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

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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 xan- thine 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.—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 150—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 200—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 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1962 American Association for Cancer Research. 1240 Cancer Research Vol. 22, November 1962 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 /miólesof 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 jumólesofnicotinamide, tumor weight in vivowas the same as that previous 5 Amólesof adenosine triphosphate, 50 /amólesof ly described (33). NaF, and 0.5 /umole of uracil-2-C14 containing 5 Analytical methods.—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 37°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 jumólesofuracil and muscle, prepared as before (33), were used for reduced in the final expression. the determination of allantoin and nucleic acids. Materials.—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 —30°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 íasewas 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.
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