Catabolism of Xanthine and Uracil in Tumor-Bearing Rats'1

Catabolism of Xanthine and Uracil in Tumor-bearing Rats'1

CHUNGWu ANDJEREM. BAUER

(Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan)

SUMMARY The urinary excretion of allantoin and uric acid was greatly increased in rats bear ing Walker carcinoma 256. The increase was greater with more advanced tumor growth. A similar increase was also observed in the allantoin concentration of the plasma and liver of these rats. An increase in the RNA and DNA content and a decrease in the RNA/DNA ratio were found in the muscle of the tumor-bearing animals. Liver xanthine oxidase activity was increased in rats bearing Walker 256 and Guerin carcinomas and NovikofT and Morris 3683 hepatomas but was unchanged in rats bearing Jensen sarcoma, Morris 5123, and Morris 3924-A hepatomas, when compared with their re spective controls fed ad libitum. Liver uracil reductase activity showed a decrease in rats bearing Morris 5123 and Morris 3924-A hepatomas but no change in rats bearing Walker carcinoma 256 and Novikoff and Morris 3683 hepatomas. These findings indi cate that the effect of different tumors on a given enzyme in the host system need not be qualitatively uniform. Finally, unlike the other hepatomas tested, Morris 5123 hepatoma was found to possess xanthine oxidase activity approaching that found in a normal liver.

That the growth of a malignant tumor causes tivity has not been studied in detail in tumor-bear many disturbances in the metabolism of the host ing rats. A survey of this enzyme activity in the is well known. It can alter the concentrations of the liver of these rats has hence been made and is also substrates of an enzyme in the tissue, change the reported here. These results will provide a com amount or the activity of the enyzme, and/or af parative study of xanthine oxidase and uracil re fect the end-product excretion in the urine. All ductase activities in the liver of rats bearing tu these effects can be demonstrated when the deg mors of different origins in order to determine radation of purines and pyrimidines is studied in whether the effect of these tumors on the two en tumor-bearing animals, and these observations are zymes is qualitatively uniform. In addition, it is presented in this report. Liver xanthine oxidase of interest to note the difference in xanthine oxi activity in tumor-bearing animals has been re dase activity among the hepatomas used in this ported to be unaffected by tumor growth (5, 18). study. However, because of the changes observed in the tissue nucleic acid concentration and in the urinary MATERIALS AND METHODS excretion of uric acid and allantoin in rats bearing Animals.â€”Male Sprague-Dawley rats weighing Walker carcinoma 256, it was considered desirable 200-300 gm. were used to receive Walker carcino to re-examine liver xanthine oxidase activity in ma 256, Jensen sarcoma, Guerin epithelioma, and rats bearing this and other tumors. Of late, the Novikoff hepatoma. Female Buffalo rats weighing enzymatic steps involved in the degradation of 150â€”250gm.were used to carry Morris hepatoma thymine and uracil in the rat have been elucidated 5123 (Sublines B and D, 25th generation). Male (6, 13, 14, 20, 31), and the initial reduction of A X C rats weighing 200â€”250gm. were used to uracil to dihydrouracil has been shown to be the inoculate Morris 3683 and Morris 3924-A hepa rate-limiting step in the over-all degradation of tomas. The Walker 256, Jensen, and Guerin tu uracil (6, 14). However, liver uracil reductase ac- mors were obtained originally from the Upjohn * The work was supported in part by a research grant Company, Kalamazoo, Michigan, and were main (C1719) from the National Cancer Institute, U.S. Public tained in this laboratory. The rats bearing the Health Service. four hepatomas and the normal Buffalo and A X C Received for publication July 7, 1962. strain rats were obtained through the courtesy of 1239

Dr. Harold P. Morris of the National Cancer In the C14O2formation from uracil 2-C14by a differ stitute. When these animals were received, they ence in C14countings before and after the enzymic were put on a semisynthetic diet for a period of reaction. This procedure is more convenient and from 1 to 4 weeks, depending on the growth rates possibly more accurate than the one with uracil of the tumors. When possible, the tumors were 6-C14and isolating labeled /3-alanine by chromatog- allowed to grow to a size corresponding to 20-^0 raphy for counting. The method actually employed per cent of total body weight before the animals in assaying uracil reductase activity in liver was were sacrificed. The animals bearing the other tu as follows: Because of the instability of this en mors were also kept on the same diet. The com zyme (19), its activity was always assayed within position of the diet was essentially the same as the a few hours after the animals were sacrificed. The one described previously (33) with the exception liver homogenate was prepared in a 0.08 M phos of replacing cod liver oil with vitamins A and D phate buffer of pH 7.4 to contain 200 mg liver/ml and of including vitamin Bi2. homogenate. To the side-arm of a 25-ml. Warburg Only in those experiments in which tissue and flask were introduced 2 /miÃ³lesof triphosphopyri- urinary constituents were determined were the dine nucleotide, 20 /umoles of glucose-6-phosphate control animals pair-fed to the animals bearing and 0.2 unit (21) of glucose-6-phosphate dehydro- Walker carcinoma 256. In all other instances, the genase dissolved in the phosphate buffer, each animals were fed the diet ad libitum. The pro being contained in 0.2 ml. To the main chamber cedure for urine collection and for estimation of of the flask were added 100 jumÃ³lesofnicotinamide, tumor weight in vivowas the same as that previous 5 AmÃ³lesof adenosine triphosphate, 50 /amÃ³lesof ly described (33). NaF, and 0.5 /umole of uracil-2-C14 containing 5 Analytical methods.â€”Urinary allantoin was de mjuc. of radioactivity, each being dissolved in 0.2 termined by the method of Young and Conway ml. also. One ml. of the homogenate was finally (34). Allantoin in the plasma was determined by added to the main chamber. The flask was incu the same method after the plasma was deprotein- bated at 37Â°C.and flushed with N2 for 10 min. At ized with 2.5 times its volume of 5 per cent ZnSO,i- the end of this period the sytem was closed, and 7H20 and of 0.3 N Ba(OH)2. When allantoin was the reduced-triphosphopyridine-nucleotide-gener- determined in the liver, a ZnSO.i-Ba(OH)2 protein- ating system in the side-arm was tipped in. The free filtrate of the liver homogenate was prepared. reaction was allowed to proceed for 10 min. and After hydrolysis of allantoin in the filtrate with was terminated with the addition of 0.2 ml. of 65 0.5 N NaOH, it was found necessary to treat the per cent TCA. A control flask was prepared in the alkaline hydrolysate with Norit to remove the same manner with the exception that TCA was pigment formed, which would otherwise interfere added before the homogenate. The radioactivity with the subsequent color development. Urinary in 0.1 ml. of the TCA filtrate was determined in uric acid was determined by the method of Dubbs an aluminum planchet with a Nuclear-Chicago et al. (11). Total nucleic acid as well as UNA1 and gas-flow counter. The difference between the con DNA was extracted and determined according to trol and the reaction samples was due to the loss the method of Schneider (27). Lyophilized liver of CI4O2,which was converted to jumÃ³lesofuracil and muscle, prepared as before (33), were used for reduced in the final expression. the determination of allantoin and nucleic acids. Materials.â€”All the chemicals used in this study Xanthine oxidase was assayed according to the were commercial preparations. method of Litwack et al. (23). Samples taken at 60- and 90-min. incubation times were analyzed, RESULTS and the results were averaged. When it was not The daily urinary excretion of both allantoin possible to run the assay on the same day, the and uric acid was determined in the rats bearing liver was frozen immediately at â€”30Â°C.No ap Walker carcinoma 256 and in the pair-fed controls preciable loss of the enzyme activity was ob during the entire period of tumor growth. The re served in 2 weeks at this temperature. Uracil reduc sults are presented in Charts 1 and 2. The division Ãasewas assayed by a combination of the methods of tumor-bearing rats into groups with increasing of Fritzson (15) and of Canellakis (6). The first sizes of tumor is arbitrary and merely serves to method permits the use of liver homogenate rather correlate tumor growth with biochemical altera than the soluble fraction prepared therefrom. This tions. It is evident from the data that there was is a great advantage. The second method measures an increase in the excretion of both allantoin and 1The abbreviations used are the following: RNA, ribonu- uric acid in the tumor-bearing rats and that the cleic acid; DNA, deoxyribonucleic acid; TCA, trichloroacetic increase was progressive with tumor growth. Fur acid. thermore, the control animals, which had various

degrees of restriction on food intake, excreted very increase also depended on the stages of tumor constant amounts of the two compounds through growth as it did in the urine. out the entire experimental period, indicating that, The increase in liver nucleic acid of tumor- under the conditions of pair-feeding, dietary re bearing animals observed in this study is consistent striction had not been severe enough to cause a with the results of Cerecedo et al. (8), who showed derangement in the over-all degradation of the pu- an increase in both liver RNA and DNA of rats rines. bearing Walker carcinoma 256. In addition, it is The increased urinary excretion of allantoin by shown in Table 1 also that there was an increase the tumor-bearing rats appeared to be a result of in both muscle RNA and DNA of these tumor- the increase in plasma allantoin concentration bearing animals. The summation of the values for (Chart 3) which was paralleled by a similar in RNA and DNA agrees well with the value for crease in the liver (Table 1). In the plasma the total nucleic acid determined separately. Further-

500-400-.EÃŽ2 ^Ã¯r31-40 -Â£LUCONTROL TUMOR-BEARINGJ40.1-

,_300-o Ã»_<ÃŽ u> >, -5200-o Â£â€¢=s5 loo-

o-0 1.0iI-4Ã¬iiI.I-IO 11-20 2I-: 41-50

( TumorWeightv TotalBody 100 Weigh10r Â«Ã¯â€” CHART1.â€”Urinary excretion of allantoin by the control and tumor-bearing rats at various stages of tumor growth. Height of bar indicates the mean value for each group. The vertical line through each bar indicates the range of values, and the numerical figure represents the number of animals used. The rats of each control group were restricted to the same food intake as the corre sponding tumor-bearing rats.

CONTROL

70-â€¢0 OCMmmu144Ji10.1-1.0] ' i umvn

1"60-

Q_5 -ii0 Â«40-Â£* Â«o e 3Â°- â€¢ÃŠÂ§r. g 20-10-

0-â€¢ I.I-IO II-20 41-50X31-40

TumorWeightIO12I-?Total Body Weight7 100 CHART2.â€”Urinary excretion of uric acid by the control and tumor-bearing rats at various stages of tumor growth. For explanation of bar graph construction see Chart 1.

more, despite the increase in the RNA and DNA of Walker 256, Jensen, and Guerin tumors on the content, the ratio of RNA/DNA in the muscle of xanthine oxidase and uracil reductase activities of tumor-bearing animals was decreased. It may be the host liver. There was an increase in xanthine pointed out that the values are expressed on a dry oxidase activity in rats bearing Walker carcinoma weight basis. Although animals bearing different 256. A similar increase was also observed in rats sizes of tumor (tumor weight from less than 10 per bearing Guerin epithelioma. On the other hand, cent to more than 40 per cent of total body weight) there was no change in the activity of this enzyme were used, no clear-cut difference in either liver or in the liver of rats bearing Jensen sarcoma. The muscle nucleic acid was observed among them, and difference in the effect of the three tumors cannot the results were averaged as a single group. be explained except to point out that Jensen is the The results on urinary and tissue allantoin sug fastest growing tumor of the three. It is of interest gest that there might be an increase in xanthine that uracil reductase was not altered significantly oxidase activity in the animals bearing Walker car in the rats bearing Walker 256, indicating a lack cinoma 256, since uricase is not rate-limiting in of parallelism in the effect of the tumor on the en the catabolism of xanthine to allantoin (3) and no zymes catabolizing xanthine and uracil. change in uricase activity was observed in rats Recently, Morris 5123 hepatoma has created bearing this tumor (22). Table 2 shows the effect considerable interest because of its resemblance to

LJ CONTROL

14- LU TUMOR-BEARING

12-10-8-6-4-

lÃ

2-0"EÃ±j|JI-IO

II-20j1"IiÃ±21-30 31-40 41-50

Tumor Weight 1Total Body Weight' X IOÂ°

CHART8.â€”Plasmaallantoin of the control and tumor-bearing rats with various sizes of tumor. For explanation of bar graph construction see Chart 1.

TABLE 1 LIVER AND MUSCLENUCLEICACIDS AND LIVER ALLANTOINOF RATS BEARINGWALKERCARCINOMA256 Allantoin is expressed as /imoles/gm dry liver. Total nucleic acid, RNA, and DNA are expressed as fig/mg dry tissue.

GBODPControl

nucleicacid40.7 nucleicacid7.71+0.82 + DNA7.57 DNA2.72 + 0.07t (16)t + 4.4 (12) (9) + 0.78 (18) + 0.24 (18) Tumor-bearingÂ§LIVERAllantoinO.S70.66Â±0.15 (16)Total52.5Â±4.2 (12)MUSCLE*Total8.68 + 1.11 (9)RNA5.545.96 + 0.88 (l8)DNA2.032.52 + 0.45 (l8)RNA8.48RNA/2.36

* At the 5 per cent level the difference in the mean values for each constituent between the control and the tumor-bearing groups is significant by the "t" test using paired observations. t The value after the Â±sign shows the standard deviation from the mean. ÃŽThenumber in the parentheses indicates the number of animals used. Â§Thetumors ranged in size from 7 to 44 per cent of total body weight.

normal liver in several enzyme patterns (12, 25, change in either xanthine oxidase activity or uracil 26, 32). A comparison of this and other hepatomas reductase activity in the host liver. When a change concerning their effect on the catabolizing enzymes was brought about, an increase in xanthine oxidase studied is made in Table 3. The values for the or a decrease in uracil reductase activity could be Sprague-Dawley controls are the same as shown demonstrated. Concurrent changes in these two in Table 2 and are transposed here for convenience enzyme activities did not occur in the liver of of comparison. It is of interest that the control tumor-bearing animals. In general, it may be values for different strains of rats were relatively stated that the effect of different tumors on the different. The A X C strain had higher xanthine host system need not be uniform qualitatively. oxidase activity and uracil reductase activity than Such uniformity has been conceived, however, in that of either the Buffalo or the Sprague-Dawley strain, which also happened to have the lowest TABLE 2 uracil reductase activity. Since the activity in both XANTHINEOXIDASEANDURACILREDUCTASEACTIVITY sexes of each strain was not determined it is not IN THELIVEROFNORMALANDTUMOR- known whether the activity was dependent on the BEARINGRATS sex too. Fritzson (15) reported an average value of 0.75 /Â¿moleuracil reduced per gm. liver per 10 GroupControl oxidase*8.9Â±1.3ÃŽ t0.81+0.17reductase min. from six female rats of an unspecified strain. (7)Â§ (8) Although it is not possible to make a direct com Walker-bearing^ 13.7 + 1.5 (9) 0.74 + 0.15 (8) parison of his value with any control value ob Jensen -bearing 11 9.6 + 2.5 (10) tained in this study, they appear to be in general Guerin-bearing**Xanthine15.5 + 2.1 (9)Uracil agreement. It can be seen that xanthine oxidase activity of the host liver was increased in rats * Expressed as AmÃ³lesxanthine oxidized/gin liver/hour. bearing Novikoff hepatoma and Morris 3683 hepa- f Expressed as /nmolesuracil reduced/gm liver/10 minutes. toma when compared with that of their respective ÃŽThevalue after the + sign shows the standard deviation from the mean. controls. No increase was observed in the liver of Â§Thenumber in the parentheses indicates the number of rats bearing Morris 5123 and Morris 3924-A hepa animals used. tomas. On the contrary, the uracil reductase ac # The tumors ranged in size from 25 to 40 per cent of total tivity showed a decrease in the liver of rats bearing body weight. Morris 5123 and Morris 3924-A hepatomas and no || The tumors ranged in size from 20 to 44 per cent of total body weight. change in the others. From these results it is ob ** The tumors ranged in size from 18 to 32 per cent of total vious that tumor growth need not bring about a body weight.

TABLE 3 XANTHINEOXIDASEANDURACILREDUCTASEACTIVITYINTHELIVEROFNORMAL ANDHEPATOMA-BEARINGRATSANDIN THEHEPATOMAS

ACTIVITY*Liver8.9Â±1.3ÃŽ(7)Â§OXIDASE REDUCTASE ACTrvinrfLiver0.81+0.17 RATSSprague-Dawley,STRAINop

cfBuffalo, (8) Novikoff-bearing#Control 12.9Â±1.6(6)8.7 (5)7.4 0.91+0.08(6)1.16

9AXC, + 1.1 (4) + 0.05 (4) Morris5123-bearing]|Control 8.2Â±3.0(8)13.9 +2.0(5)0.6 0.70Â±0.23(7)1.31+0.10

d"GROUPControl + 1.0 (6) (6) Morris 3683-bearing** 16.0 + 1.3 (8) + 0.3 (6) 1.17 + 0.18 (8) Morris 3924A-bearingftXANTHINE13.3 + 1.9 (6)Tumor0.7Â±0.60.510.3 (5)URACIL1.00Â±0.14 (6)

* Expressed as jumÃ³lesxanthine oxidized/gm tissue/hour. t Expressed as AmÃ³lesuracilreduced/gm liver/10 minutes. | The value after the Â±sign shows the standard deviation from the mean. Â§Thenumber in the parentheses indicates the number of animals used. # The tumors ranged in size from 5 to 22 per cent of total body weight. || The tumors ranged in size from 3 to 11 per cent of total body weight. ** The tumors ranged in size from 5 to 18 per cent of total body weight, ft The tumors ranged in size from 13 to 20 per cent of total body weight.

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1962 American Association for Cancer Research. 1244 Cancer Research Vol. 22, November 1962 tumor-bearing rats with respect to liver catalase contribute to the end product of purine catabo- activity (17). lism. Second, an increased rate of turnover of nu When the xanthine oxidase activity in the four cleic acids in the tumor-bearing animals as re hepatomas was examined, only Morris 5123 hepa- ported by many workers (1, 10, 24) can also result toma showed an activity approaching that of a in an increased formation of the end product. normal liver (Table 3). In the other three hepa The situation in the liver could be quite different tomas, the activity was barely measurable. Ac from that in the muscle, for the liver mass was tually in some of these determinations the activity increased slightly during tumor growth. Burton was nearly zero. Uracil reducÃaseactivity has been and Begg (5) showed that the liver xanthine oxi reported to be present in Morris 5123 hepatoma dase activity in tumor-bearing rats was the same and undetectable in Novikoff hepatoma (25). as that in the control animals on a high protein diet. In the present study the animals were fed a DISCUSSION 25 per cent casein diet ad libitum. Although the The increase in the urinary excretion of allan- control value agrees well with that determined by toin by rats bearing Walker carcinoma 256 ob these authors (5), the activity found in the host served here has been observed also by Burton and liver was not merely maintained at the normal Begg (5), although they did not correlate the in level but was actually increased above the normal crease to tumor size. The increase they reported level. At leasl this is true in rats bearing Walker was more than twice the highest recorded in this 256, Guerin, Novikoff, and Morris 3683 tumors. study on a comparable 25 per cent protein diet. The increase in xanthine oxidase activity cannot Young and Dinning (35) showed that vitamin E- readily explain the high urinary excretion of al deficient rabbits had a much greater urinary ex lantoin and uric acid, for an extremely small ac cretion of allantoin than did their controls. It is tivity in vivo was sufficient to maintain normal conceivable that there are similarities in these two urinary excretion (4). The mechanism of the in clinical conditionsâ€”malignancy and vitamin E de crease in the enzyme activity in the host liver ficiencyâ€”insofar as the loss of muscle mass and is made more obscure by the fact that in rats the degradation of purines are concerned. For, in bearing certain types of tumor, such an increase addition to the similarity in increased allantoin in the liver was not observed. Of interest is the excretion, there was an increase in both RNA and finding that only Morris 5123 hepatoma pos DNA content and a decrease in the ratio of RNA/ sessed xanthine oxidase activity comparable to DNA in the muscle tissue in vitamin E deficiency that found in liver, whereas the other three hepa (35) as in tumor growth observed here. Perhaps tomas tested had no significant activity. This in both the increase in the content and the decrease formation is consistent with the evidence hitherto in the ratio should be considered as results of an accumulated (25, 26, 32), which indicates that extensive and continuous muscle loss. It is reason Morris 5123 hepatoma is more like normal liver able to assume that, during the loss of muscle mass, tissue than is any other hepatoma. the nucleic acids were degraded at a much slower The enzyme reducing uracil has been referred to rate than were other constituents of muscle, there as dihydrouracil dehydrogenase in the literature by resulting in an increase in the nucleic acid con (15, 19). The name "uracil reduÃ©lase"appears to tent. At the same time the muscle tissue should be preferable, because it is short and, more im lose its cytoplasmic RNA faster than its nuclear portantly, it indicates correctly the direction of DNA to account for a decrease in the RNA/DNA the enzymatic reaction studied. The reverse reac ratio. Zigman and Allison (36) have reported an tion to which the name "dihydrouracil dehydro increase in ribonuclease activity in tissues of tu genase" can be aptly applied occurs to only an mor-bearing rats. The increase in the allantoin ex insignificant extent (15). A similar preference of cretion by the rats with the most advanced tumor "thymine reducÃase" to "dihydrothymine dehy was about 300 //moles/day. This amount can be drogenase" for the enzyme reducing thymine has formed from the degradation of about 190 mg. of been given (26). nucleic acids. If it is further assumed that the nu That there is an inverse relationship between cleic acids were made available from the loss of the capacity of a tissue to degrade uracil and its muscle mass alone, it can be shown from the data capacity to incorporate uracil into RNA has been in Table 1 that 23.8 gm. of dry muscle should have proposed by Canellakis (7) and supported by oth been lost each day. Obviously, this is not possible. ers (16, 28, 29). The liver of a tumor-bearing rat Hence, the increased amount of allantoin appear appears to be under the influence of two opposite ing in the urine must have its origin elsewhere. effectsâ€”that of the host system which is predomi Two possibilities may be considered : First, the tu nantly catabolic and that of the tumor itself which mor tissue, by virtue of its necrotic process, must is primarily anabolic. It has been demonstrated

that there were an increased mitotic rate (2) and 17. GREENSTEIN,J. P. Biochemistry of Cancer, p. 524. 2nd an increased incorporation of nucleic acid pre ed. New York: Academic Press, 1954. 18. GHEENSTEIN,J.P.; JEUKETTE,W. V.; and WHITE,J. The cursors into nucleic acids (1, 9, 10, 24, 30) in livers Relative Activity of Xanthine Dehydrogenase, Catalase, of tumor-bearing rats. These results indicate that and Amylase in Normal and Cancerous Hepatic Tissues the host liver was responding metabolically in an of the Rat. J. Nati. Cancer Inst., 2:17-22, 1941-42. anabolic fashion despite the general catabolic ef 19. GRISOLIA,S., and CARDOSO,S. S. The Purification and Properties of Hydropyrimidine Dehydrogenase. Biochim. fect noted in other tissues. In line with this think Biophys. Acta, 26:430-31, 1957. ing is the demonstration that the uracil reducÃase 20. GRISOLIA,S.,and WALLACH,D.P. Enzymic Interconver activity of the host liver was either lower than or sion of Hydrouracil and /3-Ureidopropionic Acid. Biochim. the same as that found in the normal liver. A high Biophys. Acta, 18:449, 1955. er activity in the host liver has not been observed. 21. KORNBERG,A. Enzymatic Synthesis of Triphosphopyri- dine Nucleotide. J. Biol. Chem., 182:805-13, 1950. REFERENCES 22. LAN,T. H. A Study of D-AminoAcid Oxidase, Uricase, and 1. ANDERSON,E.P.; YEN, C. Y.; MANDEL,H. G.; and SMITH, Choline Oxidase in the Livers and Isolated Cell Nuclei P. K. Ureidosuccinic Acid as a Precursor of Nucleic Acid of Rats Bearing Transplanted Tumors. Cancer Res., 4:37- Pyrimidines in Normal and Tumor-Bearing Mice. J. Biol. 41, 1944. Chem., 213:625-33, 1955. 23. LITWACK,G.; BOTHWELL,J. W.; WILLIAMS,J. N., JR.; 2. ANNAU,E.; MANGINELLI,A.; and ROTH, A. Increased and ELVEHJEM,C. A. A Colorimetrie Assay for Xanthine Weight and Mitotic Activity in the Liver of Tumor-bearing Oxidase in Rat Liver Homogenates. J. Biol. Chem., 200: Rats and Mice. Cancer Res., 11:304-6, 1951. 303-10, 1953. 3. AXELHOD,A. E., and ELVEHJEM,C. A. The Xanthine 24. PAYNE,A. H.; KELLY,L. S.; BEACH,G.; and JONES,H. B. Oxidase Content of Rat Liver in Riboflavin Deficiency. The Effect of Neoplasia on the Turnover of Nucleic Acids J. Biol. Chem., 140:725-38, 1941. Studied with Formate-C" and Glycine-2-C14.Cancer Res., 4. BASS,A. D.; TEPPERMAN,J.; RICHERT,D. A.; and WEST- 12:426-28, 1952. ERFELD,W. W. Excretion of Uric Acid and Allantoin by 25. PITOT,H. C.; POTTER,V.R.; and MORRIS,H. P. Metabolic Rats Depleted of Liver Xanthine Oxidase. Proc. Soc. Exp. Adaptations in Rat Hepatomas. I. The Effect of Dietary Biol. Med., 73:687-89, 1950. Protein on Some Inducible Enzymes in Liver and Hepa- 5. BURTON,A. F., and BECO, R. W. The Relation of Diet, toma 5123. Cancer Res., 21:1001-8, 1961. Hormones, and Tumors to the Activity of Liver Xanthine Oxidase in the Rat. Can. J. Biochem. Physiol., 36:881-87, 26. POTTER,V. R.; PITOT,H. C.; ONO,T.; and MORRIS,H.P. The Comparative Enzymology and Cell Origin of Rat 1957. Hepatomas. I. Deoxycytidylic Acid Deaminase and Thy 6. CANELLAKIS,E.S. Pyrimidine Metabolism. I. Enzymatic mine Degradation. Cancer Res., 20:1255-61, 1960. Pathways of Uracil and Thymine Degradation. J. Biol. Chem., 221:315-22, 1956. 27. SCHNEIDER,W.C. Phosphorus Compounds in Animal Tis sues. I. Extraction and Estimation of Desoxypentose Nu 7. . Pyrimidine Metabolism. III. The Interaction of cleic Acid and of Pentose Nucleic Acid. J. Biol. Chem., the Catabolic and Anabolic Pathways of Uracil Metabo 161:293-303, 1945. lism. Ibid., 227:701-9, 1957. 8. CERECEDO,L. R.; MCCARTHY,P. T.; SINGER,E. J.; and 28. SKÃ–LD,O.Enzymes of Uracil Metabolism in Tissues with McGuiNNESs, E. T. Nucleic Acid and Amino Acid Pat Different Growth Characteristics. Biochim. Biophys. Acta, terns in Tumor-Bearing Rats. Exp. Med. Surg., 13:85-91, 44:1-12, 1960. 1955. 29. STEVENS,L., and STOCKEN,L. A. Thymine and Uracil 9. CERECEDO,L. R.; SISTERSMITH,M. J.; and VICENTE,J. Catabolism in Faetal and Young Rat Liver. Biochem. Tumor-Host Relationships Studied in Vitro: Experiments Biophys. Research Comm., 3:155-56, 1960. with Cell Free Systems. Arch. Biochem. Biophys., 92: 30. TYNER, E. P.; HEIDELBERGER,C.; and LEPAGE, G. A. 484-86,1961. Intracellular Distribution of Radioactivity in Nucleic Acid 10. CONZELMAN,G. M., JR.; MANDEL,H. G.; and SMITH, Nucleotides and Proteins Following Simultaneous Adminis P. K. The Effect of Tumor Growth and X-Radiation on the tration of P32and Glycine-2-C14.Cancer Res., 13:186-203, Incorporation of Radiocarbon from 4-Amino-5-imidazole 1953. carboxamide-C14 into Nucleic Acids. Cancer Res., 14:100- 31. WALLACH,D. P., and GRISOLIA,S. The Purification and 102, 1954. Properties of Hydropyrimidine Hydrase. J. Biol. Chem., 11. DUBBS,C. A.; DAVIS,F. W.; and ADAMS,W. S. Simple 226:277-88, 1957. Microdetermination of Uric Acid. J. Biol. Chem., 218: 32. WEBER,G.; BANERJEE,G.; and MORRIS,H. P. Compara 497-504,1955. tive Biochemistry of Hepatomas. I. Carbohydrate En 12. DYER, H. M.; CULLINO,P. M.; ENSFIELD,B. J.; and zymes in Morris Hepatoma 5123. Cancer Res., 21:933-37, MOIIKIS,H. P. Transaminase Activities of Liver Tumors 1961. and Serum. Cancer Res., 21:1522-31, 1961. 33. Wu, C., and BAUER,J. M. A Study of Free Amino Acids 13. FINK, R. M.; FINK, K.; and HENDERSON,R.B. /3-Amino and of Glutamine Synthesis in Tumor-Bearing Rats. Can Acid Formation by Tissue Slices Incubated with Pyrimi cer Res., 20:848-57, 1960. dines. J. Biol. Chem., 201:349-55, 1953. 34. YOUNG,E. G., and CONWAY,C.F. On the Estimation of 14. FRITZSON,P.The Catabolism of C14-LabeledUracil, Dihy- Allantoin by the Rimini-Schryver Reaction. J. Biol. Chem., drouracil, and |8-Ureidopropionic Acid in Rat Liver Slices. 142:839-53, 1942. J. Biol. Chem., 226:223-28, 1957. 35. YOUNG,J. M., and DINNING,J. S. A Relationship of Vita 15. . Properties and Assay of Dihydrouracil Dehydro- min E to Nucleic Acid Metabolism. J. Biol. Chem., 193: genase of Rat Liver. Ibid., 236:719-25, 1960. 743^7, 1951. 16. . The Relation between Uracil-Catabolizing En 36. ZIGMAN,S., and ALLISON,J. B. Ribonuclease Activity of zymes and Rate of Rat Liver Regeneration. Ibid., 237: Protein-depleted and Tumor-bearing Rats. Cancer Res., 150-56, 1962. 19:1105-8, 1959.

Chung Wu and Jere M. Bauer

Cancer Res 1962;22:1239-1245.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/22/10/1239

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/22/10/1239. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.