Download Energy Metabolism and Requirements in the

[CANCER RESEARCH 37, 2336-2347, July 1977]
Energy Metabolism and Requirements in the Cancer Patient1
Vernon R. Young
Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Summary
As a basis for assessing energy metabolism and require
ments in cancer patients, selected aspects of whole-body
energy metabolism are considered, with particular refer
ence to basal energy metabolism and factors that affect it.
The importance of protein metabolism in relation to whole
body energy metabolism is emphasized. The need to con
sider the intimate relationships between protein and energy
nutrition and metabolism in the comprehensive evaluation
of the energy needs of cancer patients also is stressed.
Published data on the basal metabolic rate of patients with
malignant disease are difficult to evaluate for their meta
bolic and nutritional significance. Quantitative estimates of
the utilization of major fuel sources in cancer patients are
still quite limited, but the available data suggest that there
may be a change in the pattern of fuel utilization, with lipid
sources predominating, an altered regulation of glucose
metabolism, and a reduced efficiency of energy utilization
in some, but not all, cancer patients. The best balance of
the major exogenous energy sources and level of total
energy intake sufficient to meet the energy demands of
organs and the whole body cannot be easily predicted and,
therefore, only crude guidelines can be suggested.
Introduction
Investigations of the characteristics of energy metabolism
and of the assessment of energy requirements in cancer
patients are limited. However, the maintenance of cell and
organ function involves decreased entropy, and this implies
an increased requirement for energy. Thus, an adequate
understanding of the metabolism and utilization of fuel
sources and of the regulation of whole-body energy ex
penditure is important in considerations of nutritional ther
apy for cancer patients.
An important question to explore is whether the presence
of cancer per se presents a unique set of problems in
relation to energy metabolism and requirements, or
whether the problems are similar to those of patients with
nonmalignant disease. Because cachexia, accompanied by
reduced food intake, is often a prominent feature of ad
vanced cancer (17, 77, 80), it could be argued that there is a
failure to maintain normal regulation and efficient patterns
of fuel utilization and, therefore, body protein composition
and cell mass. Hence, some selected aspects of energy
metabolism and factors that alter basal metabolism and the
I Based
on
a paper
presented
at
the
Conference
on
Nutrition
Therapy, November 29 to December 1, 1976, Key Biscayne, Fla.
2336
and
utilization and need for energy will be reviewed here as a
basis for assessing the status of energy metabolism and
requirements in the cancer patient. It is hoped that this brief
review will help to identify those aspects of energy metabo
lism and nutrition that deserve more critical and extensive
investigation, in order to develop more effective and ra
tional approaches to the nutritional support of patients with
malignant disease. Major emphasis will be given here to
data from human studies.
Basal and Resting Metabolic Rate
Physical activity and basal metabolism are among the
major factors that determine total daily energy expenditure.
The former will not receive detailed mention here; for the
present, it will be assumed that, in energy expenditure due
to physical activity, differences between cancer patients
and those suffering from other disease states and normal
subjects are due to the intensity of physical exercise and
time devoted to such activities. The metabolic aspects of
energy expenditure and utilization will receive the major
focus in this paper.
For individuals who spend a large portion of the day ‘
‘at
rest,―
the BMR,2 defined as the energy output of an individ
ual under standard resting conditions (bodily and mentally
at rest, 12 to 18 hr after a meal, in a neutral, thermal
environment), accounts for a significant proportion of total
daily energy expenditure (16). It is appropriate, therefore, to
consider first the biochemical basis of the BMR and some of
the factors that affect it.
At the outset, it must be noted that a precise determina
tion of BMR is not easy to achieve in practice (20), and a
more useful measure of metabolic rate may be obtained by
measurement of the resting metabolic rate (14). This may be
determined in a person at rest, 2 to 4 hr after a light break
fast. However, a distinction between basal and resting me
tabolism does not require particular emphasis in the discus
sion that follows and, forthe present purpose, these param
eters of energy metabolism will be used synonymously.
Resting energy metabolism represents the combustion of
fuel sources needed to provide energy for metabolic proc
esses involved in maintaining the function and integrity of
cells and body organs and for the mechanical processes
involved in keeping the body alive. Synthetic processes,
such as protein, nucleic acid and lipid synthesis and gluco
neogenesis, transport processes, including the pumping of
ions to maintain ion gradients within cells and organelles
and, finally, mechanical processes involving muscular ac
Cancer
2 The
abbreviation
used
is:
BMR,
basal
metabolic
rate.
CANCERRESEARCHVOL. 37
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Energy Requirements
tivity, require energy inputs. These are obtained from high
energy phosphate compounds, usually ATP, generated dur
ing the oxidation of the major energy-yielding substrates.
Hence, these various processes and their associated energy
needs constitute a biochemical basis of the basal rate of
energy expenditure. Various factors alter the activities of
these processes and the types of substrate used for supply
ing energy.
The contribution made by the various body organs to
BMR in the healthy adult is summarized in Table 1. It has
been estimated that the liver accounts for approximately
27% of resting metabolism, with the brain, skeletal muscle,
and remainder also being important sites of total body
energy expenditure (65). Thus, the proportion ofthese body
organs in relation to total body weight will affect values for
BMR when expressed per unit body weight or surface area.
Because the relative contributions of the body organs to
total body weight change with growth and development
(53), aging (72), malnutrition (21), and pathological states,
interpretation of the metabolic significance of differences in
BMR among differing groups of patients must be cautious.
It is possible that alterations in the body organ compart
ments would bring about differences in BMR without any
real change in the status of energy metabolism within the
organs themselves.
this lactate is more or less quantitatively resynthesized to
glucose (45). This cyclic metabolic pathway, involving con
version of glucose to lactate and the return of lactate to
glucose, is termed the Con cycle. Utilization of lactate for
glucose synthesis is an energy-requiring process, and an
increased rate of conversion of lactate to glucose has been
proposed as a mechanism for the increased energy expend
iture of the tumor-bearing patient (17, 25). It is well known
that tumors show high rates of anaerobic glycolysis with
production of lactic acid (24, 79), and studies in cancer
patients show increased lactate production.
Holroyde et al. (36) recently reported a series of studies
on Con cycle activity in a heterogeneous group of patients
with metastatic carcinoma (Table 3). Patients without pro
gressive weight loss appeared to have normal glucose me
tabolism, but Con cycle activity was increased in patients
with progressive weight loss, showing that lactate produc
tion rates were higher in these patients.
Gold (25) proposed that the increased rate of resynthesis
of glucose in the liver from the lactate produced by the
tumor acts as a significant energy drain on host tissues.
However, from the data shown in Table 3 and from addi
tional estimates of the rate of lactate production and recy
cling in cancer patients (68, 81), increased Con cycle activ
ity does not appear to account for a significant fraction of
daily energy expenditure. Thus, if 6 moles of high-energy
Fuel Sources in Relation to Resting Metabolism
The major substances used as sources of energy in mam
malian tissues are glucose, fatty acids, ketone bodies,
amino acids, and lactate (9, 45). Although these are inter
changeable sources of energy in the whole organism, mdi
vidual organs show some specificity with respect to their
use of fuel sources (Table 2).
For a well-nourished adult subject in the basal state,
glucose is utilized at a rate of 140 g/day, equivalent to 560
kcal. The oxidation of amino acids, liberated during the
course of tissue protein breakdown, can be estimated to
amount to 75 g/day, or 375 kcal. The rest of the daily energy
flux is accounted for largely by the oxidation of 130 g
triglyceride, equivalent to 1170 kcal.
In the resting human adult, about 20 g lactate are formed
daily, mainly by blood cells, and, in the fasting organism,
Table 2
Fuels of individual tissues
[Modified
from Krebs (45).]
energyTissueGlucoseEryth
Major source of
rocytes, leukocytes, re
nal medulla, brain, skeletal
muscle
(exercise),
some
malignant tumors, fetal tis
mucosaFree
fatty acids―Liver,
sues, intestinal
kidney cortex, cardiac
muscle,skeletal muscle(ex
exercise)Ketone
bodies―Cardiac
cept in severe
muscle, renal cortex,
brainOther
skeletal muscle,
sourcesAmino
energy
(minor)Lactate
acids
fromglucose)Ethanol,
(derived
glycerol,
pen
toses (minor)
Table 1
Distribution
of oxygen utilization
aresting, among the major body organs in
manFor
healthy
a 65-kg man [from Passmore
(65)].Oxygen
and Draper
con
sumption
total)LiverOrgan
27splanchnic
(including
mm)
67
area)Brain
19Kidneys
47
7Heart
10Skeletal
18Remainder
muscles
17
26
45
19Total
48
280
(ml/
Resting
metabo
lism (% of
a These
amounts
sources
can
be
used
in
quantitatively
significant
by tissues shown.
Table 3
Glucose turnover and Con cycle activity in patients
carcinoma
Calculatedfrom
data of Holrodye et
al.(36).Status
of
body wt
turn
over rate
cycle
activity
with metastatic
glucose
oxidation
(mg/kg/
lossGlucose
(mg/kg/hr)Con(mg/kg/hr)% turnoverGlucose
hr)Progressive
±26@
None196
100
110@26b90
a Mean
± S.D.
for
8 patients.
S Mean
± S.D.
for
6 patients.
±21
19±243
±7
18±262
±4
48±6
JULY 1977
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2337
V. R. Young
phosphate are consumed for each mole of glucose pro
duced from lactate (51), this would involve a substrate en
ergy requirement of about 110 kcal. From the data provided
by Holroyde et al. (36), it can be estimated that less than
10% of daily energy expenditure can be accounted for by
the conventional cost of lactate recycling. Analyzing this
problem from a somewhat different perspective, it can be
estimated that, if 15% of total lactate production is oxidized
to CO2and H2O,and 85% of lactate is converted to glucose,
there will be a maintenance of high-energy phosphate bal
ance. This assumes, of course, that lactate is the only
metabolite being utilized (51). It is difficult to accept, there
fore, that changes in Con cycle activity are a significant
cause of the marked body wasting in patients with progres
sive neoplasia. Nevertheless, it is of interest that Holroyd et
al. (36) observed highest Con cycle activity in patients with
greatest total energy expenditure.
The pattern of fuel sources changes markedly if fasting
continues significantly beyond the usual overnight period.
For a fast lasting 3 days or longer, glucose oxidation is
decreased, in parallel with reduced rates of gluconeogene
sis (9, 64) and the oxidation of fatty acids and ketone bodies
is increased, with the brain making major use of the latter as
its principal fuel source (63). A picture of fuel utilization
during short and long-term fasts is shown in Chart 1. This
change in the pattern of fuel sources and utilization is
accomplished by alterations in substrate availability, in hor
monal balance, and by the regulatory effects of ketone
bodies on amino acid oxidation in peripheral tissues (71).
In terms of energy requirements, glucose and lipid
sources are utilized with about the same efficiency, at least
when assessed in terms of the potential yield of ATP (44)
from isocaloric intakes of glucose and fat. Protein is some
POSTABSORPTIVE
BRIEF
FAST
(2-3
what less efficient as a source of energy, depending upon
the amino acid composition of the protein and because
energy is used for the elimination of nitrogen via urea syn
thesis (44).
It should be recognized, however, that an estimation of
the availability.of utilizable energy from carbohydrate (glu
cose) and lipid fuel sources, based on calculation of maxi
mum ATP yield, may have limited significance in relation to
an assessment of the status of energy metabolism and
substrate utilization in the whole organism. Various factors
serve to modify the yield of utilizable energy which may be
derived from the combustion of these fuel sources. The
importance of these factors may vary among individuals and
within subjects due to changes in physiological and patho
logical states (34).
The efficiency of generation of ATP might vary due to
changes in the coupling of oxidative phosphorylation, and
the efficiency of utilization of ATP does not necessarily
remain constant, due to factors such as tissue phosphatase
activity and ion concentration. Furthermore, a variable ac
tivity of “futile―
cycles would result in changes in the
amount of energy available for use in energy-requiring
processes. These cycles occur when there are 2 opposing
metabolic pathways in the cell in which the reactions in the
forward and reverse directions are catalyzed by separate
enzymes (40, 60). For example, 3 futile cycles in carbohy
drate metaboli@mare shown in Chart 2. In one direction, the
GLUCOKINASE
GLUCOSE
CYCLE
AlP
GLUCOSE
ADP
GLUCOSE 6P
DAYS)
GLUCOSE
6P PHOSPIIATASE
PHOSPHOFRUCTOKINASE
@
FRUCTOSE
6P
FRUCTOSE 6P
PROLONGED
(_v
GLUCOSE ,“
diP
FAST
FRUCTOSE
%t-_..-J
‘•@),‘
KETONE
FRUCTOSE
BODIES
•q
diP
PHOSPHATASE
PEP
CYCLE
‘
AMINO
ACIDS
Chart 1. Major patterns of fuel utilization in the postabsorptive state
(overnight fast) and after short- and long-term fasts. Glucose utilization is
high in the postabsorptive state with depletion of glycogen reserves and
gluconeogenesis increasing during the short-term fast. Subsequently gluco
neogenosis and flow of amino acids from muscle are reduced with a rise
in blood ketone bodies and increased utilization by the brain. Thus, the
quantitative contribution of the fuel sources to overall body energy metabo
iism depends upon the nutritional state. This picture is based principally
on work reviewed in Refs. 9, 63, 64, and 71. FFA, free fatty acids.
2338
ADP
AP
GOP
ATP
PEP
DECREASED
PYRUVATE
PEP
@“-GTP ADP.*―j
PYRUVATE
CARBOXYKINASE
OAA
CARBOXYLASE
OAA
(CYJ@)(,Mit)
Chart 2. Three futile cycles in carbohydrate metabolism: the glucose 6phosphate (glucose 6F), fructose 6-phosphate (fructose 6P), and phospho
enolpyruvate (PEP) cycles. The variable activity of these cycles, which do
not involve a net change in the levels of reactants (e.g. , glucose, fructose 6phosphate or phosphoenolpyruvate), will result in changes in rates of ATP
generation, relative to rates of ATP hydrolysis. Taken from Katz and Rogns
tad (40). OAA, oxaloacotic acid; CYTO, cytoplasmic; MIT, mitochondrial.
CANCERRESEARCHVOL. 37
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Energy Requirements
reaction requires the participation of a high-energy corn
pound, such as ATP, while the reaction in the opposite
direction is energetically spontaneous. Although there is no
net flux of reactants in these cycles, the cycling causes ATP
hydrolysis, and thus an energy ‘
‘wastage.―
However, the
recycling may not be as wasteful as it appears, as pointed
out by Katz and Rognstad (40), if these cycles serve a role in
metabolic regulation.
Although there are no adequate experimental data to
estimate the fraction of total ATP formed and used in recy
cling, a variation in the activity of futile cycles has been
proposed as a basis for adaptation to high-energy intakes
(74) and for differences in the propensity of individuals with
generous energy intakes to become obese (39). Similarly,
it can be speculated that the changes in the availability of
to, the sodium pump is relatively small.
Cell protein synthesis appears to be of quantitative sign if
icance in relation to the utilization of energy substrates
under basal conditions, and various observations may be
used to support this concept. Thus, the relationship be
tween the intensity of whole-body protein metabolism in
mammalian species and adult body size is described by the
same power of body weight as is basal energy metabolism
among these species. Brody (7) showed that the variation in
obligatory nitrogen losses, assumed to be an index of the
dynamic state of body protein metabolism, among 9 mam
malian species, ranging in size from the mouse to the cow,
correlated with the 0.72 power of body weight, expressed in
kg (Chart 3). This is essentially the same function of body
weight that best correlates basal energy metabolism among
ATP and in the efficiency of energy utilization might arise as these various species (43). More recently, Munro (58) re
a consequence of changes in recycling in disease states viewed this aspect of body protein metabolism and corn
and under the varying conditions of therapy. This problem
puted the power function of body weight that best corre
deserves investigation.
lated various parameters of tissue and whole-body protein
Another factor that must be mentioned is that, if glucose
metabolism, including albumin and ceruloplasm turnover
or other carbohydrate sources are converted first to fat for and liver RNA content, among mammals of different body
the temporary storage of energy, before being used to meet size. The estimates of Munro (58), together with those of
energy requirements, there is a reduction in the amount of Brody (7), demonstrate a close relationship between the
utilizable energy obtained from the intake of a given amount
intensity of body protein ‘r*ietabolismand rate of energy
of carbohydrate. Krebs (45) estimated that this loss of utiliz
expenditure in mammals, including man.
Estimates of the rate of whole-body protein synthesis in
able energy is equivalent to 2 molecules of ATP per C2
adult human subjects provide additional support for the
segment of long-chain fatty acid or about 7% of the utiliza
ble energy to be stored. Flatt (18) estimates the loss of view that protein turnover (synthesis and breakdown) ac
counts for a significant proportion of basal energy expendi
utilizable energy to be equivalent to about 20% of the ca
ture. Table 4 summarizes some published estimates of rates
loric value of the glucose channeled into lipogenic path
ways, and this appears to be a significant energy cost. of whole-body protein synthesis in well-nourished adult
subjects. Although the estimates vary, depending upon the
Whatever the precise value, there is an energy cost associ
ated with storage and the later utilization of fuels. Hence method used forthe determination (86), whole-body protein
the efficiency of substrate utilization for meeting the basal synthesis approximates 3 to 4 g per kg body per day or 200
to 300 g for a 70-kg subject. Assuming each mole of peptide
energy requirement will be determined, in part, by the meta
bolic pathways followed before the fuel sources reach the bond requires the equivalent of about 5 moles of ATP and
that ATP is formed from glucose at a cost of 18 kcal/mole
terminal stage of oxidation.
(44), it can be calculated that about 180 kcal of substrate
would be required to support this amount of peptide bond
Significance of Ion Pumping and Protein Turnover in En
synthesis. This would be equivalent to about 10% of basal
ergyExpenditure
Two processes thought to account for a significant frac
tion of the basal energy expenditure are ion pumping and
protein turnover (synthesis and breakdown). The mainte
nance of electrochemical gradients through the active
transport of ions requires energy; it has been suggested
that 40 and 52% of the in vitro aerobic energy expenditure of
kidney cortex and brain slices, respectively, is linked to
sodium-potassium pumping (91). Similarly, the transport of
sodium and potassium in liver (15) and tumor cells (48) has
been estimated to account for 35 and 85% of energy metab
olism in these tissues, respectively. Support for the concept
that ion pumping is an important component of basal en
ergy metabolism is suggested from the increased metabolic
rate in response to thyroid hormone and catecholamines
which appears to be due to increased ATP utilization as a
consequence of altered activity of sodiurn-potassium-ATP
ase (35). However, Himms-Hagen (35) has concluded that,
for most normal tissues, the proportion of total cell and
organ energy metabolism controlled by, or directly related
z
z
w
0
2
>---
—
:@—
I0,000
5,000
U)
0
z
w
0
0
z
w
I ,000
500
I 00
50
Ql
.0
10
00 500kg
BODY WEIGHT (N)
Chart 3. Schematic relationship between the obligatory urinary nitrogen
loss (urine nitrogen output after initial adaptation to a very low or protein-free
intake) and adult body size in mammalian species. As shown, the output of
nitrogen is related to the 0.72 power of body weight (expressed in kg)
suggesting, as discussed in the text, that nitrogen output or metabolism is
closely correlated to energy metabolism. Drawn from the data of Brody (7).
JULY 1977
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1977 American Association for Cancer Research.
2339
V. R. Young
energy expenditure. This estimate does not account for the
energy costs of amino acid transport, RNA synthesis, turn
over of the —CCAterminus of tRNA, synthesis of nonessen
tial amino acids, and energy cost of protein breakdown.
Furthermore, it is assumed that the oxidation of glucose
results in the generation and availability of 36 moles ATP
per mole glucose oxidized, but as discussed earlier, this
maximum yield of ATP is subject to variation and in all
likelihood it will be less. Millward et al. (54) have estimated
the energy cost of protein synthesis to be about 1.4 kcal/g
protein. On this basis, protein turnover in the adult subject
would account for about 25% of the basal metabolic rate.
These figures underestimate the quantitative contribution
of protein synthesis and breakdown to basal energy metab
olism. Thus, it is reasonable to assume that about one-half
of resting energy metabolism may be associated with pro
tein turnover. For this reason, it would be anticipated that
the replenishment of tissue and organ protein content in the
initially depleted patient would require an increased energy
intake above that required for normal maintenance. Fur
thermore, evidence indicating a high energy cost of growth
in infants and children (47, 66) supports this view.
Finally, resting energy metabolism per unit of body
weight declines with progressive growth and development
within a mammalian species (43). This fall parallels the
reduced intensity of whole-body protein synthesis during
this period (e.g., Ref. 88). We (95) have explored the rela
tionship between whole-body protein synthesis rates and
energy metabolism in human subjects at various ages, and
the results of these studies are shown in Table 5. It can be
seen that there are marked differences in the intensity of
whole-body protein synthesis, expressed per unit of body
weight, among the various age groups. However, these
differences are not as evident for whole-body protein syn
thesis expressed per unit of resting energy metabolism.
These observations emphasize further the close and, pre
sumably, causal relationship between whole-body protein
turnover and resting energy metabolism.
Changes in host tissue and total-body protein metabolism
due to the presence of a growing tumor (26), physical
trauma (19), and surgery (62) and alterationsthat may occur
as a result of chemotherapy and radiation treatment would
influence also the utilization and requirements for energy.
Thus, a critical assessment of energy utilization and re
quirements in the cancer patient should take into account
these intimate interrelationships
energy metabolism.
among body protein and
Factors Affecting BMR
Age, nutritional
status, temperature,
hormones,
and
pathologicalstates,includingtrauma and infection,
affect
the resting metabolic rate. The effects of age have been
discussed by others (43, 66, 72). Also, changes in deep body
temperature are well established (20). If body temperature is
raised by 1°,either by fever or by warming the body, the
metabolic rate increases by about 12%.
The effect of nutritional state is important in the context
of energy metabolism, particularly because body nutrient
depletion is common in cancer patients. The effects of
starvation and undernutrition on basal metabolism have
received considerable investigation, and this has been the
topic of several reviews (20, 30, 42, 87). Brief fasting does
not change total-body oxygen consumption and, thus, heat
production, but a longer period of restricted food intake
does influence whole-body energy expenditure (31).
Chart 4 summarizes results, discussed previously by Oar
row (20), of a study by Benedict et al. (2). The major findings
of this study are shown here to emphasize a number of
points that should be considered in evaluating results of
studies of energy metabolism in cancer patients. First, it
can be seen that undernutrition reduces BMR to a greater
extent than the effect on body weight. Thus, the fall in BMR,
under these conditions is due to changes in the metabolic
activity of tissue as well as a loss of active tissue mass. On
the basis of studies during acute starvation, Grande et a!.
inpremature
Total daily protein
synthesis
Table 5
in relation
to energy metabolism
womenSummarized
babies, infants, young male adults, and elderly
fromPicou
from Young et al. (94). Studies with infants
and Taylor-Roberts
(67).Total
synthesisg/kg/Group
g/kcalNewborn
body protein
Age
0.09Infant
day
1-46 days
7Young
0.01Elderly
adult
18
0.15 ±
10-20 mos.
20-23 yr
3
0.1 1 ±
69-91 yr
2
0.11 ±0.03
Table 4
Some estimates of the mean rate of whole-body protein synthesis in adult subjects,
determined
by constant
infusion
Subjects
Author(s)3
No. and sex
M
Label
protein syn
thesis (g/kg/
day)
19-50
L-[U-'4CjLysine
2.6
Waterlow (85)
3 M, 1 F―
6 M
5 M
52-75
31-64
31-46
L-[1-14C]Leucine
L-[U-14C]Tyrosine
L-[a-15N]Lysine
4.1
4.6
3.5
O'Keefe et al. (62)
James et al. (38)
Halliday and Mc
4 M, 2 F
20-25
[15N]Glycine
3.0
Keran (33)
Steffeeet a!. (75)
a Preoperative
2340
Age (yr)
of labeled
acidWhole-body
amino
patients.
Other
studies
involved
healthy
subjects.
CANCERRESEARCHVOL. 37
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Energy Requirements
CHRISTMAS
THANKSGIVING
0
I7OO@
0
U
z
0 I600@
IU
I 500 P
S
a.
I4
Ui
I
-i
4
I40O@
U)
4
I300[
@i
:
@
SEPT
OCT
NOV
DEC
JAN
FEB
27
27
26
26
25
24
Chart 4. Changes in basal heat production and body weight in 7 healthy
subjects studied for the effects of a restricted energy intake. Taken from
Benedict et al. (2). The dietary restriction began on October 4, 1917, and
finished on February, 3, 1918, but it was interrupted with a free-choice diet
between November 29 to December 2, inclusive, and December 20 to January
6, inclusive.
refeeding than during initial adaptation to a fast in a healthy
subject.
In addition to undernutrition, the effects of excessive
energy intakes on energy expenditure and BMR have been
reviewed recently by others (20, 52, 74). Overfeeding of
normal subjects does not always result in the expected
weight gain despite unaltered physical activity. Various
studies indicate that, over a period of excess energy intake,
there is an increase in oxygen consumption in the resting
state and that this thermogenic effect of high energy intakes
is greater during exercise (52, 74).
From these various observations it is difficult to general
ize about the effect of nutritional state on basal metabolism.
It will depend upon when it is measured, how it is calcu
lated, and current as well as previous nutritional history.
These points should be kept in mind in the critical evalua
tion of energy metabolism in cancer patients.
Physical trauma, e.g., due to burns or leg fracture, alters
the basal metabolic rate, the degree of change depending
upon the severity of trauma (92). The hypermetabolism may
cause a marked weight loss if it is not met by substantial
increases in energy intake, and Wilmore et al. (93) have
proposed that the calorigenic action of catecholamines is
the cause of the increased metabolic rate. However, the
mechanism of increased heat production in burned patients
requires further exploration, and accelerated rates of gluco
neogenesis and ureagenesis would account, in part, for this
increase in metabolic rate (92). Furthermore, it seems likely
that an increased rate of whole-body protein turnover is an
important factor. Recent studies (C. L. Kien, J. F. Burke, and
V. R. Young, unpublished results) summarized in Table 7, on
the effects of thermal injury, have shown that the rates of
whole-body protein synthesis and breakdown are higher in
children with larger burns. This higher rate correlates with
Table6
(31) suggested that the loss of tissue accounts for about
30% of the decrease
in metabolism.
On the other hand, in
long-term undernutrition, the loss of tissue is a major factor
determining the reduction in energy expenditure (20).
The results shown in Chart 4 also indicate that basal
metabolism is rapidly restored to normal levels upon refeed
ing. In this case, BMR, expressed per unit of body weight,
increases to greater than normal during early refeeding. An
increased rate of energy expenditure also occurs after
meals in children during early recovery from severe protein
calorie malnutrition (1, 8, 46). Brooke and Ashworth (8)
propose that this increased energy expenditure with refeed
ing is due to the increased rate of protein synthesis which
would involve an increased rate of ATP generation and
utilization. Of additional interest is that the fall in BMR with
continued fasting in obese subjects (5) also appears to be
‘.
related
constant
to
a
fall
[‘5N]glycine
in
whole-body
infusion
protein
model,
synthesis.
we
(J.
Using
C.
a
Changesin
breakdownin
rates of whole-bodyprotein synthesis and
fastFrom
5 moderately obese women after a 1-weektotal
V.R. unpublished resultsofJ. C. Winterer, B. R. Bistrian, and
withthe
Young. Estimatesof protein synthesisand breakdownmade
useof the [15N]glycine
(67).Protein
model of Picou and Taylor-Roberts
synthesis
(g/kg/day)Control
Diet period
1.8Fast
1.8%
Protein
break
down
1 .9
1.4―
change
a Different
(g/
kg/day)
—26
from control
0
(p < 0.05).
Table7
Effect of extent of
synthesisand
thermal injury on whole-body protein
childrenUnpublishedbreakdown rates in
Young.Burn
results of C. L. Kien, J. F. Burke, and V. R.
controlswere
patients ranged in age from 5 to 12years; unburned
ages 4 to 18 years.Whole-body
Winterer,
B. R. Bistrian and V. R. Young, unpublished results) have
observed that there is a significant decrease in the overall
body protein synthesis rate during a week-long fast in obese
women (Table 6).
Finally, the results of Benedict et al. (2) suggest that BMR
falls more rapidly with fasting after a period of temporary
protein
Burn size (%
surface
Breakdown0
area)
3.10.5-25
3.325-60
3.960
No. of obser
vations
(g/kg/day)
Synthesis
11
4
10
3.5
4.0
5.2
10
7.1
6.3
JULY 1977
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2341
@
—@
V. R. Young
the increased basal metabolic rate and energy expenditurefree
fatty acid oxidation, as well as carbon dioxide produc
which occur in extensive body burns (92).tion,
in 5 patients with metastatic malignant disease; stud
It must be concluded, therefore, that the basal metabolicies
andrate
were conducted in patients under basal conditions
changes in response to various physiological and path
areological
during glucose loading. The results of their studies
conditions. This makes it difficult to evaluate fullyshown
ofthe
in Charts 5 and 6. Under basal conditions, rates
limited published data obtained in studies of energyglucose
andmetabolism
and free fatty acid ([1-'4Cjpalmitate) oxidation,
in patients with malignant disease, and to de
betweentermine
total CO2 production did not differ substantially
whether cancer has a direct influence on energycancer
glucosemetabolism
patients and controls. However, when a
and, particularly, on energy requirements.load
was given, these investigators observed that the oxida
patientsResting
tion of free fatty acid was suppressed less in cancer
that there was a lower rate of ‘
‘slow―
oxidation of
Metabolism in Cancer Patientsand
5).In
glucose, compared with controls (Chart
of the contribution to CO2 production by
Table 8, a summary is made of some results of studies
nonprotein sources, unlabeled by the administered
on the basal metabolic rate in patients with cancer. In view
[14C]glucose and [14C)palmitate, indicated that glucose
of the various factors that affect metabolic rate, and , in part,
loading reduced their oxidation in normal subjects but not
because of the limited information supplied in many of the
in cancer patients (Chart 6). Waterhouse and Kemperman
papers, it cannot be concluded that resting metabolism is
(83) interpret this finding to mean that continued intracellu
consistently increased in the cancer patient, compared with
loading.increased
lar oxidation of free fatty acids occurs with glucose
healthy controls. Resting energy metabolism appears to beCalculation
in many patients with Hodgkin's disease or leuke
GLUCOSEPOOL(“aol,/kglNORMAL
GLUCOSE OXIDATION
FFA OXIDATION
BMR'samong
mia. There is considerable variation in reported
presumably@NCERreflects
and within the various studies. This
+6
differences in methodological and biological varia
bles, as well as possible effects of different cancers and
+6
06
severity and stage of disease. In a study of the partition of
+6
energy expenditure between host and tumor in tumor-bear
I
ing rats, Morrison (56) did not find evidence of a consistent
change in resting metabolism.
Iaaol,/Rg/h,I
NORMAL
RAPID
-
@
@
Response of Energy Metabolism to Dietary Intake In the
Cancer Patient
CANCER
SLOW
+6
0.5 -
02healthy II fi
Potentially of greater nutritional significance is the possi
bility that the response of the cancer patient to semistarva
tion or nutritional rehabilitation may differ from that of.4
5. Estimates of glucose pool and rates of glucose (“rapid―
and
subjects or from patients suffering from nonmalig
“slow―
pools) and free fatty acid (FFA) oxidation in normal and cancer
nant diseases. Waterhouse and Kemperman (83) have ex
patients studied under basal conditions and during a glucose load (+G).
amined this possibility by determining rates of glucose andChart
Drawn from tabular data of Waterhouse and Kemperman (83).
Table 8
A listing of some published results on thebasal metabolic rate of cancer
patientsDescription
of popu
lationBMRCommentAuthor(s)Leukemia,
16 casesUsually
(3)Chronic
(89)leukemia,
myelocyticLow,
>120%
detailsBoothby
and Sandi
ford
normalFew
normal,Watkin
casesincreasedMalignant
4
(82)5
disease,—10%
aboveWaterhouse
casesnormalMultiple
myeloma—14-60%
(73)Carcinoma,
detailsSilver
et a!.
(73)izednormalLeukemia,
local
—6-57%aboveFew
detailsSilver
et al.
(73)and myeloid—12-91%
lymphaticnormalMalignant
detailsSilver
et al.
above
normalFew
(84)plasms,
neo
0-30%
aboveFew
Steinfield4 disease,Low
et al.
aboveWaterhouse
casesnormalLeukemiaIncreasedFew
4
(55)Neoplastic
and aboveWatkin
detailsMinot
and Means
and
casesnormal(90)Various
cancers,
9Usually
casesnormalhouse
2342
aboveTerpeka
and
Water
(76)
CANCERRESEARCHVOL. 37
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Energy Requirements
This suggests that there is a disturbance in normal homeo
static mechanisms involving the utilization of glucose and
other important fuel sources in patients with malignant
disease. In this context, changes in hormonal balance may
be of significance, and Goodlad et a!. (28) found reduced
insulin production in tumor-bearing male rats. Thus, an
alteration in insulin function might account for the abnor
mal glucose regulation.
The nutritional implications of these findings are more
difficult to assess. If glucose is not oxidized directly but is
first converted to fat before supplying utilizable energy, this
would involve an energy cost and, thus, a relatively higher
energy intake to meet the needs of body tissues.
Whether gluconeogenesis is inhibited by exogenous glu
cose as effectively in the cancerous as in the normal patient
does not appear to have received critical investigation.
However, sepsis increases gluconeogenesis, and this path
,
TOTAL
—UNLABE LE
GLUCOSE
RAPID
COD PRODUCTION
Im moIR/kg/h,I
NORMAL CANCER
NORMAL
NON
SLOW
CANCER
way is not responsive to the administration of glucose dur
ing the stress of infection (32). Thus, of possible interest in
relation to metabolic regulation by exogenous substrate is
the observation that treatment of rats with hepatocarcino
gens results in a loss of dietary feedback control of choles
terol biosynthesis (70). Additional studies would be desira
ble to explore the regulation of carbohydrate and lipid me
tabolism and the dynamic interrelationships between glu
cose, lipid, and amino acid metabolism in cancer patients.
Several investigators (12, 84, 89, 90) have stated that the
level of energy intakes needed to maintain body energy
balance are higher for cancer patients than for other sub
jects. Thus Waterhouse et a!. (84) determined energy bal
ance, using the indirect method of Newburgh etal. (59) in a
group of 4 patients with leukemia, Hodgkin's disease, and
carcinoma of the pancreas. The results obtained with 2 of
these patients are summarized in Chart 7, and it may be
seen for 1 patient that, even at a liberal energy intake, body
energy balance was markedly negative throughout. This
implies that, in some but not all cancer patients, dietary
energy sources are utilized with relatively low efficiency.
However, it must be recognized that the precision of the
estimates of energy balance made by Waterhouse et al. (84)
is not known and that accurate determinations of energy
balance are difficult to undertake. The magnitude of the
error in energy balance which could lead to marked body
weight loss is quite small compared with the range of en
ergy intakes and requirements within a group of subjects
(20). Furthermore, Garrow (20) concluded from his review
of the literature that rarely is energy balance established
over a period of a week or even longer periods in normal
subjects, and that an energy imbalance of up to 60,000 kcal
is tolerated by the control system in many people. It is not
surprising that little is known about the quantitative effects
of cancer on energy utilization and body energy balance in
human subjects.
As reviewed above, continued weight loss and clinical
deterioration have been observed in some patients, even
when given generous energy and protein intakes. However,
the effects of the cancer or treatment conditions may not be
NORMAL CANCER
- PROTEIN
NORMAL
CANCER
+6
+6
4@G
30 +6
/
2.0 -
.0
Ti
‘:___
n
Chart 6. Total carbon dioxide production and the contributions from oxi
dation of labeled glucose and fatty acids and from unlabeled nonprotein
sources in normal subjects and in cancer patients studied under basal
conditions and during a glucose load (+G). Drawn from tabular data of
Waterhouse and Kemperman (83).
CALORIE
(Kcols
INTAKE
@IO'@/6days)
M.J. (HODGKINS DISEASE)
J. F(ACUTE
15S
14.2
4.2
7.1
14.2
I
U
Ill
iz
6.2
67
S
III
6.7 19.5
LEUKEMIA)
14.2
4
a
‘O
(0
I,,
Chart 7. Estimated body energy bal
ance in relation to energy intake during
consecutive 6-day experimental periods in
2 cancerpatients.Drawnfromtabulardata
of Waterhouse
et al. (84).
0
-2
N
N,
0
U
-4
-6
Ui
U
2
-8
4
4
@1
Ui
‘10
12
0
@.1
4
I
@Z
U
@
JULY 1977
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2343
V. R. Young
exerted directly on the yield or availability of utilizable en
ergy from energy sources. Changes in energy balance or in
the capacity to achieve body energy equilibrium may be
secondary to alterations in the status of protein metabolism
in body tissues.
@
@
Goodlad et a!. (27-29) and Clark and Goodlad (11) have
shown that myofibrillar protein synthesis in skeletal muscle
of tumor-bearing rats is reduced and they (11) have con
cluded that this impairment is due to a defect in the capacity
of the 40 S ribosome subunit to promote a postinitiation
step in polypeptide synthesis. Lundholm et a!. (50) have
examined in vitro protein synthesis in muscle biopsies ob
tamed from a heterogeneous group of cancer patients, and
the results of these studies are shown in Chart 8. Protein
synthetic activity was impaired and the rate of protein
breakdown was increased in muscle samples from cancer
patients, compared with metabolically healthy controls.
However, Lundholm et al. (50) also observed that protein
synthesis in muscle from cancer patients, as well as normal
subjects, could be stimulated by the addition of high levels
of amino acids to the incubation medium (Chart 8). This
suggests that in the cancer patient there is a reduced effi
ciency of amino acid utilization for muscle protein synthesis
at normal levels of amino acid supply, but that this may be
overcome by raising the supply of amino acids to muscle.
The favorable gains in body weight and nitrogen retention,
as well as reduced morbidity and mortality, achieved by i.v.
feeding of cancer patients ( e.g., Ref. 13), support this
conclusion.
Energy Requirements of the Cancer Patient
Partly because the effects of cancer on host tissue and
whole-body energy metabolism are only partially under
stood, it is not possible to be precise about the minimum
intake of energy which would be sufficient to meet energy
needs and maintain body energy balance in cancer patients.
Furthermore, the balance between major exogenous energy
SYNTHESIS
DEGRADATION
P < 0.025
150 U)
-I
0
I-@
WITH
@
AMINO
U
ACID
SUPPLEMENTATION
z
—
U
:,
n.s.
100
@
-
P<0.05
>
@@uUL
Chart 8. Rates of in vitro protein synthesis and degradation by muscle
fibers from cancer patients, in relation to normal subjects. The relative
response of protein synthesis in vitro to high levels of amino acid supplemen
tation (10 times normal plasma levels) obtained with muscle samples from
cancer patients and control subjects is also shown. Drawn from results of
Lundholm
2344
et al. (50).
0 -
@0
—
z
20
-
Ui
U
-I0
-I
4
z
MEAN ENERGY
-20
REQUIRE MENT
Ui
(9
0 -30
-
z
0.5
.0
CALORIE S DELIVE RED
BASAL
ENERGY
1.5
20
EXPENDITURE
Chart 9. Schematic depiction of results of Rutten et al. (69) showing
relationship between energy intake (expressed as a fraction of calculated
basal energy expenditure) and changes in body nitrogen balance in 13
postoperative patients, including a total of 4 patients with cancer of the lung.
bladder, esophagus, and uterus.
sources, glucose or other carbohydrates, and lipid, which
would promote maximum efficiency of energy utilization,
cannot be stated yet. There are no more than a few studies
that help to provide only crude guidelines for this purpose.
Rutten @t
a!. (69) have shown in a group of postsurgical
patients, including some with cancer, that hyperalimenta
tion with a fluid providing 160 kcal/g nitrogen could support
body nitrogen balance when total energy intake approxi
mated 1.7 to 2.0 times the calculated basal metabolic rate
(Chart 9). Similarly, at nitrogen intakes of 240 mg nitrogen
per kg per day, or more than twice the nitrogen allowance
for healthy adults (16), Long et al. (49) concluded that
energy balance was achieved in a group of septic patients,
including 2 with cancer of the bladder, with energy intake
being about 1.5 times basal energy expenditure.
The studies of Rutten et a!. (69) and Long et al. (49)
provide only a partial basis for assessing the adequacy of
levels of energy intake, and studies of this kind should be
extended , particularly in view of the close interrelationships
between energy and protein in nutrition and metabolism.
We (22, 23) and others (10, 37) have explored the sensitivity
of body nitrogen balance to changes in energy intake in
healthy subjects. In these studies it was shown that gener
ous intakes of energy result in a sustained increase in
nitrogen retention and dietary nitrogen utilization. How
ever, the effects of changes in the level of energy intake on
protein and energy utilization may be modified by the level
of protein intake (57). Hence, the definition of an adequate
energy intake for the nutritional therapy of the cancer pa
tient is dependent upon a variety of dietary and host factors.
These factors, together, will determine the appropriate en
ergy intake for the individual patient. Finally, the attending
physician and hospital dietitian have little useful informa
tion to follow in deciding on the level and sources of energy
to provide a particular patient and they must rely upon the
clinical progress of the patient, supplemented with some
objective biochemical and physiological assessment of the
patient's nutritional state.
Better knowledge of the interrelationships among energy
CANCERRESEARCHVOL. 37
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Energy Requirements
and protein metabolism clearly would help to develop better
diagnostic aids for the evaluation of nutritional status and
lead to the design of improved nutritional therapies for
treatment of cancer patients. In addition, this information is
necessary for an understanding of the anorexia that is re
garded as a major contributory factor to body energy loss
and the eventual cachexia in cancer patients (77). Ob
viously, energy balance will not be achieved if intake and
absorption fail to meet the energy demands of the body.
Alterations in intestinal function due to alimentary tract
neoplasms or the effects of surgery, chemotherapeutic
agents, and radiation may affect energy metabolism by
changing the digestive-absorptive phase of nutrient utiliza
tion. This topic is discussed elsewhere in this symposium.
The regulation of energy intake in normal and cancer
patients is beyond the scope of this paper, and the reader is
referred to reviews which have discussed this aspect of
energy metabolism in normal subjects (e.g., Ref. 61) and in
relation to cancer (78). Of particular interest, however, is a
review by Bray and Campfield (6) which considers the var
might offer an approach to testing hypotheses proposed to
explain the actual or relative reduction in food intake and
development of negative energy balance which occurs dur
ing the onset and development of neoplasia. Of significance
in the present context is that the model involves considera
tions of important energy-yielding substrates, glucose, and
fatty acids, and of the amino acid levels in blood plasma.
Changes in glucose, fatty acid metabolism, and in amino
acid and protein metabolism in cancer patients have been
discussed above. Furthermore, differences in blood amino
acid levels of cancer patients, compared with controls, have
been described (e.g., Refs. 4, 41).
An adequate exploration of energy metabolism and nutri
tion should, for these reasons alone, include as many ob
servations as possible within a single patient, on the utiliza
tion and metabolism of the principal fuel sources (carbohy
drate, lipids, and protein). There is also a great need to apply
and improve upon modern methods for measurement of
whole-body energy expenditure in human subjects in gen
eral and in patients with malignant disease in particular.
ious metabolic factorsinvolvedin the regulationof food
intake. These investigators proposed that body energy
stores are the regulated variable and that energy intake or
expenditure is altered to maintain a particular level of total
caloric storage. The major features of the control system
discussed by Bray and Campfield are given in Chart 10. As
seen from this chart, the plasma concentrations of amino
acids, glucose, glycerol, and free fatty acids, as well as the
state of peripheral metabolism, including the quantity of
adipose tissue, glycogen, and protein, serve as feedback
signals on the ventromedial nucleus, which is assumed to
be the long-term monitor of energy balance in the body.
This model was proposed to provide a possible framework
which might help identify possible changes of system error
in relation to obesity, or body energy excess. Similarly, it
Conclusion
Based on the above, it is clear that various factors affect
basal and total daily energy expenditure. This makes it
difficult to assess the significance of published data on
basal metabolism in cancer patients. Also, there are signifi
cant quantitative relationships between whole-body energy
and protein metabolism, and these must be considered in
assessing energy status and requirements in cancer pa
tients who may often be depleted of body protein and re
quire vigorous nutritional support to reverse this state and
to maintain adequate nutritional status. Although the lim
ited data available suggest that the pattern of fuel utilization
CONTROLLER
I. NEURAL
COR T E X
SUBCORT ICAL
AUTONOMIC
NERVOUS
SYSTEM
CONTROLLER
2. GASTROINTESTINAL
STOMACH
INTESTINAL
CALORIE
SYSTEM
STORAGE
STORED
@IEDISTRIBUTION
MUCOSA
CALORIES
3. HUMORAL
CALORIE
DISPOSAL
PANCREAS
P I T U I TA R Y
ADRENAL
GONAD
PLASMA
GLUCOSE
PLASMA
FREE
FATTY
ACIDS
PLASMA GLYCEROL
PLASMA AMINO ACIDS
PERIPHERAL
METABOLIC
FEEDBACK
STATE
ELEMENTS
Chart 10. Simplified elements of the system responsible for regulation of body energy stores in human subjects, as proposed by Bray and Campfieid (6).
The model consists of a controller, acting upon the controlled system, with effectors including plasma glucose, amino acids, fatty acids, and status of
metabolism in peripheral tissues.
JULY
1977
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2345
V. R. Young
in neoplastic disease states may differ from that of healthy
subjects, with lipid sources predominating, an altered regu
lation
of glucose
metabolism,
and less efficient
utilization
of
food energy, further studies are needed to verify and estab
lish the nutritional and metabolic significance of this obser
vation.
Whether
particular
cancers,
other
than
those
di
rectly involving the neuroendocrine system, affect energy
metabolism and requirements in different ways cannot be
determined from the available literature, nor is the role of
severity of the disease state, in this regard, adequately
understood . Only crude guidelines can be suggested for the
levels of energy intake and optimum relationship between
protein and energy requirements for the feeding of cancer
patients. A better understanding of the characteristics of
the utilization and metabolism of the major fuel sources in
cancer patients should lead to improved diagnostic tests for
assessing body energy balance and needs during the var
ious phases of the disease and under the differing condi
tions of therapy. In part, this will require much better infor
mation on the regulation of energy metabolism and utiliza
tion of energy sources at the whole-body level in healthy
subjects.
References
1. Ashworth,
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
A. Metabolic
Rates during
Recovery
from
Protein-Calorie
Malnutrition: The Need for a New Concept of Specific Dynamic Action.
Nature, 223: 407-409, 1969.
Benedict, F. G., Miles, W. R., Roth, P., and Smith, H. M. Human Vitality
and Efficiency under Prolonged Restricted Diet. Publication No. 280, p.
701. Washington, D. C.: Carnegie Institute of Washington, 1919.
Boothbay, W. M., and Sandiford, I. Summary of the Basal Metabolism
Data on 8,614 Subjects with Especial Reference to the Normal Standards
for the Estimation of the Basal Metabolic Rate. J. Biol. Chem. , 54: 783803, 1922.
Brackenridge, C. J. The Tyrosine and Tryptophan Content of Blood
Serum in Malignant Disease. Clin. Chim. Acta, 5: 539-543, 1960.
Bray, G. A. Effect of Calorie Restriction on Energy Expenditure in Obese
Patients. Lancet, 2: 397-398, 1969.
Bray, G. A., and Campfield, L. A. Metabolic Factors in the Control of
Energy Stores. Metabolism, 24: 99-117, 1975.
Brody, S. Bioenergetics and Growth. New York: Reinhold Publishing
Co., 1945.
Brooke, 0. G., and Ashworth, A. The Influence of Malnutrition on the
Post-prandial Metabolic Rate and Respiratory Quotient. Brit. J. Nutr., 27:
20. Garrow, J. S. Energy Balance and Obesity in Man. Amsterdam, The
Netherlands: North-Holland Publishing Co., 1974.
21. Garrow, J. S., Smith, R., and Ward, E. E. Electrolyte Metabolism In
Severe Malnutrition, p. 168. New York: Pergamon Press, 1968.
22. Garza, C., Scrimshaw, N. S., and Young, V. R. Human Protein Require
ments: The Effect of Variations in Energy Intake within the Maintenance
Range. Am. J. Clin. Nutr., 29: 280-287, 1976.
23. Garza, C., Scrimshaw, N. 5., and Young, V. R. Human Protein Require
ments. Evaluation of the 1973 FAO/WHO Safe Level of Protein Intake for
Young Men at High Energy Intakes. Brit. J. Nutr. , In press.
24. Gold, J. Metabolic Profiles in Human Solid Tumors. I. A New Technique
for the Utilization of Human Solid Tumors in Cancer Research and Its
Application to the Anaerobic Glycolysis of Isologous Benign and Malig
nant Colon Tissues. Cancer Res., 26: 695-705, 1966.
25. Gold, J. Cancer Cachexia and Gluconeogenesis. Ann. N. Y. Acad. Sci.,
230: 103-110,1974.
26. Goodlad, G. A. J. Protein Metabolism and Tumor Growth. In: H. N.
Munro (ed), Mammalian Protein Metabolism, Vol. 3, Chap. 20, pp. 415444. New York: Academic Press, Inc., 1969.
27. Goodlad, G. A. J., and Clark, C. M. Activity of Gastrocnemius and Soleus
Polyribosomes in Rats Bearing the Walker 256 Carcinoma. European J.
Cancer, 8: 647-651 , 1972.
28. Goodlad, G. A. J., Mitchell, A. J. H., McPhail, L., and Clark, C. M. Serum
Insulin and Somatomedin Levels in the Tumor-bearing Rat. European J.
Cancer, 11: 733-737, 1975.
29. Goodlad, G. A. J. . and Raymond, M. J. The Action of the Walker 256
Carcinoma and Toxohormone Incorporation into Diaphragm Protein.
European J. Cancer, 9: 139-145, 1973.
30. Grande, F. Man under Caloric Deficiency. In: Handbook of Physiology:
Adaptation to the Environment. Sect. 4, Vol. 1, Chap. 59, pp. 911-937.
Washington, D. C.: American Physiological Society, 1964.
31. Grande, F., Anderson, J. T. , and Keys, A. Changes of Basal Metabolic
Rate in Semistarvation and Refeeding. J. Appi. Physiol., 12: 230-238,
1958.
32. Gump, F. E., Long, C. L.. Geiger, J. W., and Kinney, J. M. The Signifi
cance of Altered Gluconeogenesis in Surgical Catabolism. J. Trauma,
15:
704-710,
1975.
33. Halliday, D., and McKeran, A. 0. Measurement of Muscle Protein Syn
thetic Role from Serial Muscle Biopsies and Total Body Protein Turnover
in Man by Continuous Intravenous Infusion of L-[a-'NjLysine. Clin. Sd.,
49: 581-590,1975.
34. Hegsted, D. M. Energy Needs and Energy Utilization. Nutr. Reviews, 32:
33-38, 1974.
35. Himms-Hagen, J. Cellular Thermogenesis. Ann. Rev. Physiol., 38: 315351, 1976.
36. Holroyde, C. P., Gabuzda, T. 6., Putnam, R. C., Paul, P., and Reichard,
G. A. AlteredGlucoseMetabolismin MetastaticCarcinoma.cancer
Res., 35: 3710-3714, 1975.
37. lnoue, G., Fujita, Y. , and Niiyama, V. Studies on Protein Requirements of
Young Men Fed Egg Protein and Rice Protein with Excess and Mainte
nance Energy Intakes. J. Nutr. , 103: 1673—1687,
1973.
38. James, W. P. T., Garlick, P. J., Sender, P. M., and Waterlow, J. C.
Studies of Amino Acid and Protein Metabolism in Normal Man with
L(U―C)TyrOsifle.Clin. Sci., 50: 525-532, 1976.
39. James, W. P. T., and Trayhern, P. An Integrated View of the Metabolic
407-415, 1972.
and Genetic Basis for Obesity. Lancet, 2: 770-773, 1976.
Cahill, G. F., Jr. Starvation in Man. New Engi. J. Med., 282: 668—675, 40. Katz, J., and Rognstad, R. Futile Cycles in the Metabolism of Glucose.
1970.
Current Topics Cellular Regulation, 10: 237-289, 1976.
Calloway, D. H. Nitrogen Balance of Men with Marginal Intakes of Pro
tein and Energy. J. Nutr., 105: 914-923, 1975.
in Leukemic Blood. Blood, 12: 635—643,
1957.
Clark, C. M., and Goodlad, G. A. J. Muscle Protein Biosynthesis in the
42. Keys, A., Brozek, J,, Henschel, A., Mickelsen, 0., and Taylor, H. L. Basal
Metabolism. In: The Biology of Human Starvation. Vol. 1, Chap. 17, pp.
Tumor-bearing Rat. A Defect in the Post-initiation Stage of Translation.
Biochem. Biophys. Acta, 378: 230-240, 1975.
303-339. Minneapolis: University of Minnesota Press, 1950.
43, Kleiber, M. The Fire of Life. New York: John Wiley & Sons, 1961.
Copeland, E. M., Macfayden, B. V., and Dudrick, S. J. Intravenous
Hyperalimentation in Cancer Patients. J. Surg. Res., 16: 241-247, 1974.
44. Krebs, H. A. The Metabolic Fate of Amino Acids. In: H. N. Munro and J.
Copeiand, E. M., Macfayden, B. V., Lanzolti, V. J. , and Dudrick, S. J.
B. Allison (eds.), Mammalian Protein Metabolism, Vol. 1, Chap. 5, pp.
Intravenous Hyperalimentation as an Adjunct to Cancer Chemotherapy.
125-176. New York: Academic Press, Inc., 1964.
45. Krebs, H. A. Some Aspects of the Regulation of Fuel Supply in Omnivo
Am. J. Surg., 129: 167-173, 1975.
rous Animals. Advan. Enzyme Regulation, 10: 397-420, 1972.
Durnin, J. V. G. A., and Passmore, R. Energy, Work and Leisure. Lon
don: Heinemann Publishing Co., 1967.
46. Kreiger, I. The Energy Metabolism in Infants with Growth Failure Due to
Elshove, A., and van Rossum, G. 0. V. Net Movements of Sodium and
Maternal Deprivation, Undernutrition and Causes Unknown. Metabolic
Potassium, and Their Relation to Respiration, in Slices of Rat Liver
Rate Calculated from Insensible Loss of Weight. Pediatrics, 38: 63-76,
Incubated in vitro. J. Physiol., 168: 531-553, 1963.
1966.
FAO/WHO. Protein and Energy Requirements. Report of an Ad Hoc
47. Krieger, I., and Chen, Y. C. Calorie Requirements for Weight Gain in
Expert Committee. World Health Organization Technical Report Series
Infants with Growth Failure due to Maternal Deprivation, Under-nutri
No. 522. Geneva, Switzerland: World Health Organization, 1973.
tion, and Congenital Heart Disease—ACorrelation Analysis. Pediatrics,
44: 647-654, 1969.
Fenninger, L. D., and Mider, G. B. Energy and Nitrogen Metabolism in
48. Levinson, C., and Hempling, H. G. The Role of Ion Transport in the
Cancer. Advan. Cancer Res., 2: 229—252,
1954.
Flatt, J. P., 1976. Personal communication, cited by Sims, E. A. H. See
Regulation of Respiration in the Ehrlich Mouse Ascites-Tumor Cell.
Ref. 74.
Biochim. Biophys. Acta, 135: 306—318,
1967.
49. Long, C. L. , Crosby, F., Geiger, J. W., and Kinney, J. M. Parenteral
Fleck, A. Protein Metabolism after Injury. Proc. Nutr. Soc. EngI. Scot.,
Nutrition in the Septic Patient; Nitrogen Balance, Limiting Plasma Amino
30: 152-157,1971.
2346
41
. Kelley,
J.J.,and
Waisman,
H.A.Quantitative
Plasma
Amino
Acid
Values
CANCERRESEARCHVOL. 37
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1977 American Association for Cancer Research.
Energy Requirements
Acids and Calorie to Nitrogen Ratios. Am. J. Clin, Nutr., 29: 380-391,
1976.
50.Lundholm,
K.,Bylund,
A.C.,Hoim,J.,andScherstén,
T.Skeletal
Muscle
51,
52.
53.
54.
55.
56.
57.
58.
59.
60.
Metabolism in Patients with Malignant Tumor. European J. Cancer, 12:
465—473,
1976.
McGilvery, R. W. In: Biochemistry, a Functional Approach, pp. 280-281.
Philadelphia: W. B. Saunders Co., 1970.
Miller, D. S., and Mumford, P. An Experimental Study of Overeating Low
and High-Protein Diets. Am. J. Clin. Nutr., 20: 1212—1222,
1967.
Miller, S. Protein Metabolism during Growth and Development. In: H. N.
Munro (ed), Mammalian Protein Metabolism Chap. 26, pp. 183-233.
New York: Academic Press, Inc., 1969.
Millward, D. J., Garlick, P. J. , James, W. P. T., Sender, P. M., and
Waterlow, J. C. Protein Turnover. In: D. J. A. Cole, K. N. Boorman, P. J.
Buttery, D. Lewis, R. J. Neele, and H. Swan (eds.), Protein Metabolism
and Nutrition, pp. 49-69. London: Butterworth & Co. , Ltd., 1976.
Minot, G. R., and Means, J. H. The Metabolism-Pulse Ratio in Exophthal
mic Goiter and Leukemia. Arch. Internal Med., 32: 576-580, 1924.
Morrison, S. D. Partition of Energy Expenditure between Host and Tu
mor. Cancer Res., 31: 98—107,
1971.
Munro, H. N. General Aspects of the Regulation of Protein Metabolism
by Diet and Hormones, In: H. N. Munro and J. B. Allison (eds.), Mamma
han Protein Metabolism, Vol. 1, Chapt. 10, pp. 381-481 . New York:
Academic Press, Inc., 1969.
Munro, H. N. Evolution of Protein Metabolism in Mammals. In: H. N.
Munro (ed), Mammalian Protein Metabolism, Vol. 3, Chap. 25, pp. 133182. New York: Academic Press, Inc., 1969.
Newburgh, L. H., Johnston, M. W.. Lashmet, F. H., and Sheldon, J. M,
Further Experiences with the Measurement of Heat Production from
Insensible Loss of Weight. J. Nutr., 13: 203-221 . 1937.
Newsholme, E. A,, and Start, C. Regulation in Metabolism. New York: J.
Wiley & Sons, Inc.,1973.
61. Novik, D., Wyrwicka, W., and Bray, G. A. (eds.). Hunger: Basic
Mechanisms and Clinical Implications. New York: Raven Press, 1976.
62. O'Keefe, 5, J. D., Sender, P. M., and James, W, P. T. Catabolic Loss of
Body Nitrogen in Response to Surgery. Lancet, 2: 1035-1038, 1974.
63. Owen, 0. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G.,
and Cahill, G. F., Jr. Brain Metabolism during Fasting. J. Clin. Invest.,
46: 1589-1595,1967.
64. Owen, 0. E., Patel, M. S., Block, B. S. B., Kreulen, T. H., Reichle, F. A.,
and Mozzoli, M. A. Gluconeogenesis In Normal, Cirrhotic and Diabetic
Humans. In: R. W. Hanson and M. Mehlman (eds.), Gluconeogenesis,
Chap. 15, pp. 533-559. New York: John Wiley & Sons, 1976.
65. Passmore, R., and Draper, M. H. The Chemical Anatomy of the Human
Body. In: R. H. S. Thompson and E. J, King (eds.), Biochemical Disor
ders in Human Disease, pp. 1-19. London: J. & A. Churchill, Ltd., 1964.
66. Payne, P. R., and Waterlow, J. C. Relative Requirements for Mainte
nance, Growth and Physical Activity. Lancet, 2: 210-21 1, 1971,
67. Picou, D,, and Taylor-Roberts, T. The Measurement of Total Protein
Synthesis and Catabolism and Nitrogen Turnover in Infants in Different
Nutritional States and Receiving Different Amounts of Dietary Protein.
Clin.
Sci.,
36:283-296,
1969.
68. Reichard, G. A., Jr., Mowry, N. F., Hochella, N. J., Putnam, R. C., and
Weinhouse, S. Metabolism of Neoplastic Tissue. xVll. Blood Glucose
Replacement Rates in Human Cancer Patients. Cancer Res., 24: 71-76,
1964.
69. Rutten, P., Blackburn, G. L., Flatt, J. P., Hallowell, E., and Cochran, D.
Determination of Optimal Hyperalimentation Infusion Rate. J. Surg.
Res.,
18:477-483,
1975.
70. Sabine, J. R. Metabolic Controls in Precancerous Liver. VII. Time Course
of Loss of Dietary Feedback Control of Cholesterol Synthesis during
Carcinogen Treatment. European J. Cancer, 12: 299-303, 1976.
71. Saudek, C. D,, and Felig, P. The Metabolic Events of Starvation. Am. J.
Med.,60:117-126,
1976.
72. Shock, N. Energy Metabolism, Caloric Intake and Physical Activity of the
Aging. In: L. A. Carlson (ed), Nutrition and Old Age, pp. 12-21 . Uppsala,
Sweden: Swedish Nutrition Foundation, 1972.
73. Silver, 5. , Poroto, P., and Crohn, E, B. Hypermetabolic States without
Hyperthyroidism (Nonthyrogenous Hypermetabolism). Arch . Internal
Med.,85:479-482,1950.
74. Sims, E. A. H. Experimental Obesity, Dietary Induced Thermogenesis
and Their Clinical Implications. Clin. Endocrinol. Metab., 5: 377-395,
1976.
75. Steffee, W. P., Goldsmith, R. S., Pencharz, P. B., Scrimshaw, N. S., and
Young, V. A. Dietary Protein Intake and Dynamic Aspects of Whole Body
Nitrogen Metabolism in Adult Humans. Metabolism,25: 281-297, 1976.
76.Terpeka,
A, A., andWaterhouse,
C. Metabolic
Observations
during
Forced Feeding of Patients with Cancer. Am. J. Med., 20: 225-238, 1956,
77. Theologides, A. The Anorexia-Cachexia Syndrome: A New Hypothesis.
Ann. N. Y. Acad. Sci., 230: 14-22, 1974,
78. Theologides, A. Anorexia-producing Intermediary Metabolites. Am. J.
Ciin. Nutr., 29: 552-558, 1976.
79. Warburg, 0. Metabolism of Tumors. London: Constable and Co. , 1930.
80. Warren, S. The Immediate Causes of Death in Cancer. Am. J. Med . Sci.,
184:610—615,
1932.
81. Waterhouse, C. Lactate Metabolism in Patients with Cancer. Cancer, 33:
66-71, 1974.
82. Waterhouse, C. How Tumors Affect Host Metabolism. Ann. N.Y. Acad.
Sci., 230: 86-93, 1974.
83. Waterhouse, C., and Kemperman, J. H. Carbohydrate Metabolism in
Subjects with Cancer, Cancer Res., 31: 1273-1278, 1971.
84. Waterhouse, C. L. , Fenninger, L. D. , and Keutmann, E. H. Nitrogen
Exchange and Caloric Expenditure in Patients with Malignant Neoplasm.
Cancer,4: 500-514, 1951.
85. Waterlow, J. C. Lysine Turnover in Man Measured by Intravenous Infu
sion of L-[u-'[email protected]. Sci., 33: 507—515,
1967.
86. Waterlow, J. C. The Assessment of Protein Nutrition and Metabolism in
the Whole Animal. In: H. N. Munro (ed), Mammalian Protein Metabo
lism, Vol. 3, Chap. 28, pp. 325-390. New York: Academic Press, Inc.,
1969.
87. Waterlow, J. C., and Alleyne, G. A. 0. Protein Malnutrition in Children:
Advances in Knowledge in the Last Ten Years. Adv. Prot. Chem. 25: 117-
241,1971.
88. Waterlow, J. C., and Stephen, J. M. L. The Measurement of Total Lysine
Turnover in the Rat by Intravenous Infusion of L-(U-―CjLysine.Clin. Sci.
33: 489-506,1967.
89. Watkin, D. M. Nitrogen Balance as Affected by Neoplastic Disease and Its
Therapy. Am. J. Clin. Nutr., 9: 446-460, 1961.
90. Watkin, D. M., and Steinfield, J. L. Nutrient and Energy Metabolism In
Patients with and without Cancer during Hyperalimentation with Fat
Administered Intravenously. Am. J. Clin. Nutr., 16: 182-212, 1965.
91. Whittam, R. J. F. Hoffman (ed.), The Cellular Functions of Membrane
Transport. Englewood Cliffs, N. J.: Prentice-Hall, 1964.
92. Wilmore, D. W. Nutrition and Metabolism following Thermal Injury. Clin.
Plastic Surg., 1: 603—619,1974.
93. Wilmore,D. W., Lang,J. M., Mason,A.D.,Skreen,
R.W.,and Pruitt, B.
A. Catecholamines: Mediator of the Hypermetabolic Response to Ther
mal Injury. Ann. Surg., 180: 663-668, 1974.
94. Young, V. R., Steffee, W. P., Pencharz, P. B., Winterer, J. C., and
Scrimshaw, N. S. Total Human Body Protein Synthesis in Relation to
Protein Requirements at Various Ages. Nature, 253: 192-194, 1975.
95. Young, V. A., Winterer, J. C., Munro, H. N., and Scrimshaw, N. S.
Muscle and Whole Body Protein Metabolism, with Special Reference
to Man. In: M. F. Elias, B. E. Eieftheriou, and P. K. Elias (eds.),
Special Review of Experimental Aging Research: Progress on Biology,
pp. 217-252. Bar Harbor, Maine: EAR, Inc., 1976.
JULY 1977
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1977 American Association for Cancer Research.
2347
Energy Metabolism and Requirements in the Cancer Patient
Vernon R. Young
Cancer Res 1977;37:2336-2347.
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