Searches for Expbitable Biochemical Differences
between Normal and Cancer Cells
VII. Anabolism and Catabolism of Purines
by Minced Tissues*
GLYNN P. WHEELER AND
Jo A N N
ALEXANDER
(Kettering-MeyerLaboratory,t Southern ResearchInstitute, Birmingham, Ala.)
SUMMARY
Minced neoplasms and minced tissues of the host animals were incubated with
xanthine-8-C 14, hypoxanthine-8-C 14, adenine-8-C 14, or guanine-8-C~4; and aqueous
alcoholic extracts of these mixtures were examined by means of the chromatographicradioautographic technic. It was found that relatively less catabolism and more
anabolism occurred in the neoplastic tissues than in most of the host tissues examined.
The relevance of these findings to the possible roles of catabolism and anabolism in
control of growth is discussed.
As reported in the preceding paper of this series
(9), a study of the metabolism of labeled purines in
vivo by animals bearing tumors showed that the
patterns of anabolism and catabolism appeared to
be generally similar for the tumors and the livers
and intestines of the host animals. The presence of
relatively high concentrations of the radioactive
metabolic products in the blood, however, showed
that the radioactive materials that were isolated
from one tissue might actually have been formed
in another tissue and transported by the blood to
the tissue being examined. Thus, the in vivo results
might not give a real measure of the capacities of
the various tissues for intracellular anabolism and
catabolism of purines. To avoid this possibility
and to remove other possible systemic effects, experiments were performed with freshly excised and
minced tissues. This report describes these experiments and presents the results.
M A T E R I A L S AND M E T H O D S
Source,~ of tissues.--The host animals and ages
of the Adenocarcinoma 755 (Ad-755), Sarcoma 180
* This work was supported by the Cancer Chemotherapy
National Service Center, National Cancer Institute, under the
National Institutes of Health, Contract No. SA-43-ph-~433,
and by grants from the Charles F. Kettering Foundation
and the Alfred P. Sloan Foundation.
Received for publication October 14, 1960.
(S-180), Leukemia LI~10 (LI~10), and Novikoff
hepatoma (Nov. hep.) were the same as in the preceding study (9). The host animals and ages of the
other transplantable neoplasms employed in this
study were as follows: Leukemia IA946 (IA946),
AKR mice, 7 days; Leukemia L5178 (L5178),
D B F 1mice, 1~ days; Human Sarcoma 1 (HS), cortisonized golden hamsters, 11 days. The Nov. hep.
was grown intraperitoneally, and all the other tumors were grown subcutaneously. In one experiment 27 18-day-old embryos obtained from three
mice were used.
Radioactive compounds.--The following radioactive compounds having the indicated specific activities (in mc/mmole) were used: hypoxanthine8-C 14, 5.14; adenine-8-C 14, 1.52; adenine-8-C 14 sulfate, 1.48 and 3.3~; guanine-8-C 14, 0.662; xanthine8-C TM, 3.69. Adenine and adenine sulfate were considered to be equally satisfactory as substrates,
and the availability of the compounds at the time
the experiment was performed determined which
form of adenine was used.
Experimental procedure.--The animals were
killed by cervical fracture, and the desired tissues
were removed as quickly as possible and placed in
ice-cold Petri dishes. After the tissues were finely
t Affiliated with Sloan-Kettering Institute for Cancer Research, New York.
399
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Cancer Research
400
minced with knives, 1 gm. of the minced tissue
was suspended in 10 ml. of Krebs-Ringer phosphate solution (pH 7.4) containing glucose (0.1 per
cent) and adenosine triphosphate (0.0~ per cent),
and the radioactive substrate (1-~.5 #c.) was
added. This mixture was incubated in a Dubnoff
Metabolic Shaking Incubator for 4{ hours at
37 ~ C. in an atmosphere of oxygen. During the incubation oxygen was passed through the chamber
~
ALLANTOIN
URIC ACID
___.--
~] UNKNOWNS
I
HYPOXANTHINE
m
I
|
Xo-I-XoR
HxR + IMP
i
m
ADENINE
BB
mm
GUANINE
II
AdR 4- AMP+ ADP+ ATP+ DPN
CHART1.--Key to subsequent charts. The following abbreviations are used in the charts: Xa, xanthine; XaR, xanthosine;
HxR, inosine; IMP, inosine monophosphate; AdR, adenosine;
AMP, adenosine monophosphate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; D PN, diphosphopyridine
nucleotide; L, liver; I, intestine; Sp, spleen; K, kidney; H,
heart; B, brain; Ln, lung; E, embryo; A, Adenocarcinoma 755;
S, Sarcoma 180, L1, Leukemia LI~10; L4, Leukemia 1,4946;
LS, Leukemia L5178; N, Novikoffhepatoma; HS, Human Sarcoma No. 1. The numbers above the columns ill the charts
show the total quantities of radioactivity (counts/see) that
were recovered from the respective chromatogralns.
Vol. ~1, April 1961
at a rate of 7-8 cubic feet per hour. Following the
incubation the solid material was separated by
centrifugation, and the supernatant solution was
discarded. The sediment was suspended in 10 ml.
of water, the suspension was poured into 40 ml. of
boiling absolute ethanol, and boiling was continued for 5 minutes. The methods for separating and
concentrating the extracts, for chromatography
and radioautography, and for radioassay of the
separated components of the extract were the
same as those described in the preceding paper
(9).
RESULTS
The experimental results are presented in the
form of column graphs showing the per cent distribution of radioactivity among the radioactive
compounds detected on the chromatogram, and
the total radioactivity (counts/see) recovered
from the chromatogram is shown by the number
above the column. Thus it is possible to compare
the quantities of radioactivity recovered from the
chromatograms of the extracts of the various tissues and also to compare the distribution of the
radioactivity among the various components of
the extracts. The use of the same code (Chart 1) to
identify the compounds in all the graphs facilitates
comparisons of the results for different substrates
and for different tissues.
The values presented for the livers and the intestines of the mice are average values t h a t were
obtained from the experiments with the various
strains of mice bearing the various types of tumors, since the metabolic patterns were similar
enough to permit the use of the average value. In a
number of instances replicate experiments were
performed. More experiments were run with hypoxanthine-8-C 14as substrate than with any other
labeled substrate, and the data that are presented
for this substrate are based upon from one (in the
TABLE 1
COMPARISONOF THE QUANTITIESOF RADIOACTD'EPURINESADDED TO
THE MINCES AND THE QUANTITIESOF SOLUBLEPURINESNORMALLY
PRESENT IN THE TISSUES
QUANTITY OF LABELED PURINE ADDED
QUANTITY OF THAT PUBINE IN POOL
TmSUE
Substrate:
Liver
Intestine
S-180
Hypoxanthine-8-C
0.92
0.49
1.26
14
A d e n i n e - 8 - C 14
G u a n i n e - 8 - C 14
0.81; 0.36*
1 . 4 2 ; 0.64,
1.46; 0.67
7.15; 7.82*
8.02; 8.78
8.80; 9.6~
* Two sets of data are given for these precursors because two different lots of
compound having different specific activities were used in the experiments.
radioactive
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Research.
WHEELER AND ALEX_ANDEa--Anabolism and Catabolism of Purines by Minced Tissues 401
case of certain of the tumors and host tissues) to
seventeen (in the case of mouse liver) experiments.
Although the quantities of total radioactivity
recovered from the chromatograms differed considerably for the various tissues, there was no evidence of preferential retention or loss of any of the
components of the extracts by any of the tissues,
and hence comparisons of the distributions of radioactivity are justifiable.
The quantities of radioactive compounds that
were added to the minces were relatively large
compared with the pools of the acid-soluble purines. Table 1 shows the ratios of the quantity of
added labeled compound to the soluble pool of
157
89
7:5
78
78
156
108
82
I
~
i
thine in any of the tissues. With all three species,
mouse, rat, and hamster, relatively more degradation of xanthine to uric acid and allantoin occurred
in the host livers and intestines than in the five
tumors tested.
Chart 4 shows the data obtained with hypoxanthine-8-C 14 for several mouse tissues and Ad-755,
and Chart 5 shows similar data for rat tissues and
234
133
138
7
i
Xo
XoR
/
HAMS TE-R
L
IIII
I
A
MOUSE
S
Li
CUART3.--Catabolism of xanthine-8-C ~4by hamster tissues
and HS.
L
I
N
RAT
CHART ~.--Catabolism of xanthine-8-C t4 by mouse tissues,
rat tissues, Ad-755, S-180, LI~10, and Nov. hep.
that respective purine. The pool is defined as the
quantity of purine isolated following the acid
hydrolysis of a trichloroacetic acid extract of a unit
weight of wet tissue, and the values for pool sizes
that were used in calculating the ratios of Table 1
have been previously reported (1). These data
show that "substrate quantities" rather than
"tracer quantities" were used.
Charts ~ and 3 show the extent of degradation
of xanthine-8-C TM that occurred in the various tissues. There was no evidence of anabolism of xan-
Nov. hep. Residual substrate was present in most
tissues at the time the experiment was terminated,
and for all tissues except rat liver and rat intestine
there was evidence of both anabolism and catabolism. More extensive degradation to uric acid and
allantoin occurred in the liver and intestine than in
the other tissues. If xanthine, uric acid, and allantoin are considered to be the catabolic products
derived from hypoxanthine, these charts show
that less catabolism occurred with Ad-755 and
Nov. hep. than with any of the host tissues, with
the exception of brain and mouse embryo. These
exceptions are not surprising, because the brain is
relatively inactive metabolically, and most of the
radioactivity was present in the unaltered substrate, whereas the embryo, like neoplasms, is
metabolically and mitotically quite active. On the
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Research.
Cancer Research
40s
other hand, if inosine, inosinic acid, adenosine,
adenosine monophosphate, adenosine diphosphate, adenosine triphosphate, and diphosphopyridine nucleotide are considered to be anabolic
products of hypoxanthine, more anabolism occurred with Ad-755 and Nov. hep. than with the
host tissues of the mouse and the rat. Similar differences were observed between the results for
S-180, LI~10, L4946, and L5178 and the results
253
~
78
~
245
l
329
200
285
172
~
l
145
227
l
-Hx
Vol. ~1, April 1961
adenine-8-C 14 than with xanthine-8-C ~4 or hypoxanthine-8-C TM. Less catabolism and more anabolism occurred in the Ad-755, S-180, Ll~210, Nov.
hep., and HS than occurred in the liver and intestines of the host animals.
Chart 10 shows the results obtained with guanine-8-C TM as substrate. Small quantities of free
substrate were found in the extracts of mouse intestine and Nov. hep., but none was found in the
extracts of the other tissues. Extensive deamination occurred in each of the tissues, and the distribution of radioactivity is very similar to that
observed when xanthine-8-C TM was the substrate
(Chart 2).
to=
3
43
5e
toz
los
141
I
iJ.i ~ i ! !::::.
-
-
m
?; ??&: : :
1
4se
ohsl
~ -U.A.
IIII
fhypoxanthnle8
for mouse liver and intestine as shown in Chart 6
and also between the results for HS and those for
hamster liver and intestine as shown in Chart 7.
Charts 8 and 9 show data that were obtained
with adenine-8-C TMas substrate. The total activities for the intestines are notably less than for the
other tissues for all three species. Because of the
low quantity of radioactive material recovered for
the hamster intestine, it is doubtful whether the
data for this tissue are meaningful. Relatively
much less degradation to xanthine, uric acid, and
allantoin occurred in all tissues with adenine-8-C TM
as substrate than occurred with xanthine-8-C TMor
hypoxanthine-8-C TMas substrate, even though radioactive free hypoxanthine was present. Conversely, in all tissues larger portions of the substrate were converted to anabolic products with
L
I
SP
K
ii
,
H
B
LU
N
RAT
CHART 5 . - - A n a b o l i s m a n d catabolism of h y p o x a n t h i n e - 8 C 14 b y r a t tissues a n d N o v . hep.
DISCUSSION
Potter (5-7) has presented and developed the
hypothesis that neoplastic growth results from
loss of a normal balance between anabolism and
catabolism and that this imbalance is due chiefly
to decreased catabolism, perhaps resulting from
the deletion of catabolic enzymes. Although this
imbalance might exist in any or several of the
areas of metabolism, he has considered it chiefly in
the area of biosynthesis of deoxyribonucleic acids.
Rutman, Cantarow, and Paschkis (8) and Ca-
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Research.
139
L
im
78
I
I00
118
116
76
92
34
150
97
102
106
57
296
-. 'j- lj jij
=-,,...
ill
J
114
i~--Ad
i
A
S
LI
L4
L5
MOUSE
I
A
S
LI
L
M OUSE
CHA~T 6.--Anabolism and catabolism of hypoxanthine-80 4 by mouse tissues, Ad-755, S-180, LlO~10, L4946, and L5178.
176
L
!
46
N
RAT
CHArtT 8.--Anabolism and catabolism of adenine-8-C 14 by
mouse tissues, rat tissues, Ad-755, S-180, LI~10, and Nov. hep.
93
28
I
--!
13
128
.i
-Ad
-- Hx
~ HxR
IMP
m
i
i
I
i
i
--Tides
i
i
i
--Tides
i
i
i
i
i
i
i
I
i
i
I
m
i
i
i
i
i
m
I
- - i
i
w
i
.Hx
i
i
I
i
~-U.A.
I
L
I
HS
HAMSTER
CHART 7.--Anabolism and catabolism of hypoxanthine-8C 14 by hamster tissues and HS.
L
I
---~-u.A.
I -All.
HS
HAMSTER
CHART 9.--Anabolism and catabolism of adenine-8-C 14 by
hamster tissues and HS.
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404
Cancer Research
Vol. s
April 1961
nellakis (3, 4) have obtained data that led them to
suggest that the extent of incorporation of pyriinidines into nucleic acids is determined by the extent
of degradation of the pyrimidines by the respective
tissue. Bergel, Bray, Haddow, and Lewin (2) have
also suggested that the extent of nucleic acid synthesis that occurs in a tissue is dependent upon the
extent of catabolism of building blocks, and these
workers suggest that xanthine oxidase might be
the critical enzyme in maintaining a balance. Pre-
products that were formed intracellularly within a
tissue and those that were formed in other tissues
and transported by the blood to that particular
tissue. In the in vitro experiments described here,
data were obtained for the isolated tissues. The
free-hand mincing leaves many intact cells that
retain much of their metabolic activity. This
metabolic activity includes both anabolism and
catabolism. Hence, the use of minces makes it possible to obtain some information about the extent
of balance between anabolism and catabolism in
79
80
37
81
112 92
80
the various tissues. The application of the chromatographic-radioautographic technic to extracts
the tissues is useful for such a study, because it
I
-- Gu. of
is possible to detect and isolate both anabolic and
catabolic products from the same preparations.
Both intermediary products and end products of
anabolism and catabolism are detected, and therefore information is obtained for the various steps
along the metabolic path. The data show the net
results of the multiple enzymic reactions occurring
within the cells, and it is possible that differences
-J 3R
in net results for neoplastic tissues and for host
tissues may be more significant than differences in
concentrations of specific enzymes. In these experiments only inorganic salts, glucose, adenosine
triphosphate, and substrate were furnished to the
cells, and no effort was made to accomplish maxi-Unk.
~-U.A.
mum enzyme activity by the adjustment of pH or
addition of co-factors--each tissue was dependent
upon its own supply of vitamins, co-factors, and
amino acids.
--All.
Because of the diversity of metabolic patterns
of various normal tissues and a similar diversity of
metabolic patterns of neoplastic tissues, it is difL
I
A
S
L
I
N
ficult to compare the metabolism of "normal tissues" and "cancer tissues." For most experimental
MOUSE
RAT
animal tumors it is difficult to obtain an analogous
CHART 10.--Catabolism of guanine-8-C14by mouse tissues,
normal tissue. One possible approach in dealing
rat tissues, Ad-755, S-180,and Nov. hep.
with this problem is to examine a number of norviously reported results from this laboratory (1) mal tissues and a number of cancer tissues and
have been consistent with the hypothesis that the determine if the normal tissues have any property
rate of cell division might be controlled by a bal- in common and if this property is lacking in the
ance between anabolic events leading to nucleic cancer tissues. Accordingly, in the present study
acids and catabolic events that degrade potential several minced mouse tissues (liver, intestine,
nucleic acid precursors. Numerous investigators spleen, kidney, heart, brain, lung, embryo, blood
have assayed tumors and normal tissues for many cells, and blood plasma) were incubated with
enzymes, but few of them have made direct com- hypoxanthine-8-C TM, and similarly a number of
parisons between levels of anabolic activity and minced mouse neoplasms (Ad-755, S-180, L1~10,
levels of catabolic activity. In the experiments re- L4946, and L5178) were incubated with this laported here the data show the relative extents of beled substrate. Since both anabolism and catabosimultaneously occurring anabolism and catabo- lism occurred, it was possible to determine the delism of a specific substrate within a single sample of gree of balance between these two types of processes in the host tissues and in the neoplastic
tissue.
As was pointed out in the introduction, in vivo tissues. For this purpose inosine, inosinic acid, adeexperiments did not distinguish between metabolic nine, adenosine, adenosine monophosphate, adeno-
i
" l- i
i
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Research.
AND ALEXANDER--Anabolism and Catabolism of Purines by Minced Tissues 405
]u
sine diphosphate, adenosine triphosphate, and diphosphopyridine nucleotide were considered to be
anabolic products, and xanthine, xanthosine, uric
acid, and allantoin were considered to be catabolic
products. Table ~ contains the data obtained by
combining the values for the various compounds
in these two categories. The values of the ratio,
catabolic products/anabolic products, are also
given. The ratio for each mouse tumor is smaller
than the ratio for any host tissue with the exception of brain, spleen, and embryo. As was pointed
out under "Results," these exceptions are not surprising in view of the low metabolic activity of the
brain and the high metabolic and mitotic activity
of spleen and embryo. Likewise, the ratio for Nov.
hep. was lower than the ratios for the rat tissues,
and that for HS was lower than those for hamster
liver and intestine. (It is not known to what extent
the differences between the values for the hamster
tissues and those for the HS are due to the species
differences in metabolic rates.) The ratios for tumors were also smaller than those for host liver
and intestine when adenine-8-C TM was the substrate. (Hypoxanthine, inosine, and inosine monophosphate were included as anabolic products of
adenine-8-C TM since the purine ring of these compounds is at the same level of oxidation as adenine.) Thus it can be stated that in these experiments relatively more catabolism occurred in the
host tissues than in the cancer tissues, but it is
possible that the ratios would have been somewhat
different for other periods of incubation.
It is emphasized that some catabolism occurred
in every tissue, and that for some neoplasms the
values of the ratio, catabolic products/anabolic
products, was only slightly lower than the values
TABLE 2
ANABOLISM AND CATABOLISM OF VARIOUS MINCED TISSUES
PER CENT OF TOTAL RADIOACTIVITY
Precursor: hypoxanthine-8-C TM
SPECIES
Free
substrate
Mouse
Rat
Liver
Intestine
Spleen
Kidney
Heart
Brain
Lung
Blood--cells
Blood--plasma
Embryo
Ad-755
S-180
L1210
L4946
L5178
Liver
Intestine
Spleen
Kidney
Heart
Brain
Lung
Nov. hep.
Hamster
Precursor: adeniue-8-C 14
Tissue
Liver
Intestine
HS
i
i
I
,i
i
i
1
3
30
13
17
75
3
35
30
65
19
13
35
68
26
Anabolic Catabolic
9products products!J
(A)* ' (c)t
I
2
!
1
22
7
8
i
20
17
~5
26
29
14
21
17
!
'
C/A
97
96
48
80
75
5
80
65
70
10
52
58
51
13
57
48.5
96.0
2.2
11.4
9.4
0.25
4.7
0.4
2.0
2.0
3.6
0.6
3.4
0
0
0
8
23
80
3
5
~
1
12
13
4
15
17
34
98
99
88
79
73
5
80
61
49.0
99.0
7.3
6.1
18.2
: 0.33
4.7
1.8
4
5
10
37
91
88
54
I
I
2
9
18.2
8.8
1.4
I
Anabolic Catabolic
products products
(A)~
(C)?
Free
substrate
11
11
48
61
87
90
10
10
2
0
5
3
9
i
0
!
C/A
41
27
0.85
0.44
3
0
0.30
0
89
80
77
80
9
20
18
17
0.10
0.25
0.22
0.21
34
40
57
60
1.5
87
12
0.14
73
29
90
26
71
9
0.36
2.44
0.10
I
1.67
I
1
* Inosine, inosine monophosphate, adenine, adenosine, adenosine monophosphate, adenosine diphosphate, adenosine triphosphate, and diphosphopyridine nucleotide.
t Xanthine, xanthosine, uric acid, allantoin, unknowns.
~/Hypoxanthine, inosine, inosine monophosphate, adenosine, adenosine monophosphate, adenosine diphosphate,
adenosine triphosphate, and diphosphopyridine nueleotide.
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406
Cancer Research
for some of the host tissues. However, the
uniformity of the lower values for the neoplasms
is perhaps significant, and it is possible that a
small difference in this ratio could have a critical
influence on the rate of growth and mitosis.
Since no anabolic products were detected in the
experiments with guanine-8-C 14 and xanthine-8C ~4as substrates, no ratio of catabolic products to
anabolic products can be calculated. Charts ~ and
3, however, show that more oxidative degradation
of xanthine to uric acid and allantoin occurred in
the host liver and intestine than in the tumors. In
agreement with these results the data of Chart 10
show that, although there was extensive deamination of guanine-8-C ~4to xanthine by the livers, intestines, and tumors, subsequent degradation of
the xanthine to uric acid and allantoin was less
extensive in the tumors than in the livers and intestines. These results along with those obtained
with hypoxanthine-8-C 14 and adenine-8-C 14 indicate that the levels of xanthine oxidase activity
are lower for the neoplasms than for most of the
host tissues that were examined. Other investigators have obtained similar results, but a review of
their results and a consideration of whether xanthine oxidase is the limiting enzyme for degradation of purines by tumors are withheld for inclusion in the following paper of this series, where
supplementary experimental evidence is presented.
Although the data presented here show that less
catabolism of purines occurs in the neoplasms than
in the host tissues, the significance of this fact
might be questioned, since most of the purines
normally present in the cells are probably ribonueleotides rather than free bases. If various minced
tissues were incubated with labeled ribonucleotides, the results might be questioned because of
possible differences in the permeability of the cells
to ribonueleotides. To circumvent this difficulty,
suspensions of sonically ruptured cells were in-
Vol. ~1, April 1961
cubated with labeled purines and labeled purine
ribonucleotides, and the results of such experiments are reported in the following paper of this
series.
ACKNOWLEDGMENTS
The authors wish to express their appreciation to Dr.
H. E. Skipper, Dr. L. L. Bennett, Jr., and Dr. R. W. Brockman
for their contributions in discussions of this work and to the
following people for their technical assistance: Mrs. Margie
Grammer, Mrs. Patricia Fisher, Mrs. Joan Harrill, Mrs. Ann
Dodson, Miss Linda Simpson, Mrs. Jane Hazelrig, Miss Frances Newman, Miss Tommie Lou Barker, Miss Gall Yerby,
and Mrs. Joyce Watkins.
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Cancer Cells. VI. Metabolism of Purines in vivo. Cancer
Research, 9.1:390-98, 1961.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1961 American Association for Cancer
Research.
Searches for Exploitable Biochemical Differences between
Normal and Cancer Cells. VII. Anabolism and Catabolism of
Purines by Minced Tissues
Glynn P. Wheeler and Jo Ann Alexander
Cancer Res 1961;21:399-406.
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