~ h a n g e .Thus,
~ ~ . ~ ~ calorie and protein intake.42
to properly assess the effect of preoperative nutritional
support on outcome, it becomes important to ensure
comparable repletion of malnourished patients by pro-
viding nutritional support until a standard endpoint
(normalization of skeletal muscle function) is reached.
Therefore, although the studies noted above purport
to show that preoperative TPN is or is not effective in
improving the results of surgical treatment for cancer,
the crucial clinical question remains unanswered: Does
biologically effective repletion (to a standard endpoint)
of specifically malnourished patients by use of an opti-
mal TPN mixture have a beneficial effect upon postoper-
ative outcome? Note that we refer to the use of an opti-
mal TPN mixture. However, we are only able to discuss
recent improvements in TPN mixtures; the optimal
mixture still awaits discovery.
In the studies discussed above, conventional crystal-
line amino acid-glucose solutions (4.25% amino acid
and 25% dextrose) were used for TPN. The known meta-
bolic sequelae of using these solutions to replete mal-
nourished cancer patients are positive N-balance and
weight gain. The latter is predominantly due to accretion
of water and fat.35
Glucose intolerance and abnormal liver functions are
the most common metabolic complications of conven-
tional TPN. A recent randomized clinical trial suggests
that these can be significantly reduced by replacing 30% literature regarding the potential benefits of BCAA solu-
glucose calories by fat.36Eighty-eight patients received
either conventional TPN (CON-TPN = 259/0 dextrose,
4.2590 amino acids) or modified TPN (MOD-TPN =
159/0 dextrose, 20% fat, 5% amino acids) in isocaloric and
isonitrogenous amounts. Treatment groups were:
Group A: no surgery, TPN only; Group B: postoperative
TPN: Group C: preoperative and postoperative TPN.
Serial blood samples were analyzed for glucose, albu-
min, triglycerides, insulin, and LFTS. Nine patients de-
veloped hyperglycemia and were removed from study.
Seven had received CON-TPN and two MOD-TPN
(P< 0.05). In Group A, insulin rose 50% less with quently test a single branched-chain amino acid and ex-
MOD-TPN. There was a 50% smaller rise ( P < 0.05) in
triglycerides, SGOT, and SGPT on MOD-TPN.
In addition to the improved energy source, detailed
investigations of protein metabolism have led to im-
provements in the N sources of TPN. In vitro isotopic
studies of protein synthesis in muscle fibers from cancer
patients demonstrated decreased synthesis and in-
creased d e g r a t i ~ nThe
. ~ ~decreased efficiency of synthe-
sis was overcome by increasing the exogenous amino
acid supply, suggesting that higher protein intake might
Landel et al. 233
be advantageous in cancer patients. Similarly, hypoal-
buminemia, which occurs frequently in cancer pa-
t i e n t ~ resulting
, ~ ~ ~ ~from ~ decreased synthesis and in-
creased cataboli~rn,~.~' can be reversed by adequate
Studies on the mechanism of the TPN effect on mus-
cle metabolism in malnourished cancer patients have
been hampered by the lack of specific methods to inves-
tigate muscle turnover. Protein turnover in mammalian
tissues and whole body has recently been reviewed by
Walterlow et ~ 1In the . ~relatively
~ few protein turnover
studies of malnourished cancer patients prior to and fol-
lowing TPN,44-47 all used [ lsN]glycine as the nonra-
dioactive stable isotope. [ 15N]glycine gives a whole body
integrated view of N metabolism similar to that obtained
from an N balance study, but does not distinguish be-
tween muscle or hepatic protein turnover. As expected,
total protein turnover is increased with the provision of
intravenous nutrients; synthesis exceeds catabolism.
However, in addition to being metabolically nondis-
criminatory, the use of [ "Nlglycine has other limita-
tions which are overcome with the use of the primed
continuous infusion [ I-13C]leucinemethod. This pro-
vides a relatively quick method of determining muscle
synthetic and catabolic rates. When used in studies of
normal volunteers who received a high leucine intake, a
decrease in protein breakdown relative to synthesis was
Although branched-chain amino acids (BCAA) are
commonly thought ofas a group in terms oftheir roles in
amino acid metabolism, some of the confusion in the
tions arose from the use of early prototype solutions in
which valine was the favored amino acid in the solution.
This usage was based on data derived from rat studies
which cannot be applied to humans.
Because leucine, isoleucine, and valine share the same
enzyme systems (branched-chain amino acid transferase
and branched-chain alpha-ketoacid dehydrogenase for
their initial degradative steps), the branched chain
amino acids are commonly thought of as a group in
terms of their roles in amino acid homeostasis. Thus,
both in vivo and in vitro experimental protocols fre-
trapolate results to the group as a hole.^^,^^ We studied
aspects of the in vivo and in vitro relationships of leucine
and valine metaboli~rn.~'
In the in vivo studies, we examined both leucine and
valine kinetics under circumstances where intake of one
amino acid was reduced from a surfeit to a deficient
level. Fifteen normal-weight, young, adult volunteers
participated in five dietary protocols. In each study, s u b
jects received a crystalline amino acid mixture (pat-
terned after the amino acid composition of egg proteins)
234 CANCERJanuary I Supplement 1985 VOl. 5 5

TABLEI . Plasma Leucine, Valine, and Insulin Concentrations in small but insignificant decline in plasma insulin levels.
Subjects Consuming Graded Levels of Leucine or Valine
Plasma leucine levels remained unchanged.
Plasma concentration Leucine flux decreased and leucine oxidation declined
Dietarv when dietary leucine consumption was decreased. Va-
line flux rose dramatically with decreased dietary leucine
intake, but the fraction of valine flux oxidized was re-
Study I duced by 30%.Valine flux and oxidation also declined
Leucine80* 130f 9 272 2 16 80f2 20k2
Leucine 4* 80f 8 1004?70 78f4 1Ok2 with reduced dietary valine intake. However, leucine
Study II flux remained unchanged and the fractional oxidation
Valine70t 135 k 6 280 2 7 89 k 5 12? 3 rate tended to increase but not significantly so, as dietary
Valine 16t 120 f 7 I07 f 7 73 f 4 I2k 2
Valine 4 t 127?13 12OfII 83f4 9?1 valine consumption declined.
In order to determine whether the leucine-induced
Dietary valine intake = 70 mg/kg/d. t Dietary leucine intake = 80 changes in valine metabolism we observed in our human
mg/kg/d.
subjects were a direct substrate-mediated effect, we un-
dertook a series of correlative in vitro experiments where
which furnished an N equivalent of 0.8 g protein&/ the results of substrate alteration alone could be tested.
Intact epitrochlearis muscles were obtained from 120-to
day. The subject’s total energy requirement, based on his
prior calorie intake, was furnished as mixed carbohy- 130-g male Sprague Dawley rats kept for at least 5 days
drate and fat with appropriate vitamin and mineral sup- on an ad libitum Purina Lab Chow diet (22% crude
plementati~n.~~ The diets, consumed for 6 days prior to protein). Single 20- to 30-mgmuscles were incubated for
leucine infusion study, were identical in each protocol two hours in Krebs-Henseleit buffer containing 5.5 mM
except that the intake of valine or leucine was adjusted to glucose, 1 m M calcium chloride, 5 mM Hepes, and
two different levels for leucine and three different intakes 0.15% dialyzed bovine serum albumin. Branched-chain
for valine as described below. Total nitrogen intake, amino acids were added in varying amounts (see below)
however, was kept isonitrogenous by replacement of the either alone or in the presence of other amino acids at
reduced branched-chain amino acid with added aspartic normal rat plasma concentrations.
acid in appropriate amounts. On the morning of the Table 2 shows the effects of increasing incubation me-
seventh day, while consuming hourly aliquots of their dium content of leucine or valine on muscle substrate
test diet, each subject was infused with either release in the absence of other extracellular amino acids.
As leucine concentration increased from zero to a supra-
L-[ l-’3C]leucine or with L-[ l-13C]valineto determine
branched-chain amino acid flux and oxidation as pre- physiological level, muscle keto-isocaproate release in-
viously de~cribed.’~ creased, but there was a pronounced drop in keto-iso-
Table 1 shows the plasma leucine, valine, glucose, and valerate release and a lesser (but still significant) decline
insulin concentrations at different branched-chain in released valine. When extracellular valine content was
amino acid intake levels. When dietary leucine intake increased there was essentially no effect on muscle leu-
was decreased, plasma leucine and insulin declined sig- cine or keto-isocaproate release even though ketoiso-
nificantly (Student’s t test; P < 0.05). Plasma valine, on valerate release increased dramatically. These effects
the other hand, rose significantly (P< 0.05) on the low were seen in the presence of all other amino acids as well.
dietary leucine intake. When dietary valine consump- The above data suggested that leucine was reducing
tion was reduced, plasma valine fell and there was a the size of intracellular valine and keto-isovaleratepools.
Leucine’s role in accelerating muscle protein synthesis
and keto-isocaproate’s effect of attenuating muscle pro-
TABLE
2. Effectsof Leucine and Valine on tein breakdown would have this result.54
Muscle Substrate Release Our results help explain leucine’s reported in vivo ef-
Substrate released (nmoles/min/g) fects on plasma valine level^.^^^^^ Thus our data demon-
Addition strate that direct substrate effects alone can explain the
(uM) Leucine Ketoisocaproate Valine Ketoisovalerate observed in vivo responses. Furthermore, the divergent
Leucine actions of leucine and valine both in muscle and in the
0 - 0.3 2.6 0.5 intact organism reaffirm both the need to consider each
200 - 1.5 2.3 0.2 branched-chain amino acid as functionally unique and
lo00 - 3.2 I .9 0. I
the potential hazards of extrapolating to the group as a
Valine
0 4.2 0.4 - 0.3 whole information obtained with a single index
200 4.4 0.3 - I .9 branched-chain amino acid.
loo0 4.0 0.3 - 6.7
Our studies in normal humans, in vitro, and in stressed
No. I AMINOACIDMETABOLISM
IN CANCER-BEARING
STATES
cancer patientss7 clearly indicate that, of the three
BCAA, leucine regulates protein metabolism in mal-
nourished cancer patients, rather than the three BCAA
as a group. In a randomized clinical trial, 20 malnour-
ished postoperative cancer patients received either a
conventional TPN solution (BCAA :non-BCAA =
+
25 : 75; leucine 156 mg/dl) or a branched-chain
enriched solution (BCAA :non-BCAA = 45 :5 5 ; leu-
cine = 70 mg/dl). The results showed no significant dif-
ference in N balances between the groups during the 14
days of TPN administration. However, a positive N-bal-
ance trend occurred in the group ofpatients receiving the
TPN solution containing the high leucine concentra-
tion. There was a corresponding decrease in urinary
3-MH :creatinine ratio with the high leucine TPN as
compared to the branched-chain enriched solution with
a low leucine concentration, suggestingthat the observed
urinary changes were due to decreased muscle protein
breakdown.
In a further trial, 40 malnourished cancer patients
(predominantly with malignancies of the GI tract) un-
dergoing major surgery were studied. Afer surgery, these
patients were randomized to receive isocaloric, isonitro-
genous amounts of either standard TPN (STD-TPN)
(25% dextrose/4.25% crystalline amino acid containing
BCAA : non-BCAA = 25 :75), or a crystalline amino
acid solution enriched with BCAA (25% dextrose/lO%
fat/3.590 amino acid containing BCAA: non-BCAA =
45:55). There were sustained increases in the plasma
levels of the total, essential, nonessential, glycogenicand
BCAA in the 20 postoperative cancer patients who re-
ceived the BCAA-enriched TPN solution. This was re-
flected in improved N accretion and positive N balance.
These results may be interpreted to indicate that BCAA
spare body protein by reducing amino acid efflux from
skeletal muscle. This is associated with increased protein
synthesis and decreased protein breakdown.
From these in vitro and in vivo studies described
above, we conclude that: (1) the enhanced N-balance
occumng in malnourished stressed postoperative cancer
patients given TPN is dependent on leucine intake and
not on the total BCAA intake alone; (2) of the three
BCAA, leucine is the significant controlling factor in
decreasing muscle protein breakdown; (3) the mecha-
nism responsible for the enhanced N accretion is de-
creased breakdown relative to protein synthesis. Re-
cently, Kern et uI.~*have used the leucine enriched
solution in stressed patients. They confirmed our find-
ings and demonstrated decreases in postoperative pro-
tein catabolism.
In further analyzing our data from our study on the
nitrogen accretion effects of TPN with varying amino
acid compositions in malnourished cancer patients, it
was noted that the concentration of the large neutral
Landel et al. 235
amino acids (LNAA) were altered.59Using these LNAA
concentrations, the brain levels of tryptophan and tyro-
sine were calculated in order to determine the availabil-
ity of these amino acids for brain neurotransmitter syn-
thesis. This calculation is possible since Fernstrom and
Fallerm have demonstrated that the brain level of tryp-
tophan (or tyrosine) correlated significantly with their
plasma levels relative to the concentrations of the other
LNAA. The brain levels are expressed as (1) ratio6' of
plasma tryptophan (tyrosine) to the sum of phenylala-
nine, leucine, isoleucine, valine and tyrosine (trypto-
phan); or (2) the brain influx rate calculated62from the
kinetic constants which were determined for each
LNAA by Pardridge and O l d e n d ~ r f The. ~ ~ results of
these calculations showed (1) no significant difference
between preoperative and postoperative brain levels of
trytophan (below normal) and tyrosine (within or above
normal); (2) postoperative STD-TPN did not change
brain tryptophan concentration from preinfusion values
while BCAA-TPN decreased it; (3) preinfusion brain
tyrosine levels were decreased by either form of TPN.
Thus, neither type of TPN corrected the low postopera-
tive trytophan levels nor helped maintain the normal
postoperative brain tyrosine level. These results imply
low substrate levels for serotonin and catecholamine
synthesis, thus affecting functions dependent on their
control.
While the initial nutritional objective (enhancement
of nitrogen accretion) of infusing TPN containing
BCAA-enriched amino acids was realized, these ob-
served amino acid imbalances should lead to considera-
tion of other TPN effects on organ function.
We have reviewed evidence which indicates that mal-
nutrition is an important problem in cancer patients and
which provides an incomplete yet useful conceptual
structure of the basic causative mechanisms. Further, we
have seen that provision of nutritional support as TPN
may have a beneficial effect, and have explored areas of
recent improvement in TPN formulation. With regard
to clear and comprehensive indications for the use of
TPN, or with regard to an ideal TPN formulation -one
which would preferentially replete the host and inhibit
the tumor-at present, there are no valid data and hence
no perspective.
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