ARCHIVES OF BIOCHEMISTRY
AND BIOPHYSZS
Vol. 268, No. 2, February
1, pp. 66’7-675,1989
Nitrogen Metabolism
in Tumor Bearing Mice’
JAVIER MARQUEZ:
FRANCISCA
SANCHEZ-JIMl?NEZ,
MIGUEL ANGEL MEDINA,
ANA R. QUESADA,
AND IGNACIO
NUNEZ DE CASTRO
Departamento
de Bioquimica
Received
y Biologia
May
5,1988,
Molecular,
29071 M&ga.,
Facultad
Spain
and in revised
form
de Ciencias,
September
Uniuersidad
de Mblaga,
27,1988
In experiments with whole animals infested with a highly malignant strain of Ehrlich
ascites tumor cells, serial concentrations
of amino acids were determined
for host
plasma, ascitic fluid, and tumor cells, throughout
tumor development. Concentration
gradients of glutamine, asparagine, valine, leucine, isoleucine, phenylalanine,
tyrosine,
histidine, tryptophan,
arginine, serine, methionine,
and taurine from the host plasma
toward the ascitic liquid were established; while on the other hand, concentration gradients from the ascitic liquid toward the plasma were established for glutamate, aspartate, glycine, alanine, proline, and threonine. With the exception of aspartate the concentrations of these amino acids were highest inside the cells. Arginine was the only amino
acid not detected in tumor cells. I?z z&o incubations of tumor cells in the presence of
glutamine and/or glucose, as the energy and nitrogen sources, confirmed the amino acid
fluxes previously deduced from the observed relative concentrations
of amino acids in
plasma, ascitic liquid, and tumor cells, suggesting that glutamate,
alanine, aspartate,
glycine, and serine can be produced by tumors. These findings support that changes in
amino acid patterns occurring in the host system are related to tumor development.
4 1989 Academic
Press. Inc.
Tumors compete with the host for nitrogen compounds needed for the synthesis of
nucleic acids and proteins. Glutamine
appears to be the principal of several amino
acids involved in nitrogen transport from
host to tumor (1). A previous work reports
a net flux of glutamine
and asparagine
from the host to the tumor, together with
a reverse flux of ammonia, glutamate, and
aspartate from the tumor to the host (2).
The increased rate of protein synthesis in
growing tumors demands a continuous
supply of essential amino acids (3,4). Sev’ This study was supported
the Comisibn
Asesora
de
Tknica
and 8711518 from
Sanitarias
de la Seguridad
’ To whom correspondente
University
Missouri-Kansas
Sciences, 109 BSB, Kansas
era1 nonessential amino acids are also required as precursors of the nitrogen containing compounds for tumor cell proliferation. Plasma free amino acid pool may be
the main source of those amino acids.
However, in contrast with other pathological situations, a characteristic
pattern of
the plasma amino acids in neoplastic conditions have not been found (5-8). Krause
et ah (9) have pointed out that the plasma
amino acid patterns seen in tumor bearing
humans and animals are largely anecdotal,
being measurements
made at isolated intervals rather than a complete series of
measurements made over the whole period
of tumor development.
Consequently,
it
appeared that a study of the overall amino
acid movement and interchange
between
host and tumor is called for. Mice inoculated with highly malignant
ascites tumor
cells were considered to be an appropriate
by Grants 0962/84 from
Investigacibn
Cientitica
y
Fondo de Investigaciones
Social.
should be addressed
at:
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City, MO 64110.
667
0003-9861/89
$3.00
Copyright 6 1989 by Academic Press. Inc.
All rights of reproduction
in any form reserved.
668
MARQUEZ
model for such studies because the simultaneous determination
of the complete
range of amino acid concentrations
in the
different fluid compartments,
plasma, ascitic liquid, and cells, at frequent intervals
would permit the inference of the flux directions of each amino acid. The results
presented here show marked differences in
the essential and nonessential amino acid
profiles influenced by the stage of tumor
development. Furthermore,
in vitro incubations of freshly harvested cells satisfactorily confirmed the apparent directions of
the amino acid fluxes inferred i~z. viva,
showing a behavior parallel to that observed in the whole animal and appearing
as a valuable model very helpful in our understanding of the nitrogen balance.
MATERIALS
AND
METHODS
E/lrlich
ascites cells. A hyperdiploid
Lettre
strain
was maintained
in 2-month-old
female albino Swiss
mice OF l(SPF
Ice) purchased
from Panlab (Barcelona, Spain). The animals
received
standard
Panlab
food, type A.03, with a caloric content
of 3200 kcal/
kg. Cells were harvested
as described
elsewhere
(2).
The integrity
of fresh cells was tested by permeability to 0.01% (w/v) erythrosine.
Prepamfion
qf sntnp~es. To determine
the free
amino acid concentrations
in both plasma and ascitic
liquid, mice in four different
groups of 21 were inoculated at different
times with 5 X lo6 tumor cells from
four different
infested animals
and sequential
analyses of the whole series were carried out 1,2,4,7,11,14,
and 16 days after tumor transplant.
Nontransplanted
animals
were used as controls.
Blood and ascitic fluid
samples were taken and processed
as described
with
minor modifications
(2). Heparinized
blood was immediately
centrifuged
at 2OOOg for 5 min. The tumor
samples
were extracted
from the peritoneal
cavity
and the ascitic fluid was obtained
by centrifuging
the
tumoral
suspension
at 2000s for 5 min. The plasma or
ascitic fluid samples (100 ~1) were prepared
for highperformance
liquid
chromatography
determination
of amino acids as described
previously
(10). To determine the intracellular
concentrations
of the free
amino acids, immediately
after extraction
from the
animals
whole cells were centrifuged
at 2000g for 90
s through
1 ml of silicone oil mixture
(AR 200 and AR
20, 2.41 (w/w);
Wacker-Chemie,
Munich)
in a 3-ml
polypropylene
tube, loaded with 0.5 ml of 1 M HCIOa
as the bottom
layer. Thereafter,
the upper layer and
silicone oil were carefully
removed,
and the supernatants of the bottom
layer were neutralized
with cold
KOH solution
and centrifuged
again at 11,SOOg for 5
ET
AL.
min. Parallel
experiments
were carried
out using 0.4
M mannitol
instead of perchloric
acid as the bottom
layer, so that the slight
amino acid contamination
from residual
a&tic
liquid could be subtracted
(only
detected
less than 2% for glycine,
alanine,
and proline). To calculate
the cellular
concentrations
of the
free amino acids, the total aqueous volume of the cells
was determined
by a semiautomatic
image analyzer
system IBAS 1 (Kontron,
RFA) and the assumption
was made that the aqueous volume is 60% of the total
cell volume.
The total aqueous volume thus obtained
was 0.60 _+ 0.03 ~1110~ cells. This calculated
aqueous
volume was very similar
to that reported
for another
strain of Ehrlich
ascites tumor cells (11).
Incubation
conditions.
Collected
cells were suspended
in phosphate-buffered
saline,
consisting
of
159 mM NaCI, 6 mM KCI, 11 mM phosphate,
pH 7.4.
The cellular
suspension
was maintained
under an atmosphere
of 95% Oz and 5% CO? for 15 min at 37°C
in a Grant Instruments
(Cambridge,
England)
metabolic incubator
with continuous
shaking (140 strokes/
min); 0.5-ml amounts
were collected
at intervals
of 5,
10, and 15 min during
this initial
preincubation
period. At the end of this period solutions
of glutamine
and glucose were added to give final concentrations
of
glutamine,
0.5 mM; glucose, 5 mM; and glutamine
plus
glucose, 0.5 and 5 mM, respectively.
Cellular
density
was always adjusted
to 60 X lo6 cells/ml.
Aliquots
of
0.5 ml were collected
at 5-, lo-, and 15-min intervals.
All the samples
were immediately
centrifuged
at
2OOOg for 3 min. The supernatants
were used for the
measurement
of extracellular
concentrations
of the
amino acids.
Amino
acid and votein
analysis.
The free amino
acid concentrations
were determined
by a high-performance
liquid chromatographic
method
fully validated for biological
samples
(IO). It uses precolumn
derivatization
of amino acids with dansyl
chloride
prior to a reversed-phase
separation
on a 5-pm Supelcosil LC-18 column (150 x 4.6 mm i.d., Supelco, Bellefonte,
PA) and a Spectra-Physics
(San Jose, CA)
high-performance
liquid
chromatography
system
equipped
with uv detection
at 254 nm. Each analysis
was duplicated.
Values are expressed
as means + SE;
the Student t test for statistical
significance
was used.
Protein
was measured
by the method
of Lowry
et al.
(12 ), using bovine serum albumin
as a standard.
RESULTS
A highly malignant strain of Ehrlich ascites tumor was used in this work. Figure
1 shows the tumor growth as measured by
counting the number of intact cells revealed by the erythrosine test during the
tumor development period. The life span of
the animals was 16 f 1 days after inocula-
NITROGEN
METABOLISM
IN TUMOR
BEARING
669
MICE
2.1 09
I
f
E
:
%
0
1
L
/
2
Days
4
6
after
10
14
tumm transplontatlon
FIG. 1. Growth
curve for Ehrlich
ascites tumor
after the inoculation
of 5 x lo6 cells. Each point represents the average
number
of intact cells in at feast 10
tumors.
Bars, SE.
tion. It is noteworthy
that the maximum
number of intact cells occurred between
the 9th and the 11th days after tumor
transplantation,
although
ascitic
liquid
volume increased progressively
until the
animal died (2). These results agree with
FIG. 2. Mean glutamine
(A), glutamate
(BJ, asparagine (CJ. and aspartate
(D) concentrations
in plasma
(0) and ascitic fluid (0) of tumor bearing mice during
tumor development.
Each point represents
the average value for 12 animals.
Bars, SE.
L
0
6
Days
after
12
tumor
O6
tronsplontotlon
12
FIG. 3. Mean glycine
(A), proline
(B), alanine
(C),
and threonine
(D) concentrations
in plasma (0) and
ascitic fluid (0) of tumor
bearing
mice during
tumor
development.
Each
point
represents
the average
value for 12 animals.
Bars. SE.
those previously reported by Andersson
and Heby (13).
Figure 2 shows the concentrations of
glutamine, glutamate, asparagine, and
aspartate in both plasma and a&tic fluid
throughout the life span of inoculated animals. The concentrations of glutamine and
asparagine were always higher in the
plasma than in the ascitic liquid. On the
other hand, the concentrations of glutamate and aspartate in ascitic liquid were
superior to those in plasma. Figure 3 depicts the characteristic concentration profiles of glycine, alanine, proline, and threonine in both plasma and ascitic fluid. The
concentrations of these amino acids were
higher in the ascitic liquid than in plasma,
and they reached maximum levels on the
11th day following tumor transplant. After the 11th day, the concentrations of glytine, alanine, proline, and threonine in ascitic liquid sharply decreased. This was
probably the combined result of the observed ascitic fluid volume increase and the
active cell number decrease. Plasma concentrations of glyeine, alanine, and proline
decreased in the first days, but then the
670
MARQUEZ
ET
AL.
b
5
15
25
Incubation
5
15
25
time (mlnl
FIG. 4. Glycine (A), alanine (B), threonine
(C), and serine (D) release by Ehrlich
ascites cells incuhated in buffer (0) and in the presence of 0.5 mM glutamine
(A), 5 mM glucose (0), or 0.5 mM glutamine plus 5 mM glucose (0) as the only energy and nitrogen
sources. The cellular
suspension
was
always 60 X lo6 cells/ml.
The arrows
indicate
the addition
of substrates.
Each point is the mean of
six different
experiments
in duplicate.
Bars, SE.
concentrations
of these amino acids were
similar to the control values during the remaining life of the animals. On the other
hand, the concentration
of threonine
in
plasma decreases almost 50% of the controls in the final days of life.
The results
of incubations
of freshly
harvested cells in media which contained
5 mM glucose, 0.5 mM glutamine, or 5 mM
glucose plus 0.5 mM glutamine, are shown
in Fig. 4. Cells were initially incubated in
phosphate-buffered
saline for 15 min to allow them to reach a new steady state. This
was revealed by the observation
of constant concentration
values of amino acids
released to the medium during this period.
After 15 min, glutamine, glucose, or glutamine and glucose were added to serve as
nitrogen and energy sources. Glycine concentrations
rapidly increased in the incubation medium when the cells were incubated only in the presence of glutamine
(Fig. 4A). On the other hand, when glucose
was added, glycine release fell sharply 5
min after the addition, probably because
the amino acid had been utilized for biosynthetic
processes in the presence of a
convenient energy source. The presence of
glutamine in the medium, either by itself
or with added glucose, resulted in an efflux
of alanine (Fig. 4B) and threonine
(Fig.
4C). Despite the high concentrations
of
proline found in the cells (Table I), only a
very small amount of this amino acid appeared to be released following
the addition of both glucose and glutamine to the
incubation medium (results not shown).
The concentrations
of the essential
amino acids, valine, leucine, isoleucine plus
phenylalanine
(which coeluted in the chromatogram),
and tyrosine, are depicted in
Fig. 5. In all cases, the plasma concentrations were higher than those of the ascitic
fluid; the concentrations
in both fluid compartments
tended to equalize close to
death and was coincident with the decline
in the numbers of active tumor cells whose
proliferation
had ceased. Both plasma and
ascitic liquid concentrations
tended to rise
from the seventh day after transplant.
The
similar patterns of the plasma concentrations of branched-chain
amino acids are
very striking.
Following
transplant
the
concentrations
of branched-chain
amino
acids in plasma sharply decreased. A peak
was observed on the fourth day. This increase in plasma branched-chain
amino
acid concentrations
presumably
reflected
NITROGEN
TABLE
METABOLISM
I
CELLULARCONCENTRATIONS
(mM) OFAMIINOACIDS
IN EHRLICH ASCITESCELLS
Days after tumor transplantation
Amino
acid
Seventh
Eleventh
2.9 * 0.2*
ND”
Gln
7.8 t 0.2*
Glu
4.4 f 0.2
0.80 f 0.04
1.30 zk0.04*
Asn
1.7 + 0.1
1.3 rt_0.1
Asp
15.4 f 0.7**
18.3 -t 1.1
GUY
Pro
9.2 It 0.5
14.0 t 0.5*
17.2 f 0.7*
Ala
9.2 k 0.5
2.8 f 0.3
4.6 f 0.3*
Thr
2.2 *0.1*
Val
0.93 f 0.07
ND
0.92 f 0.08*
Leu
1.8 f 0.1*
Be + Phe
0.70 k 0.04
0.26 f 0.01
0.46 f 0.06**
Tyr
1.9 f 0.1
2.1 f 0.1
LYS
ND
ND
kz
0.14 f 0.02
0.40 f 0.03*
Trp
2.0 f 0.1*
His
1.4 + 0.1
1.4 f 0.1
1.20 f 0.05
Ser
1.3 + 0.1
1.4 f 0.1
Met
4.8 + 0.2
4.5 f 0.2
CYS
Tau
3.0 f 0.2
4.5 k 0.2*
Note. Immediately after extraction from the animals, cells were centrifuged through silicone oil as described under Materials and Methods. Means f SE of
at least 10 different tumors.
a Nondetected.
bP < 0.0005.
cP < 0.05.
the increased output of these amino acids
by the muscles. The decrease observed on
the seventh day was probably due to the
high rate of tumor demand which coincided with the exponential phase of
growth. As for threonine (Fig. 4C), the i,n
vitro incubations showed that when only
glucose was present in the incubation medium the tumor cells did not release these
essential amino acids (results not shown),
although the intracellular pools were detectable, with the exception of leucine at
the seventh day (Table I).
Figure 6 shows the patterns of lysine, arginine, tryptophan, and histidine concentrations in plasma and ascitic liquid during tumor development. Arginine and lysine in plasma showed changes similar to
those described above for essential amino
acids. In contrast, the concentrations of
tryptophan significantly increased 24 h af-
IN TUMOR
BEARING
671
MICE
ter tumor transplant; afterward plasma
tryptophan tended to decrease. Histidine
in plasma remained within the normal
range. Arginine could not be detected inside tumor cells, at neither the 7th nor the
11th day (Table I). Mouse plasma has a
very high content of taurine (14); moreover, the concentrations of this amino acid
in plasma tended to increase during tumor
development; a peak was reached on the
7th day (Fig. ‘7D). The concentration of
plasma cysteine also increased (Fig. XT). In
contrast, there was an overall decrease of
plasma methionine throughout the life of
the infested animals (Fig. 7B). The concentrations of serine were always higher in
plasma than in ascitic fluid (Fig. 7A). In
the presence of glutamine alone, there was
no serine release into the incubation medium. However, when glucose was present,
either alone or with glutamine, serine was
sharply released into the incubation medium (Fig. 4D).
DISCUSSION
As Felig (15) indicates, the plasma free
amino acid concentrations under normal
A
sl
FIG. 5. Mean valine (A), leucine (B), isoleucine
+ phenylalanine (C), and tyrosine (D) concentrations
in plasma (0) and ascitic fluid (0) of tumor bearing
mice during tumor development. Each point represents the average value for 12 animals. Bars, SE.
672
MARQUEZ
A
B
225.
-75
I
Cl
D
I
75.
1
s
2 50.
P
e
’ 25.
k
-25
6
Days. otter
I
12
tunwr
I
0
6
transplantotm
12
FIG. 6. Mean lysine (A), arginine (B), tryptophan
(C), and histidine (D) concentrations
in plasma (0)
and a&tic fluid (0) of tumor bearing mice during tumor development. Each point represents the average
value for 12 animals. Bars, SE.
conditions show relatively little intra- or
interindividual variations; they are maintained at constant levels by a net balance
between the metabolic amino acid uptake
and release by the tissues. This balance can
be perturbed in the presence of the tumor
by a number of means: (a) by variations in
the ingested protein (16); (bj by changes in
the intestinal absorption (16); (c) by alterations of the nonessential amino acid biosynthesis in liver (1’7); (d) by changes in
tissue oxidative breakdown of amino acids
(18); (e) by the differences between protein
synthesis and tissue proteolytic activities
(19); and (fj by tumor demand for the essential and nonessential amino acids
needed for tumor proliferation (20). Consequently, it is extremely difficult to attribute the observed variations of plasma
amino acid concentrations specifically to
one or more of the metabolic processes
mentioned. It must be also borne in mind
that the regulation of the metabolism of
each amino acid, and its interaction with
the control process is unique. Several attempts have been made by different groups
to study amino acid variations in the
ET AL.
plasma of cancer patients and tumor bearing animals (14, 21, 22). Nevertheless, as
Kawamura et al. (3) point out these experiments were single observations at a moment of time without regard for the stage
of tumor development. We present data for
almost the entire life span of animals bearing the Ehrlich ascitic tumor. However, it
is clear that the most critical changes occur between about 1 and 12 days following
inoculation. We point out our conclusions
concerning this time period and distinguish such conclusions from those occurring during the last couple of days of life,
in which numerous complex variables interact leading to the death of the host.
Although it was not possible to find a
common profile in the variations of the
amino acid plasma concentrations during
tumor development, for specific groups of
amino acids several analogous patterns
emerged. Plasma concentrations of tryptophan and cysteine showed immediate increases following inoculation. On the other
hand, the plasma concentration profiles of
the free essential amino acids, valine, leutine, isoleucine, phenylalanine, lysine, and
/-
A
IJaysatter,“lmx transplantation
FIG. 7. Mean serine (A), methionine (B), cysteine
(CJ, and taurine (D) concentrations
in plasma (0) and
ascitic fluid (0) of tumor bearing mice during tumor
development.
Each point represents
the average
value for 12 animals. Bars, SE.
NITROGEN METABOLISM IN TUMOR BEARING MICE
arginine showed common characteristics.
The sharp decrease manifested by all of
them 48 h following tumor transplantation
was most probably due to the increase in
protein synthesis in the host liver detected
during this period (23). An increase in the
plasma proteins following transplantation
was also found in mice bearing tumors (results not shown). The pronounced decrease
of branched-chain
amino acids observed
could not be attributed to a protein intake
deficiency, because the animals were well
fed and their total food intake decreased
only slightly 48 h after tumor transplantation (69 and 78% of the control values at
Days 1 and 2, respectively). Furthermore,
it is well documented that plasma concentrations
of essential branched-chain
amino acids increase in the early stage of
fasting (24) or after subjecting animals to
stress or injury (25). A well-defined peak in
essential amino acid patterns was observed 4 days after the tumor transplant.
This coincided with the initial phase of
growth of tumor cells, and probably, at
this time, large amounts of amino acids
were being liberated by the increased proteolytic activity of the host tissues (26).
Consequently, these essential amino acids
seem to be in transit from the host to the
tumor. In the final days of life, the concentration of the essential amino acids in
plasma of experimental
animals returned
to normal values; there was also a parallel
increase in the concentrations
of essential
amino acids in ascitic fluid, with the exception of arginine. The decrease of the arginine concentration in ascitic liquid and the
lack of free intracellular
arginine are not
surprising since this amino acid should be
avidly consumed by the tumor cells as a
source of ornithine needed for its accelerated polyamine biosynthesis (27).
The results of the two paired amino
acids glutamine/glutamate
and asparagine/aspartate
have confirmed glutamine
as the major nitrogen source for tumor
cells. The increase in plasma glutamine in
the first 2 days reflected the simultaneous
modulation of glutamine synthetase and
glutaminase activities in liver and kidney,
conducive to a net production of glutamine
by the host tissues (28). The low concentra-
673
tions of glutamine in ascitic fluid attest to
the avidity of tumor cells for this amino
acid (7). The incubation experiments confirmed that even in the presence of glucose,
the glutamine added exogenously was almost exhausted after 15 min of incubation
(results not shown).
The concentration
profiles of threonine
and the nonessential amino acids, glycine,
alanine, and proline, in both plasma and
ascitic fluid were very similar. The fact
that the concentrations
in ascitic fluid
were always greater than those in plasma
(triple at the 11th day) suggest that these
amino acids may be produced by the tumor
cells. Furthermore,
their concentrations
were highest inside the cells (Table I) and
the in vitro incubations confirm a net release of these amino acids by the tumor
cells. Alanine can be produced by tumor
cells de MWO from glutamine and glucose
(29). Proline and alanine are described as
end products of glutamine metabolism in
enterocytes (30) and there is a strong similarity between the pattern of substrate utilization by tumor cells and that of intestinal mucosa cells. Nevertheless, in u’tro incubations in the presence of glutamine
plus glucose did not account for the proline
release. On the other hand, it is noteworthy that the high concentrations of proline
and glycine found in the ascitic fluid might
result from the action of a tumor collagenase on the extracellular
matris surrounding the tumor cells (31). The observed concentration gradient for threonine is very
striking because threonine is always listed
as an essential amino acid. However, Sauer
ef trl, (5) also report that Walker 256 carcinomas release threonine
together with
glycine, alanine, and aspartic acid in order
to increase the net glucose production in
the host. L’ery little-information
is available on the metabolism of threonine in
mammals and further
investigation
is
needed to determine if threonine is rle ROIV~
produced in tumors.
The results for serine revealed a gradient of this amino acid from the plasma to
the ascitic liquid. The ir/ tlitro incubations
showed that tumor serine re!ease occurred
only in t.he presence of glucose. These results support the hypothesis that serine is
674
MARQUEZ
synthesized via 3-phosphoglycerate. Glytine can be formed from serine. As Snell
and Weber (32) recently pointed out, in
hepatomas serine is catabolized only by
the hydroxymethyltransferase
reaction to
produce glycine destined for nucleotide
biosynthesis. In mammals glycine may
also derive from glutamine (33).
The profiles of the sulfur amino acids
also merit mention. Methionine participates in three processes, protein synthesis,
polyamine synthesis, and transmethylation reactions (34). In the first 2 days,
plasma methionine shows the characteristic decrease exhibited by the essential
amino acids but, in contrast, its plasmatic
concentrations are not recovered during
the life span of the animals. In the ascitic
liquid, methionine increases progressively
its concentration from the 4th until the
11th day in parallel with the arrest of cellular proliferation. The balance between
plasma and ascitic liquid concentrations
indicates a net flux of this amino acid from
the host to the tumor, as should be expected due to the very active polyamine
biosynthesis in these cells. Malignant rodent cells show an absolute requirement
for methionine (35), and the S-adenosylmethionine descarboxylase activity is
strongly stimulated in Ehrlich ascites
cells, simultaneously with the tumoral
DNA synthesis (36). On the other hand,
plasma cysteine and taurine significantly
increased in the tumor bearing animals.
Cysteine concentration in normal tissue is
low, but that of glutathione is much
higher, and it has been assumed that,
among its many functions, glutathione
serves as a source of cysteine (37). Tumor
cells can also store both cysteine and taurine (Table I). Taurine in rats has been described as an important indicator of stress
because the plasma concentrations exhibit
an increase in stressful situations (38).
Pine et al. (14) described an accumulation
of taurine in mice mammary tumors. Taurine is biosynthesized in the liver, but at
the present time, the cause of the increased
amounts of taurine observed in the plasma
of tumor bearing animals is unknown.
Consideration of the results presented
here leads to the conclusion that the study
ET AL.
of the dynamics of amino acid interchange
between host and tumor will continue to
challenge those investigators studying the
molecular effects produced by the tumor in
the host. As Vincent (39) recently pointed
out, little is known of the remote effects resulting from tumor consumption of essential nutrients. The present work shows
that the observed concentrations of essential and nonessential amino acids exhibit
complex variations resulting from a continual interplay between the rates of their
consumption or production by both the tumor and the different tissues of the host.
ACKNOWLEDGMENTS
The authors are very grateful to Drs. M. MartinezCarrion and V. Valpuesta for their critical review.
Thanks are due to A. R. Treitero for technical assistance and to D. W. Schofield for editing the manuscript.
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