Searches for Exploitable Biochemical Differences between Normal and Cancer Cells IX. Anabolism and Catabolism of Purines by Hepatomas 5123 and H-35*

GLYNNP. WHEELER,Jo ANN ALEXANDER,ANNS. DODSON, SUSAND. BRIGGS,ANDHAROLDP. MORRIS

(Kettering-Meyer Laboratory,^ Southern Research Institute, Birmingham, Alabama; and Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

SUMMARY The extents of anabolism and catabolism in vitro of purines and purine ribonucleo- tides by rat tissues, Morris Hepatoma 5123, and Reuber H-35 hepatoma were deter mined. The results are compared with those obtained previously for Novikoff hepato ma. Hepatoma 5123 was more active catabolically than any of the host tissues exam ined, including liver; H-35 tumor was about one-half as active catabolically as the host liver; and Novikoff hepatoma was much less active catabolically than the host liver. The results show that, although a deficiency of purine catabolism may be a contribut ing factor to the uncontrolled growth of some neoplasms, deficiency of purine catab olism is not a requisite for neoplastic growth.

Previous studies (17) showed that more anab 6) were very similar to those of the host liver, it olism and less catabolism of radioactive purines seemed worth while to compare the extent of occurred with minces of several neoplasms (Leu catabolism of purines and purine ribonucleotides kemia L1210, Leukemia L4946, Leukemia L5178, by Hepatoma 5123 with that of the liver and Sarcoma 180, Adenocarcinoma 755, Human Sar other tissues of the host. Also, since studies of coma No. 1, Novikoff hepatoma) than with minces carbohydrate metabolism (13,15) of deoxycytidyl- of several tissues of the hosts. Also, more catabo ate deaminase activity (4) and of glutamic oxal- lism of purine ribonucleotides occurred with total acetic transaminase activity (2) in hepatomas sonicates of neoplasms than with total sonicates indicated that certain enzyme levels of hepatomas of tissues of the hosts (18). It was suggested that could be correlated with the rates of growth of the the deficiency of enzymes that catabolize pu tumors, it was decided also to determine the capac rines might partially account for the uncontrolled ity of the slowly growing Reuber H-35 hepatoma growth of neoplasms (18), in accordance with the (12) to catabolize purines and purine ribonucleo enzyme-deletion hypothesis of neoplasia (9). Since tides. This report presents the results of these studies by others (1, 3, 7, 8, 11) indicated that the studies and also contains some data that were enzyme contents of the Morris Hepatoma 5123 (5, obtained previously for Novikoff hepatoma but * This work was supported by the Cancer Chemotherapy that are included here to facilitate comparison of National Service Center, National Cancer Institute, under the National Institutes of Health Contract No. SA-43-ph-24S3, data for the three hepatomas. and by grants from the Charles F. Kettering Foundation and the Alfred P. Sloan Foundation. EXPERIMENTAL METHODS t Affiliated with Sloan-Kettering Institute for Cancer Re Segments of Hepatoma 5123, a transplantable search, New York, N.Y. liver carcinoma that was induced by ingestion of Received for publication February 16, 1962. N-(2-fluorenyl)-phthalamic acid in an inbred Buf- 769

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. 770 Cancer Research Vol. 22, July 1962 falo-strain rat (5), were implanted by trocar sub- been reported previously (17,18) but are included cutaneously into female Buffalo-strain rats. The here to facilitate comparison of the data for the rats were killed 8|-9 weeks later by carbon di three hepatomas. Since the radioassays of the oxide asphyxiation, and the tumors and desired compounds obtained from the Novikoff hepatoma tissues were excised quickly and placed in ice-cold were performed by a different technic and with beakers. The tumors, ranging in size from 1 to 10 the use of a different type of counter, the data for gm., and tissues from five or six rats were pooled in the total activities are not directly comparable, each experiment. but comparisons of the distributions of the activ Segments of Reuber H-35 tumor were implanted ity among the various compounds are justifiable. by trocar subcutaneously in the axillary region The data obtained with adenine-8-C14, hypo- and intramuscularly in the right hind leg of A X xanthine-8-C14, guanine-8-CH, and xanthine-8-C14 C strain rats.1 The rats were killed by carbon as substrates in experiments with minces are dioxide asphyxiation 9-12 weeks later. The sub shown in Charts 1-4. Data are given for the livers cutaneous and intramuscular tumors, weighing of the animals bearing the various hepatomas and from 2 to 9 gm., were pooled after the removal of for several other tissues of the animals bearing the the muscle tissue. Morris Hepatoma 5123. Minces were prepared by free-hand cutting with Adenine was utilized rather extensively for ana knives, and the minced tissues were added to bolic reactions by all the tissues except the brain, Krebs-Ringer phosphate buffer containing a radio as shown in Chart 1. The compounds that are con active substrate and incubated in a Dubnoff sidered here as anabolic products are adenosine, shaking incubator in an atmosphere of oxygen for adenylic acid, adenosine disphosphate (ADP), 4^ hours at 37°C. as described previously (17). adenosine triphosphate (ATP), diphosphopyri- Total sonicates were prepared by homogenizing dine nucleotide (DPN), hypoxanthine, inosine, the tissues with a Virtis homogenizer, suspending and inosinic acid. The last three of these com the homogenate in Krebs-Ringer phosphate buf pounds are included as anabolic products, because fer, and then subjecting the resulting suspension it is likely that adenine was converted to adeno to sonic vibrations by means of a Raytheon 9 KC sine or adenylic acid prior to deamination, and Magnetostriction Oscillator. After the addition of the presence of these compounds reflects a prior labeled substrates, the sonicates were incubated anabolic process. Xanthine, xanthosine, uric acid, for 60 minutes in the Dubnoff shaking incubator. allantoin, and certain unidentified minor com Alcoholic extracts of the minces and the sonicates ponents are considered to be catabolic products. were prepared and utilized for the preparation of Table 1 contains the sums of the percentages of paper chromatograms and radioautograms by de anabolic products and those of catabolic products scribed procedures (16). The radioactive areas of and also the ratios of these sums. These ratios show the chromatograms were cut out and assayed for the degrees of balance between catabolic and ana radioactivity by means of a Tri-Carb liquid scin bolic processes under the test conditions. The liver tillation spectrometer. and spleen had higher ratios of catabolism to RESULTS anabolism than the other host tissues of the animals bearing Hepatoma 5123, but the hepa The results of the radioassays are presented in toma had a higher ratio than any of the host the charts as per cent of the total radioactivity de tissues examined. The Reuber H-35 tumor and the tected on the chromatograms, in order to show the distribution of the CM among the various com host liver yielded approximately the same ratios of catabolism to anabolism, whereas the Novikoff ponents of the extracts. The total activities de hepatoma gave a much lower ratio than the host tected on the chromatograms are also indicated liver. Thus, Hepatoma 5123 and the H-35 tumor on the charts, so that the activity of any of the were very much like the host livers in the bal compounds can be calculated. Although single ances between catabolism and anabolism, but the experiments were performed with each tissue prep Novikoff hepatoma carried out more anabolism aration and each substrate, the consistency of the and less catabolism than did the host liver. results obtained with the various labeled sub The data of Chart 2 and Table 1 show that strates adds to the degree of confidence of the re there was much less anabolism of hypoxanthine- sults. The data for the Novikoff hepatoma have C14than of adenine-C14 by all the tissues except 1Dr. M. D. Reuber, who decided to stop maintaining this brain, and there was correspondingly much more hepatoma, turned over his animals bearing the H-35 hepa catabolism. Again, liver was the most active host toma to H. P. Morris in May, 1961, because Morris had an tissue catabolically, and Hepatoma 5123 and H-35 available supply of A X C strain rats in which the tumor grows. Morris is now maintaining this tumor at Bethesda. tumor were as active as the host livers, whereas

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. Per Cent of Total Activity Total Activity Tissue 0 10 20 30 40 50 60 70 80 9.0 100 cpm IMPHxR Hx LIVER 4,076

HER5I23 Hllj«5********lllllll*:v8i 4,577

KIDNEY 6,570

LUNG 9,592

SPLEEN 6,086

HEART illlllllllllBBIBI» í^ 4,216

BRAIN I5*illlllllllimilimimi m 9,170

LIVER

NOV. HER

LIVER 20,714

H-35TUM. 21,433 Key to Charts. XMP, xanthylic acid; IMP, ¡nosinicacid; nucleotide. GMP, guanylic acid; adenine tides, adenylic acid + adenosine CHART1.—Anabolismand catabolism of adenine-8-C14 by diphosphate + adenosine triphosphate + diphosphopyridine various minced tissues.

ALLANTOIN INOSINE

IlllllllllllllllURIC ACID IMP

UNKNOWNS GUANINE

XANTHINE 000000000 GUANOSINE + GMP

XANTHOSINE ADENINE

XMP ******** ADENOSINE

HYPOXANTHINE ADENINE TIDES

TABLE1 ANABOLISMANDCATABOLISMOFPURINESBYVARIOUSTISSUESANDHEPATOMAS

RADIOACTIVITYPrecursor: CENTor TOTAL

adenine-8-C14Free hypoxanthine-8-CuFree TISSUEKidneyHeartSpleenLungBrainLiverHepatoma

substrate25833181152391512Anabolicproducts substrate16594Ì65110511Anabolicproducts (A*)7139447318554434875247Catabolicproducts(Ct)27323261303357124341C/A0.380.080.520.360.060.550.751.670.140.830.87Precursor:(At)1515415271023444Catabolicproducts(Ct)692692838989998619696C/A4.61.723.05.50.398.049.01.824.024.0

5123LiverNovikof

fHepatomaLiverReuber

H-35 TumorPEH

* Adenosine, adenylic acid, ADP, ATP, DPN, hypoxanthine, inosine, and inosinic acid, t Xanthine, xanthosine, uric acid, allantoin, and certain unidentified minor components. ÃŽInosine,inosinic acid, adenosine, adenylic acid, ADP, ATP, and DPN.

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. 772 Cancer Research Vol. 22, July 1962 Novikoff hepatoma was relatively inactive cata- hepatoma. Hepatoma 5123 degraded most of the bolically. guanine to allantoin, and H-35 tumor and host Although there was evidence of some anabolism liver degraded all the guanine-C14 to allantoin; of guanine-C14 by four of the host tissues, no but Novikoff hepatoma degraded only a small anabolism occurred with the liver and the hepa- portion of the substrate to allantoin. tomas (Chart 3). All the guanine was deaminated Chart 4 shows that traces of anabolic products by the livers, Hepatoma 5123, and H-35 tumor, of xanthine-C14 were detected for several of the but there was some residual guanine with Novikoff tissues, but that, with the exception of the heart

Per Cent of Total Activity Total Activity

Tissue 10 20 30 40 50 60 70 80 90 100 cpm

5,020

4,174

4,952

5,358

5.481

4,550

9,286

LIVER 10,863

H-35 T UM. 16,800 CHART2.—Anabolismand catabolism of hypoxanthine-8-C14 by various minced tissues

Per Cent of Total Activity Total Activity Tissue 0 10 20 30 40 50 60 70 80 90 100 cpm All LIVER 2,306

HEP5I23 1,838

KIDNEY 2,488 MMMIÕIIU Ad-T AiJR HxR Hx LUNG •IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIK^***-.?* 1,953

SPLEEN 1,660

HEART 1,375

BRAIN 2,209

LIVER

NOV.HER

LIVER 41,234

H-35 TUM. 40,121 CHART3.—Anabolismand catabolism of guanine-8-C14 by various minced tissues

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. WHEELERet al.—AnabolìsmandCatabolism of Purines by Hepatomas 773 and the brain, the extent of catabolism was much as shown in Charts 5-8, perhaps owing to denatu- greater than the extent of anabolism. Hepatoma ration of some of the enzymes of anabolism during 5123 and the liver were equally active catabolical- sonic treatment. Chart 5 shows the low levels of ly and considerably more active than the Novikoff adenase in all the tissues. Hepatoma 5123 catabo- hepatoma. Experiments with xanthine-C14 used as lized hypoxanthine-C14, guanine-C14, and xan substrate were not run with H-35 tumor because thine-C14 as extensively as, or more extensively the supply of xanthine-C14 was exhausted before than, liver, and H-35 tumor was almost as active the animals bearing this tumor were obtained. catabolically as host liver, whereas Novikoff hepa In agreement with previous experiments (16) toma caused much less catabolism than host liver. much less anabolism of purine occurred with total Since the ribonucleotides are more likely to be sonicates of tissues than with minces of tissues, the normal intracellular substrates for catabolism

Per Cent of Total Activity Total Activity Tissue 0 10 20 30 40 50 60 70 80 90 100 cpm

15,786

19,329

18.415 17,664

16.614

15.880

25,044

LIVER

NOV. HER CHART4.—Anabolismand catabolism of xanthine-8-C14 by various minced tissues

Per Cent of Total Activity Total Activity Tissue 0 10 20 30 40 50 60 70 80 90 100 cpm All Unk Xa Ad LIVER ùmmiiiiiÉiiiuiuiuiimi 24,810 HEP 5123 •sëammiiiimmmiiiiii 24,582 KIDNEY UllllllllllllHIIIIIIIIIIIIIII 22,983 LUNG MIOIIBIIIIIIIIIIIIIIHIIIIIIII 22,658 SPLEEN aiimmmmiiiimmimi 23,401 HxR HEART 1IIIIEIIIII19IIIIIIIIIIIIIIIII 25,533 BRAIN iiiiiiimiiiimiiiiimimi 17,005 LIVER •Eniiiiiiiiiiiiiiiiiiiiiiiii NOV HEP. lammmimmimimmii LIVER Fiiiimimiiiiiimimimi! 26,587

H-35 TUM. F »••••••••••••••••••••••••UH23,757

CHART5.—Catabolismof adenine-8-C14 by total sonicates of various tissues

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. 774 Cancer Research Vol. 22, July 1962 than the free purine bases, and in order to circum- but only the kidney sonicate completely dephos- vent the problem of cell permeability, the catabo- phorylated the guanylic acid and xanthylic acid lism of radioactive purine ribonucleotides by total in the time interval used. (Guanylic acid-C14 was sonicates of the various tissues was studied. The not used as a substrate for H-35 tumor, because of resulting data are in Charts 9-12. depletion of the supply of this compound.) Hepa- Adenylic acid-C14 and inosinic acid-C14 were toma 5123 was more active catabolically than the completely dephosphorylated by all the tissues, various host tissues, including the liver; H-35

Per Cent of Total Activity Total Activity Tissue 10 20 30 40 50 60 70 80 90 100 cpm

XaR Xa HxR Hx LIVER 6,005

HER 5123 9,119

KIDNEY 9,064

LUNG 6,106

SPLEEN 8,347

HEART $888888888888888888888% 6,739

BRAIN 7,319

LIVER

NOV. HER

LIVER 19,151

H-35 TUM. 24,323 CHART 6.—Catabolism of hypoxanthine-8-C14 by total sonicates of various tissues

Per Cent of Total Activity Total Activity 0 10 20 30 40 50 60 70 80 90 100 Tissue cpm

3,143

3,416

3,139

2,813

3,757

3,288

2,882

52,654

40,082 CHART7.—Catabolism of guanine-8-C14by total sonicates of various tissues

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. WHEELER et al.—Anabolism and Catabolism of Purines by Hepatomas 775 tumor was about one-half as active catabolically be due chiefly to a deficiency of xanthine oxidase as the host liver; and Novikoff hepatoma was in the cancer cells (18). The consistency of the much less active catabolically than host liver. results obtained for several neoplasms raised the possibility that a deficiency of purine-catabolizing DISCUSSION enzymes might be a causative property of neo- In previous studies of the balance between plastic growth. The results reported here for Hepa- anabolism and catabolism of purines by minced toma 5123 and H-35 tumor, however, show that, animal tissues and neoplasms it was found that although a deficiency of purine catabolism may relatively more catabolism occurred with the host be a contributing factor to the uncontrolled growth tissues than with the neoplasms (,17),and the data of some neoplasms, deficiency of purine catabolism indicated that the lower catabolic activity might is not a requisite for neoplastic growth. To the

Per Cent of Total Activity Total Activity Tissue 0 10 20 30 40 50 60 70 80 90 100 cpm

XaR Xa Hx LIVER MÕ 28.235

HER 5123 32,948

KIDNEY 21,855

LUNG 26,044

SPLEEN 22,333

HEART 26,494

BRAIN 35,975

LIVER

NOV.HEP. CHART8.—Catabolismof xanthine-8-C14 by total sonicates of various tissues

Per Cent of Total Activity Total Activity 0 10 20 30 40 50 60 70 80 90 100 Tissue cpm

LIVER 19,966

HER 5123 22.488

KIDNEY 20,848 .jgggggggggggggggcoogoogqc LUNG 17,498

SPLEEN $888888888» 13,465

HEART 23,204

BRAIN 22,383

LIVER

NOV. HER

LIVER 10,272

H-35TUM. 10,198 CHART9.—Catabolismof adenosine-5'-monophosphate-8-Cu by total sonicates of various tissues

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. 776 Cancer Research Vol. 22, July 1962 contrary, in several of the experiments, Hepatoma ate deaminase, thymine reductase, glucose-6- 5123 catabolized purines more extensively than phosphatase, glutamate dehydrogenase, and cho- did the host liver. line oxidase (7,11,13). Among other enzymes that The differences in the catabolic capacities of are reported to be present in Hepatoma 5123 and Hepatoma 5123 and Novikoff hepatoma and the liver and absent in Novikoff hepatoma are glycero- similarities of the catabolic capacities of Hepatoma phosphate dehydrogenase, uracil reductase, threo- 5123 and host liver are striking. Other workers nine dehydrase, serine dehydrase, tryptophan have observed wide differences in the enzyme pyrrolase, proline oxidase, phenylalanine hy- contents of a number of rat hepatomas. Of several droxylase, arginase, ornithine transcarbamylase, hepatomas examined, Hepatoma 5123 most closely and fructose-1, 6-diphosphatase (8). No appreci- resembled liver in enzyme levels of deoxycytidyl- able 5-hydroxytryptophan decarboxylase or sero-

Per Cent of Total Activity Total Activity 0 10 20 30 40 50 60 70 8.0 90 IQQ Tissue cpm All Unk XaR Xa HxR LIVER 22,909 HEP 5123 29,367

KIDNEY 28,387 LUNG 22,032 SPLEEN ®8888888888888888888& 19,912 HEART 31,982 "S88S8SS88S88888888888S8S8S BRAIN 28,221

LIVER

NOV. HER

LIVER 19,903

H-35 TUM. 8888888888® 24,670 CHART10.—Catabolism of ¡nosine-5'-monophosphate-8-C14by total sonicates of various tissues

Per Cent of Total Activity Total Activity Tissue 10 20 30 4.0 5.0 6.0 70 80 90 100 cpm

LIVER 16,433

HER 5123 18,509

KIDNEY 17,819

LUNG 15,232

SPLEEN 17,449

HEART 14,597

BRAIN 15,670

LIVER

NOV. HER CHART11.—Catabolismof guanosine-(a' + 3')monophosphate-8-C14 by total sonicates of various tissues

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. WHEELER et al.—Anabolism and Catabolism of Purines by Plepatomas 111

tonin deaminase was detected in five transplanted rapid growth of the Novikoff hepatoma could be hepatomas, but Hepatoma 5123 had activity related to the absence of some enzymes or enzyme equivalent to liver (3). Several transplantable systems having to do with the decreased catabolic hepatomas—namely, Novikoff, Dunning LC-18, capacity of the Novikoff hepatoma. Because of the Sidransky, and Morris 3683—were lower than more extensive enzyme deletion in the Novikoff liver in glutamic-oxalacetic transaminase activ hepatoma, the balance between catabolism and ity, but the activity of Hepatoma 5123 was anabolism which appears to exist in host liver and several-fold higher than liver (2). All four of the in some "minimal-deviation type" (10) neoplasms hepatomas lower than liver in this transaminase like 5123 and H-35 may no longer be present in the activity are more rapidly growing neoplasms Novikoff hepatoma. than 5123. The present study thus points out an The deletion of many catabolic enzymes, while other metabolic area in which Hepatoma 5123 not explaining the key changes essential for neo-

Per Cent ot Total Activity Total Activity Tiec'.o 0 10 20 30 40 50 60 70 80 90 100 3 b 3 U C --•._ ' • ' ' cpm

AH XgR JCp XVP HxR>lx 10.248

9,654

11,439

LUNG 15,823

SPLEEN 12,665

HEART 12,742

BRAIN 11,039

LIVER

NOV. HER

LIVER 18.586

H-35 TUM. 13,879 CHABT12.—Catabolismof xanthosine-(2' + S')monophosphate-8-C14 by total sonicates of various tissues

differs from a number of other neoplasms and plastic growth, could be one of the explanations closely resembles liver. for the growth differential of rapidly growing H-35 tumor, which, like Hepatoma 5123, grows versus slowly growing hepatomas. Other hepato slowly, catabolizes purines and purine ribonucleo- mas of variable growth rate are under investiga tides much more extensively than Novikoff hepa tion to study such a possibility. toma but somewhat less extensively than the host Although decreased catabolism of purines is liver. Thus, the results presented in this report are not a requisite for neoplastic growth, the demon consistent with the suggestions of other investiga strated decreased catabolic capacity of a number tors (2, 4, 7, 13, 15) that some enzyme levels of of rodent neoplasms (17, 18) might still be utilized tumors may be correlated with the rates of growth in the chemotherapy of those particular neoplasms of the tumors. (10). The biological aggressiveness and rapid growth ACKNOWLEDGMENTS of the Novikoff hepatoma is outstanding, since The authors wish to express their appreciation to the fol the inoculation of the host by the injection of lowing people for their assistance in caring for and dissecting about 50 million cells results in the host's death in the animals and in performing the radioassays : Miss Tommie Lou Barker, Miss Linda Simpson, Mrs. Jane Hazelrig, and 5-7 days (14), whereas, 5123 and H-35 hepatomas Miss Edith Malone. seldom kill the host in less than 2-3 months. The REFERENCES deletion of many enzymes in the former that are 1. BOXER,G. E., and DEVLIN,T. M. Pathways of Intracel- still present in the latter suggests that the more lular Hydrogen Transport. Science, 134:1495-1501, 1961.

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. 778 Cancer Research Vol. 22, July 1962

2. DYER,H. M.; CULLINO,P. M.; ENSFIELD,B.I.; and MOR 11. POTTER,V. R.; PITOT,H. C.; ONOT.; and MORRIS,H. P. RIS, H. P. Transaminase Activities of Liver Tumors and The Comparative Enzymology and Cell Origin of Rat Serum. Cancer Research, 21:1522-31, 1961. Hepatomas. I. Deoxycytidylate Deaminase and Thymine 3. KIZER,D. E., and CHAN,S.-K. The Effect of Hepatocar- Degradation. Cancer Research, 20:1255-61, 1960. cinogenesis upon 5-Hydroxytryptophan Decarboxylase 12. REUBER,M. D. A Transplantable Bile-Secreting Hepa- and Serotonin Deaminase. Cancer Research, 21:489-95, tocellular Carcinoma in the Rat. J. Nat'l. Cancer Inst., 1961. 26:891-98, 1961. 4. MALET, F., and MALET, G. F. Nucleotide Interconver 13. WEBER,G.; BANERJEE,G.; and MORRIS,H. P. Compara sions. IV. Activities of Deoxycytidylate Deaminase and tive Biochemistry of Hepatomas. I. Carbohydrate En Thymidylate Synthetase in Normal Rat Liver and zymes in Morris Hepatoma 5123. Cancer Research, 21: Hepatomas. Cancer Research, 21:1421-26, 1961. 933-37, 1961. 5. MORRIS, H. P.; SIDRANSKY,H.; WAONER,B. P.; and 14. WEBER,G., and CANTERO,A.Glucose-6-phosphate Utili Dyer, H. M. Some Characteristics of Transplantable Rat zation in Hepatoma, Regenerating and Newborn Rat Hepatoma No. 5123 Induced by Ingestion of N-(2- Liver, and in the Liver of Fed and Fasted Normal Rats. fluorenyl)phthalamic Acid. Cancer Research, 20:1252-54, Cancer Research, 17:995-1005, 1957. 1960. 15. WEBER,G.; MORRIS,H. P.; LOVE,W. C.; and ASHMORE, 6. MORRIS,H. P., and WAGNER,B. P. Some Growth Studies J. Comparative Biochemistry of Hepatomas. II. Isotope of Transplantable Hepatomas. Proc. Am. Assoc. Cancer Studies of Carbohydrate Metabolism in Morris Hepatoma Research, 3:253, 1961. 5123. Cancer Research, 21:1406-11, 1961. 7. Prior, H. C. The Comparative Enzymology and Cell 16. WHEELER,G. P., and ALEXANDER,J. A. Searches for Origin of Rat Hepatomas. II. Glutamate Dehydrogenase, Exploitable Biochemical Differences between Normal and Choline Oxidase, and Glucose-6-phosphatase. Cancer Re Cancer Cells. VI. Metabolism of Purines in vivo. Cancer search, 20:1262-68, 1960. Research, 21:390-98, 1961. 8. PITOT,H. C.; POTTER,V.R.; and MORRIS,H. P. Metabolic 17. . Searches for Exploitable Biochemical Differences Adaptations in Rat Hepatomas. I. The Effect of Dietary between Normal and Cancer Cells. VII. Anabolism and Protein on Some Inducible Enzymes in Liver and Hepa Catabolism of Purines by Minced Tissues. Ibid., pp. 399- toma 5123. Cancer Research, 21:1001-8, 1961. 406. 9. POTTER,V. R. The Biochemical Approach to the Cancer 18. . Searches for Exploitable Biochemical Differences Problem. Federation Proc., 17:691-97, 1958. between Normal and Cancer Cells. VIII. Catabolism of 10. . Transplantable Animal Cancer, the Primary Purines and Purine Nucleotides by Sonicates. Ibid., pp. Standard. Cancer Research, 21:1331-22, 1961. 407-21.

Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1962 American Association for Cancer Research. Searches for Exploitable Biochemical Differences between Normal and Cancer Cells: IX. Anabolism and Catabolism of Purines by Hepatomas 5123 and H-35

Glynn P. Wheeler, Jo Ann Alexander, Ann S. Dodson, et al.

Cancer Res 1962;22:769-778.

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