Download Searches for Exploitable Biochemical Differences between Normal

Searches for Exploitable Biochemical Differences
between Normal and Cancer Cells
X. Catabolism of Purines by Regressing Tumors*
GLYNN P. WHEELER,Jo ANN ALEXANDER,ANN S. DODSON,ANDSUSAND. BRIGGS
(Ketiering-Meyer Laboratory,f Southern Research Institute, Birmingham, Alabama)
SUMMARY
The in vitro anabolism and catabolism of radioactive purities by minces and of radio
active purines and purine ribonucleotides by sonicates of growing and regressing tu
mors were investigated with the aid of paper chromatography, radioautography, and
radioassay. Two systems of growing and regressing tumors were used: (a) cyclophosphamide-sensitive and cyclophosphamide-resistant plasmacytomas growing bilaterally
in hamsters that were subsequently treated in vivo with cyclophosphamide,1 (b) mam
mary tumors induced in rats with 7,12-dimethylbenzanthracene,
with subsequent
surgery or treatment of the rats consisting of hypophysectomy, administration of tes
tosterone, ovariectomy, or ovariectomy plus administration of diethylstilbestrol.
More catabolism and apparently less anabolism of purines and purine ribonucleotides
occurred with preparations of regressing tumors than with preparations of growing
tumors. The significance of these results is discussed.
It has been suggested that the rate of cellular
proliferation of a tissue might be dependent upon
the degree of balance between anabolic events and
catabolic events within the cells (1, 11). During
normal growth the balance would be tipped in the
direction of anabolic events, during homeostasis
an approximately even balance would be main
tained, and during tissue atrophy the balance
would be tipped in the direction of catabolic
events. In neoplastic tissues, which exhibit un
controlled growth, the balance would probably be
tipped in the direction of anabolic events. The
mechanism of control that maintains the proper
balance in normal tissues is not known, and the
reasons for the lack of control in neoplastic tissues
* This work was supported by the Cancer Chemotherapy
National Service Center, National Cancer Institute, under Na
tional Institutes of Health Contract Nos. SA-43-ph-2433,
SA-43-ph-4358, and SA-43-ph-3784; and by grants from the
Charles F. Kettering Foundation and the Alfred P. Sloan
Foundation.
t Affiliated with Sloan-Kettering Institute for Cancer Re
search, New York, N.Y.
'Cyclophosphamide
is 2-[bis(2-chloroethyl)amino]-2H1,3,2-oxazaphosphorinane 2-oxide.
Received for publication June 18, 1962.
are also unknown. Just as the position of a pan
balance can be altered in one direction by increas
ing the load on one pan, by decreasing the load on
the other pan, or by a combination of changes of
the loads on both pans, so the metabolic balance
might be shifted toward anabolism by increasing
the rate of anabolism, by decreasing the rate of
catabolism, or by a combination of changes in both
anabolism and catabolism. It is desirable to deter
mine whether there is in general an imbalance of
anabolism and catabolism in neoplastic tissues and,
if so, whether it is associated with cause or effect,
what is the cause of this imbalance, and whether
means can be found to correct such imbalance.
According to the "deletion hypothesis" anabo
lism predominates over catabolism in neoplastic
tissues because of the loss or repression of (a) cata
bolic enzymes (1, 3), (6) systems that form en
zymes (10, 11), or (c) some specific mechanism
affecting the substrate-mediated control of the syn
thesis of enzymes (9). Although decreased activi
ties of a number of catabolic enzymes in various
areas of metabolism have been reported for neo
plastic tissues (9, 11), Bergel and co-workers have
suggested that xanthine oxidase might be the key
1309
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1310
Cancer Research
enzyme in controlling the availability of precur
sors of nucleic acids and that the uncontrolled
growth of neoplastic tissues may be due to de
creased levels of this enzyme (2). Other investiga
tors have also reported low levels of xanthine oxi
dase in rodent tumors (3, 4, 16), and studies with
unfractionated
tissue preparations
indicated that
xanthine oxidase was the rate-limiting enzyme in
the catabolism of purine ribonucleotides in several
tumors grown in mice and rats (16). The adminis
tration of xanthine oxidase to tumor-bearing
ani
mals resulted in the inhibition of growth of the tu
mor (6). On the other hand, it has been found that
certain slowly growing hepatomas of the rat have
as high xanthine oxidase activity as the liver of the
host animal (17). Therefore, low xanthine oxidase
activity is not a requisite for neoplastic growth,
but there might be a correlation between the rate
of growth of the tumor and the xanthine oxidase
activity, of that tumor; and the tumor-inhibiting
effect of xanthine oxidase mentioned above indi
cates that this enzyme might contribute to the
control of the rate of growth. It is of auxiliary
interest that there was a significant decrease in the
xanthine oxidase activity of the livers of rats fol
lowing the administration
of growth hormone (8).
In view of the above statements, one would pre
dict that a tumor that was regressing in size, either
spontaneously or as a result of physical or chemi
cal treatment,
would have increased catabolic
activity, particularly
increased xanthine oxidase
activity, compared with growing tumors, and that
this activity would contribute to the regression.
The present investigation was undertaken to de
termine the relative capacities of growing and re
gressing tumors to degrade purines and purine
ribonucleotides.
TEST SYSTEMS AND METHODS
Plasmacytomas in hamsters.—A transplantable
plasmacytoma
grown in hamsters (5) and a cyclophosphamide-resistant
subline of this tumor (13)
were used in this study. Fragments of the cyclophosphamide-sensitive
tumor were implanted subcutaneously
in the right axillary region of male
golden Syrian hamsters by means of trocars, and
fragments of the resistant tumor were implanted
subcutaneously
in the left axillary region of the
same hamsters. All the tumors grew extensively
during the 2-week period following implantation,
with the resistant tumors growing slightly more
rapidly than the sensitive tumors.
Some of the hamsters bearing bilaterally im
planted sensitive and resistant plasmacytomas
re
ceived five or six daily intraperitoneal
injections of
cyclophosphamide
at a dosage level of 10 mg/kg,
Vol. 22, December
1962
beginning on the 14th day after implantation
of
the tumors; remaining hamsters received daily in
jections of saline. During this period of treatment
the maximum and minimum dimensions of each
tumor were determined daily by means of calipers,
and the approximate weights of the tumors were
calculated with the assumptions that the tumors
were prolate spheroids with a density of 1. In the
animals receiving cyclophosphamide
the sensitive
tumors regressed in size to approximately
onethird their size at the time that treatment
was
begun, but the resistant tumors continued to grow
larger throughout the period of treatment. In the
animals receiving saline both sensitive and resist
ant tumors continued to grow at a steady rate.
Twenty-four
hours after the last injection the
hamsters were killed by carbon dioxide asphyxia
tion, and the livers, spleens, kidneys, sensitive tu
mors, and resistant tumors were removed and
pooled separately.
Minces of the various tissues were prepared by
free-hand cutting with knives, and the minced tis
sues were added to Krebs-Ringer phosphate buffer
containing a radioactive substrate and incubated
in a Dubnoff shaking incubator in an atmosphere
of oxygen for 4J hours at 37°C. an described pre
viously (15). Total sonicates were prepared by
homogenizing the tissues with a Model 27 Virtis homogenizer, suspending the homogenate in
Krebs-Ringer
phosphate
buffer, and then sub
jecting the resulting suspension to sonic vibrations
by means of a Raytheon 9KC Magnetostriction
Oscillator. After the addition of labeled substrates,
the sonicates were incubated in a Dubnoff shaking
incubator in an atmosphere of oxygen. Alcoholic
extracts of the minces and the sonicates were pre
pared and utilized for the preparation
of paper
chromatograms
and radioautograms
by described
procedures (1, 14, 15). The radioactive areas of the
chromatograms
were cut out and assayed for
radioactivity
by means of a Tri-Carb liquid scin
tillation spectrometer.
Chemically induced mammary tumors in rats (7).
—Female Sprague-Dawley
rats of the Holtzman
line weighing approximately
100 gm. were fed sin
gle doses of 15 mg. of 7, 12-dimethylbenzanthracene in 1 ml. of sesame oil per rat by stomach tube.
Approximately
12-16 weeks following the admin
istration of the carcinogen the rats that had grow
ing tumors were divided into five groups and treat
ed as follows:
Group 1—Control group; no treatment.
Group 2—Each rat was given daily injections
of testosterone at a dosage of 5 mg/
kgGroup 3—Each rat was hypophysectomized.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1962 American Association for Cancer Research.
WHEELERet al.—Catabolismiof Purines by Regressing Tumors
Group 4—Each rat was ovariectomized.
Group 5—Each rat was ovariectomized, and
beginning on the 2d day thereafter
daily doses of diethylstilbestrol at a
level of 0.01 mg/kg were adminis
tered.
The weights of the tumors were estimated, as de
scribed above, at intervals of 3 or 4 days. The ani
mals were killed by carbon dioxide asphyxiation
25 days after the performance of surgery or the
initiation of administration of hormone, and the
tumors from each group of animals were pooled.
1311
monophosphate-8-C14,1.25. The labeled substrates
were added to the minces and the sonicates at
levels of 1 to 2 /¿c/gmwet tissue.
RESULTS
The experimental results are presented in the
form of tables and charts showing the per cent dis
tribution of the radioactivity among the various
components of the extracts. In all the experiments
with minces the period of incubation was 4j hours,
and therefore the resulting data show the quanti
ties of the radioactive compounds that accumu-
TABLE1
EFFECTS
OFABLATIVE
SURGERY
ANDADMINISTRATION
OFHORMONES
UPON
THEGROWTH
OFCHEMICALLY
INDUCED
MAMMARY
TUMORS
IN RATS
OFTUMORS
WEIGHT
(GM.)At
GROUP12345RATabababcdababTREATMENT*NoneNoneTestosteroneTestosteroneHypophysectomyHypophysectomyHypophysectomyHypophysectomyOvariectomyOvariectomyO
ofsurgery
time
100%3203566866398842534246115145
ofsacrifice
time
or initi
t(B)4.85.514.03.25.51.81.44.814.06.49.28.0B/AX
ation of treat
ment
(A)1.51.520.54.814.05.53.89138.314.08.05.5At
IstilbestrolOvariectomy-|-L)
+ D iethy
iethy IstilbestrolCALCULATED
* See text for details.
t The animals were killed 25 days after the performance of surgery or the initiation of the
administration of hormone.
The effects of the surgery or administration of
hormones upon the growth of the tumors are
shown by the data of Table 1. Minces and soni
cates of the excised tumors were incubated after
the addition of labeled substrates, and extracts
were prepared and used for chromatography,
radioautography, and radioassay as described in
the preceding section.
Radioactive substrates.—The following radioac
tive compounds having the indicated specific
activities (in /¿c/mg)were used: hypoxanthine-8C14, 24.8; adenine-8-C14, 20.4; guanine-2-C14 sul
fate dihydrate, 2.3; guani ne-8-CI4, 3.99; xanthine8-C14, 33.2; barium salt of inosine-5'-monophosphate-8-C14, 0.30; adenosine-5'-monophosphate-8C14, 0.48; barium salt of xanthosine-(2' + 3')-
lated during this time. On the other hand, in the
experiments with sonicates, samples of the incuba
tion mixture were taken after incubation periods
of 15, 30, 60, and 90 minutes, and therefore the
results give some indication of the kinetics of the
chemical interconversions.
Chart 1 shows the extent of catabolism of purines by minces of cyclophosphamide-sensitive and
cyclophosphamide-resistant
plasmacytomas and
of three tissues of the hosts. Data are given for
both untreated and treated animals.
Under the conditions of these experiments
minced tissues can convert hypoxanthine to both
anabolic products (inosine, inosinic acid, adenosine, adenylic acid, ADP, ATP, and NAD) and
catabolic products (xanthine, xanthosine, uric
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1962 American Association for Cancer Research.
1312
Cancer Research
acid, and allantoin). The livers of the untreated
animals catabolized hypoxanthine more extensive
ly than the spleens, the kidneys, and the sensitive
and resistant tumors. This result is consistent
with those obtained with other experimental ani
mals and other tumors (15). Slightly more catabolism occurred with the sensitive tumor than with
the resistant tumor of the untreated animal.
Treatment of the animals with cyclophosphamide
had little effect upon the catabolic activities of the
livers, spleens, kidneys, and resistant tumors, but
the regressing sensitive tumors had relatively
greater catabolic activity than the growing sensi
tive tumors from the untreated animals.
When adenine was used as the substrate, hypo-
Vol. 22, December
xanthine, inosine, and inosinic acid may be in
cluded among the products of anabolism, because
it is probable that adenine is converted to adenosine or adenylic acid prior to deamination, since
the level of adenase in mammalian tissues is usual
ly low (12). Chart 1 shows that treatment of the
animals with cyclophosphamide had little effect
upon the catabolism of adenine by the livers,
spleen, kidneys, or resistant tumors but the re
gressing sensitive tumors catabolized adenine more
extensively than the growing sensitive tumors.
Chart 1 also shows the results that were ob
tained when guanine and xanthine were the sub
strates. Although xanthine is obtained by deami
nation of guanine, it is not considered here to be a
Catabolic
(As
of total activity
the extract)
40
60
80
of
100
lini
mr
Kidney
Hypoxanthine-8-C14
Xanthine-8-C14
20
Products
Liver
Spleen
Guanine-8-C
percent
0
Tissue
Substrote
Adenine-8-Cl4
1962
Sensitive
tumor
Resistant
tumor IflBP
minium)
Liver
Spleen
iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiini
Kidney
iiiiiiiniiiilllllllllll
Sensitive
tumor
Resistant
tumor (IffiBflffflB'SBi^1
Liver
mmTnTflmilNIIIIIIIIIH
Kidney
nr
Sensitive tumor
mm
Resistant
Liver
tumor
m
imiiiiMiiiiiMiiiiMiimiiiiiiiiiiiTnnnnnTnTTn
Kidney
Sensitive
tumor
Resistant
tumor
Illlllllllllllllllll
20
OB Untreated
mil Treated
40
60
80
100
animals
animals
CHART1.—Catabolism of C14-labeledpurines by minced tissues of untreated hamsters and of hamsters treated with cyclophos
phamide. In the experiments with adenine-8-C14 and with hypoxanthine-8-C14 as substrates the catabolic products are xanthine,
xanthosine, uric acid, and allantoin. In the experiments with guanine-8-C14 and with xanthine-8-C14 as substrates the catabolic
products are uric acid and allantoin.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1962 American Association for Cancer Research.
WHEELERet al.—Catabolism of Purines by Regressing Tumors
catabolic product of guanine since the two com
pounds are at the same level of oxidation and
oxidative catabolism is what is being considered
here. Therefore, uric acid and allantoin are con
sidered to be the catabolic products of both gua
nine and xanthine. Relatively more catabolism of
guanine and of xanthine occurred with regressing
tumors than with growing tumors.
Chart 2 shows that catabolism of hypoxanthine
to xanthine, uric acid, and allantoin by sonicates
occurred progressively with time, with slightly
more catabolism occurring with the growing sensi
1313
tive tumors than with the growing resistant tu
mors of the untreated animals. The regressing sen
sitive tumors had much greater catabolic activity
than the growing sensitive tumor and much more
than the growing resistant tumors of either the
treated or untreated animals. Similar results were
obtained when the substrate for the sonicates was
inosinic acid (Chart 3), adenylic acid (Chart 4), or
xanthylic acid (Chart 5).
Chart 6 shows the results obtained with minces
of the chemically induced mammary tumors with
hypoxanthine as the substrate. More catabolism
Resistant
Sensitive
Untreated
100
80
60
.t:
2O
<
"5
0J
100
a>
0
a.
60
40
20
All.
0J
30
60
90
O
30
60
90
Incubation Time (min.)
CHART2.—Catabolism of hypoxanthine-8-C14 by sonicates of tumors of untreated hamsters and hamsters treated with cyclophosphamide. The following abbreviations are used in this and the subsequent charts: U.A., uric acid; AIL, allantoin; Hx, hypo
xanthine; HxR, inosine; Xa, xanthine; XaR, xanthosine; Unk., unidentified components; IMP, inosinic acid; AMP, adenylic
acid; AdR, adenosine; Ad, adenine; XMP, xanthylic acid.
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Cancer Research
1314
occurred with the tumors from the testosteronetreated animals, the hypophysectomized animals,
and the ovariectomized animals than with the tu
mors from the control animals. The extent of catabolism of the tumors of the ovariectomized ani
mals that received injections of diethylstilbestrol
was intermediate between that of tumors from the
ovariectomized animals and that of the tumors
from the control animals.
Chart 7 shows that the relative catabolic activi
ties of sonicates of the mammary tumors with
inosinic acid as the substrate were similar to those
for minces of these tumors with hypoxanthine as
the substrate.
Vol. 22, December
1962
DISCUSSION
As was stated in previous papers of this series
(15, 16), the experimental methods used in these
studies were chosen for the purpose of comparing
the composite enzymic activities of various tissues
with and without different types of treatment. No
effort was made to vary the medium, the proce
dures for preparing the tissues, or the conditions of
incubation in order to attain an optimum environ
ment for any specific enzyme. Although maximum
conversions of substrates to anabolic or catabolic
products may not be realized under the chosen
conditions, the method serves the purpose of de
tecting differences in the metabolic activities of the
various tissues.
Resistant
Sensitive
Untreated
100
80-
- IMP
60
4a
H*
•1 201
ö
°
30
60
90
O
30
60
90
Treated
o
_
100
0
O
ì> 80
60.•.:'¡:¡$r
HxR
40-
20
r All.
30
60
90
90
Incubation Time(min.)
CHART3.—Catabolisra of inosine-5'-monophosphate-8-C14 by sonicates of tumors of untreated hamsters and of hamsters
treated with cyclophosphamide. See legend for Chart a for abbreviations.
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WHEELERet al.—Catabolismof Purines by Regressing Tumors
The results of these experiments show that more
catabolism of purines occurred with minces and
sonicates of regressing tumors than with minces
and sonicates of growing tumors. Since both ana
bolic and catabolic reactions occur in the minces,
it is possible to compare the relative portions of
the total radioactivity of the extracts that are pres
ent as anabolic products and as catabolic products.
Such a comparison is shown by the data of Table 2.
The ratio of catabolic products to anabolic prod
ucts (C/A) was about the same for the cyclophosphamide-resistant and the cyclophosphamide-sensitive tumors of the untreated animals. With the
tumors of the cyclophosphamide-treated animals,
however, the ratio C/A for the resistant tumor was
1315
lower than for the resistant tumor of the control
animal, but the ratio for the regressing sensitive
tumor was more then 3 times as great as that for
the growing sensitive tumor. This indicates a shift
toward greater catabolism in the regressing tumor.
For the DMBA-induced tumors the ratios were
also larger for the regressing tumors than for the
growing tumors. These results indicate that in
growing tumors there is a deficiency of catabolic
activity that correlates with an imbalance between
catabolism and anabolism. The correlation of
change in anabolic activity with growth or regres
sion of the tumors is not so well established, be
cause the extracts would not contain the endproducts of anabolism—namely, the nucleic acids;
Résistent
Sensitive
100
-AMP
80
60-
40
-H*
Õ^^XXNNVS^'
3O
-Xa
60
90
Treated
too
o
£
80
40
20
-U.A.
Incubation Time (min)
CHART4.—Catabolism of adenosme-5'-nionophosphate-8-Cu by sonicates of tumors of untreated hamsters and of hamsters
treated with cyclophosphamide. See legend for Chart 2 for abbreviations.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1962 American Association for Cancer Research.
Resistant
Sensitive
Untreated
100
XMP
80
60
40
2O
£
o
o J
i01^^
O
30
•"I"'""I1i fi
60
»,
90
Treated
100-,
u
w
£
60-
4O
20
O
30
60
90
O
30
60
Incubation Time (min.)
CHART5.—Catabolism of xanthosine-5'-monophosphate-8-C14 by sonicates of tumors of untreated hamsters and of hamsters
treated with cyclophosphamide. See legend for Chart 2 for abbreviations.
Catabolic
(As percent
Treatment
20
Products
of total activity
the extract)
40
60
80
of
100
None
Hypophysectomy
Testosterone
Ovariec
tomy
Ovariec
tomy
+ D.E.S.
CHART6.—Catabolism of hypoxanthine-8-C14 by minces of chemically induced tumors from animals that received various
treatments. The catabolic products are xanthine, xanthosine, uric acid, and allantoin. D.E.S. is diethylstilbestrol.
1316
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1962 American Association for Cancer Research.
100-,
Control
Hypophysectomized
Testosterone-treated
80
60
40I
20
<
O
g 100ü
0
30
60
90
Ovariectomized
30
60
90
Ovoriectomized +D.E.S.
« 80û.
60
4020
oO
30
60
Incubation
90
Time
O
30
60
90
(min.)
CHART7.—Catabolism of inosine-5'-monophosphate-8-C14 by sonicates of chemically induced tumors from animals that re
ceived various treatments. See legend for Chart a for abbreviations. D.E.S. is diethylstilbestrol.
TABLE 2
CATABOLISM
ANDANABOLISM
OFHYPOXANTHINE-S-C"
BYMINCESOFGROWINGANDREGRESSING
TUMORS
RADIOACTIVITYr
CENT OK TOTAL
HOBTHamsterHamsterRatTUMORCyclophosphamide-resistantplasmacytomaCyclophosphamide-sensitiveplasmacytomaDMBA-inducedTREATMENTNoneCyclophosphamideNoneCy
ree sub
strate363417671015Anabolicproducts*(A)16262310352212724Catabolicpro
plus diethylstilbestrolPER
* Inosine, inosinic acid, adenosine, adenylic acid, ADP, ATP, and NAD.
t Xanthine, xanthosine, uric acid, allantoin, and several unidentified minor components.
1317
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1318
Cancer Research
and in these experiments no measure was made of
nucleic acid synthesis. The deficiency of catabolic
activity is also indicated by the data for the soni
cates. Thus the imbalance between catabolism and
anabolism in growing tumors is at least partially
due to decreased catabolism.
It is interesting that tumors initially having low
catabolic activity had increased catabolic activity
during regression, whether the regression was
caused by administration of an alkylating agent or
by hormone deficiency. This fact poses several
interesting questions. By what mechanism is the
catabolic activity increased? Is more catabolic
enzyme formed? Is the increased activity due to
de-repression of enzyme that was present but was
repressed in some way? Is the increased activity
due to the increased availability of some necessary
activator or auxiliary system? What controls the
level of catabolism, and can this control be manip
ulated by external means for therapeutic pur
poses? Although the answers to these questions
are not yet available, the results obtained in the
experiments reported here may serve as a spur to
stimulate further investigation in this area of can
cer research.
ACKNOWLEDGMENTS
The authors wish to express their appreciation to the follow
ing for their assistance in caring for and dissecting the animals
and in performing the radioassays: Mr. E. S. Sands, Jr., Mr.
W. P. Schilleci, Mr. Charles A. Kelley, Miss Tommie Lou
Barker, Miss Linda Simpson, Mrs. Jane Hazelrig, and Miss
Edith Malone.
REFERENCES
1. BENNETT, L. L., JR.; SKIPPER, H. E.; SIMPSON,L.;
WHEELER,G. P. ; and WILCOX,W. S. Searches for Exploit
able Biochemical Differences between Normal and Cancer
Cells. V. Cellular Conservation of Purines. Cancer Res.,
20:62-81, 1960.
2. BERGEL,F.; BRAY, R. C.; HADDOW,A.; and LEWIN, I.
Enzymic Control of Purines by Xanthine Oxidase. In:
G. E. W. WOLSTENHOLME
and C. M. O'CONNOR(eds.),
Ciba Foundation Symposium on the Chemistry and Biol
ogy of Purines, pp. 256-66. London: J. & A. Churchill, Ltd.,
1957.
8. DELAMIRANDE,
G.; ALLARD,C.; and CANTERO,A. Purinemetabolizing Enzymes in Normal Rat Liver and Novikoff
Hepatoma. Cancer Res., 18:952-58, 1958.
Vol. 22, December
1962
4. FEIGELBON,P.; ULTMANN,J. E.; HARRIS,S.; and DASHMAN,T. Cellular Xanthine Oxidase and Uricase Levels in
Leukemic and Normal Mouse Leukocytes. Cancer Res.,
19:1230-33, 1959.
5. FORTNER,J. G.; MAHY,A. G.; and COTRAN,R. S. Transplantable Tumors of the Syrian (Golden) Hamster. Part II.
Tumors of the Hematopoietic Tissues, Genitourinary
Organs, Mammary Glands and Sarcomas. Cancer Res.,
21 (Suppl.) : 199-234, 1961.
6. HADDOW,
A.; DELAMIHANDE,
G.; BERGEL,F.; BRAY,R. C.;
and GILBERT,D. A. Anti-tumor and Biochemical Effects
of Purified Bovine Xanthine Oxidase in C3H and C Mice.
Nature, 182:1144-46, 1958.
7. HUGGINS,C.; GRAND, L. C.; and BRILLANTES,F. P.
Mammary Cancer Induced by a Single Feeding of Polynuclear Hydrocarbons, and Its Suppression. Nature, 189:
204-7, 1961.
8. PANDA,N. C.; GOEL,B. K.; MANSOOR,M.; and TALWAR,
G. P. Effect of Growth Hormone on Ribonucleic Acid
Metabolism. 2. Effect of Growth-Hormone Administra
tion on the Activities of S'-Nucleotidase, Adenase, Guanase,
and Xanthine Oxidase. Biochem. J., 82:176-79, 1962.
9. PITOT,H. C.; POTTER,V. R.; and MORRIS,H. P. Meta
bolic Adaptations in Rat Hepatomas. I. The Effect of
Dietary Protein on Some Inducible Enzymes in Liver and
Hepatoma 5123. Cancer Res., 21:1001-8, 1961.
10. POTTER,V. R. The Present Status of the Deletion Hy
pothesis. Univ. of Mich. Med. Bull., 23:401-12. 1957.
11.
. The Biochemical Approach to the Cancer Prob
lem. Federation Proc., 17:691-97, 1958.
12. SCHMIDT,G. Nucleases and Enzymes Attacking Nucleic
Acid Components. In: E. CHAHGAFF
and J. N. DAVIDSON
(eds.), The Nucleic Acids, 1:595, New York: Academic
Press, Inc., 1955.
13. SKIPPER,H. E., and SCHABEL,F. M., JR. Experimental
Evaluation of Potential Anticancer Agents. VII. Cross
Resistance of Alkylating Agent-Resistant Neoplasms.
Cancer Chemotherapy Rept., 22:1-22, 1962.
14. WHEELER,G. P., and ALEXANDER,
J. A. Searches for Ex
ploitable Biochemical Differences between Normal and
Cancer Cells. VI. Metabolism of Purines in Vivo. Cancer
Res., 21rS90-98, 1961.
15.
. Searches for Exploitable Biochemical Differences
between Normal and Cancer Cells. VII. Anabolism and
Catabolism of Purines by Minced Tissues. Ibid., pp. 399406.
16.
•.
Searches for Exploitable Biochemical Differences
between Normal and Cancer Cells. VIII. Catabolism of
Purines and Furine Nucleotides by Sonicates. Ibid., pp.
407-21.
17. WHEELER,G. P.; ALEXANDER,J. A.; DODSON,A. S.;
BRIGGS,S. D.; and MORRIS,H. P. Searches for Exploitable
Biochemical Differences between Normal and Cancer Cells.
IX. Anabolism and Catabolism of Purines by Hepatomas
5123 and H-35. Cancer Res., 22:769-78, 1962.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1962 American Association for Cancer Research.
Searches for Exploitable Biochemical Differences between
Normal and Cancer Cells: X. Catabolism of Purines by
Regressing Tumors
Glynn P. Wheeler, Jo Ann Alexander, Ann S. Dodson, et al.
Cancer Res 1962;22:1309-1318.
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