Corticosteroids and Transaminase Activity III. a Relationship Between Changes in Alanine Transaminase Activity and the Growth of Walker Carcinosarcoma 2 5 6*

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Corticosteroids and Transaminase Activity III. A Relationship between Changes in Alanine Transaminase Activity and the Growth of Walker Carcinosarcoma 2 5 6*

FRED ROSEN, LouIs E. BUDNICK, DOLORES K. SOLOMON, AND CHARLES A. NICHOL

(Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, N.Y.)

SUMMARY The effects of treatment with cortisol on the growth and alanine-a-ketoglutarate transaminase 1activity of Walker carcinosarcoma 256 were studied. Similarly, the effects of other conditions known to enhance gluconeogenic activity, such as diabetes, fasting, and high protein intake, were investigated. Each of these conditions was previously shown to be associated with elevated activity of alanine transaminase in liver. The administration of cortisol after the subcutaneous implantation of the Walker tumor resulted in marked retardation in the growth of the tumors and in four- to fourteen-fold increases in their alanine-a-ketoglutarate transaminase activity depend- ing on the dose administered. In rats fed diets containing 75 and 95 per cent protein, tumor growth was inhibited by as much as 75 per cent, and alanine transaminase activity was stimulated threefold. The marked growth inhibition of this tumor in alloxan- diabetic or fasted rats was not accompanied by any notable increase in the activity of this transaminase enzyme in the tumor, whereas significant elevation of the enzyme did occur in the liver of these animals. In each instance in which alanine transaminase activity in the Walker tumor was increased by the injection of corticosteroids or by other treatments, marked inhibition of tumor growth was observed.

The marked increase in alanine-a-ketoglutarate thyroxine, did not significantly affect the activity transaminase 1 activity which occurs in the liver of of hepatic alanine transaminase (16), whereas the rats treated with cortisone or cortisol (1, 4, 15) can administration of deoxycorticosterone acetate also be induced by treatment with other cor- (DOCA) decreased the activity of this enzyme in ticosteroids (16). The response of this transami- liver to one-half the normal value (17). nase has some specificity, as is indicated by the The response of alanine transaminase to cor- lack, in the same tissue, of a corresponding in- tieosteroids has been examined in other tissues crease in the activity of aspartate-a-ketoglutarate which are sensitive to this class of hormones, par- transaminase which mediates a similar transfer of ticularly the thymus gland and cortisol-responsive amino nitrogen to the same aeceptor compound tumors. Following treatment of rats with 5 rag. of (15). Several corticosteroids lacking gluconeogenic cortisol daily for 7 days, the activity of alanine activity, as well as insulin, growth hormone, and transaminase was increased fourteen-fold in thymus tissue and eightfold in Walker carcinosar- * This investigation was supported in part by a research grant (A-~684) from the National Institute of Arthritis and coma 256 (14). In contrast, the administration of Metabolic Diseases of the United States Public Health Service. DOCA lowered the activity of alanine transami- 1 Alanine-a-ketoglutarate transaminase was previously re- nase in the Walker tumor, and, at the same time, ferred to as glutamie-pyruvie transaminase. The advantage of the growth of this tumor was slightly increased. nomenclature designating first the amino acid reacting with the appropriate keto acid is apparent by comparing the names for In this study, the activity of alanine trans- the same enzyme, such as tyrosine transaminase versus glu- aminase was also examined in the Walker tumor tamic-p-hydroxyphenyipyruvic transaminase. in rats which were fasted, made diabetic by al- Received for publication November 1, 1960. loxan, or fed high protein diets, since under these 620

conditions the activity of this enzyme in liver is The data indicate clearly that cortisol was most elevated to an extent comparable to that following effective in suppressing tumor growth when given the administration of cortisol (17). subcutaneously (Table 1). Maximum increases in the alanine transaminase activity of liver and tu- MATERIALS AND METHODS mor were also associated with this mode of admin- Male albino rats of the Holtzman strain, weigh- istration. The inhibition of tumor growth ob- ing from 75 to 150 gm., were used in these studies. served in animals given cortisol orally or intraperi- Purina chow diet and water were supplied ad libi- toneally was not associated with a change in tu- turn. The standard ration contained 18 per cent mor alanine transaminase activity, although the casein, 73 per cent sucrose, 4 per cent each of salt level of this enzyme in liver was significantly in- mixture and corn oil, 0.5 per cent cod liver oil, 0.2 creased. Slow absorption of cortisol from a sub- per cent choline chloride, and the following cutaneous depot appears to be necessary for maxi- amounts of vitamins per 100 gin. of diet: thiamine mal tumor inhibition and for greatest increase in hydrochloride, riboflavin, and pyridoxine hydro- liver and tumor alanine transaminase activity. chloride, 1 rag. of each; niacin, 4 mg.; calcium pantothenate, 6 mg.; inositol, 15 mg.; p-amino- TABLE 1 benzoic acid and a-tocopherol, 20 rag. of each; EFFECT OF DIFFERENT ROUTES OF ADMINISTRATION OF biotin and folic acid, 20 gg. of each. In studies of CORTISOL ON THE GROWTH OF WALKER CARCINO- the effect of dietary protein on tumor growth and SARCOMA 256 AND ALANINE TRANSAMINASE ACTIVITY alanine transaminase activity, variations in the IN LIVER AND TUMOR protein content of a purified diet were made at the expense of the sucrose. In the diet containing 95 ALANINE TRANSAML~ASE per cent casein, the corn oil was omitted. TUMOR ACTIVITY t Commercial preparations of hydrocortisone COHTISOL* WEIGHT (GM.) acetate (cortisol) and deoxycorticosterone acetate Liver Tumor were used. Alloxan was dissolved in distilled water, and the solution was injected within 30 rain- None 6.9 _+1.5~ 11.3___1.7 0.36_+0.09 Subcutaneously 0.60_+0.12 57.2___8.7 2.7 _+0.50 utes after its preparation. Intraperitoneally 3.7 _+1.4 86.0___8.5 0.38_+0.14 The Walker carcinosarcoma 256 which is main- Orally 3.4 -+1.2 22.0-+1.67 0.28_+0.14 tained in our laboratory was obtained through the courtesy of Dr. K. Sugiura of the Sloan-Kettering * Each animal received 2.5 mg. of cortisol daily for 14 days Institute. The tumors used for transplantation starting on the day following transplantation. There were six were 12-14 days old. Individual pieces (about 1.5 rats in each group. t mMoles of substrate utilized per gin. of protein in 1 hour eu. ram.) of the tumor, prepared under aseptic at 38 ~ C. conditions, were implanted subcutaneously by ~: Average values _+ standard deviation. trocar into the right flank of the recipient animals. The methods used for sacrificing animals and The effect of treatment with different amounts preparing tissue homogenates were described pre- of cortisol on the growth and alanine transaminase viously (17). Protein was measured by means of activity of the Walker tumor isshown in Table 2. the Folin phenol reagent, with a modification of Tumor growth was inhibited by 90 per cent, and the method described by Lowry et al. (12). Blood transaminase activity increased fourteen-fold in glucose was determined by the colorimetric proce- animals given injections daily for 14 days of 30 or dure of Nelson (13). Alanine transaminase activity 50 mg. of cortisol/kg body weight. In comparison was measured by a procedure of Lowry el al. 2 with an untreated control group, hepatic alanine which is similar in principle to that described by transaminase activity was increased six-, eleven- Wroblewski and LaDue (22); however, instead of and thirteen-fold, respectively, in the tumor-bear- measuring the oxidation of DPNH spectrophoto- ing rats that were treated with 10, 30, and 50 metrically, the DPN formed is measured fluoro- mg/kg of cortisol daily for 14 days. metrically (11). Significant inhibition in the growth of Walker tumor has been observed in animals deprived of RESULTS food or on a restricted dietary intake (21) and in The transaminase response and tumor growth rats treated with amounts of cortisone that caused were studied initially in animals treated with cor- loss of body weight (19). Since the growth of the tisol by three different routes of administration. cortisol-treated rats was depressed in this experi- 20. H. Lowry, N. R. Roberts, and A. A. Atchison, to be ment, tumor growth and transaminase activity published. were also studied in pair-fed animals comparable

in weight to the rats which received 10, 30, and 50 mor was increased consistently (Table 2). Al- rag. of eortisol/kg body weight. In these animals, though the relative significance of increased tumor tumor growth was impaired by 42, 68, and 65 per growth is influenced by the variability in the cent, respectively, whereas the alanine transami- growth of individual tumors, this same effect of nase activity of the tumors was not appreciably DOCA has been observed in several other experi- affected by the food restriction. Thus, the effect of ments. cortisol is different from other effects on the tumor The effect of feeding diets containing different due to reduced dietary intake and loss of body levels of protein to rats bearing the Walker tumor weight. is shown in Table 3. The animals were fed the puri- Cortisol and other corticosteroids with marked fied diets for 1 week prior to implantation of the activity measured by the liver glycogen or anti- tumor and continued on the diets during the 15- inflammatory assays produce significant increases day period of tumor growth. In comparison to rats in the alanine transaminase activity of liver. In fed the 18 per cent casein diet, the growth of the contrast, treatment with DOCA actually decreases tumors in the animals maintained on the 50, 75, the activity of this enzyme in liver. When tumor- and 95 per cent protein diets was reduced sig- bearing animals were treated with 30 rag. of nificantly. In this and two similar experiments, the DOCA per kg. for $ weeks, the transaminase ac- ration containing 75 per cent protein produced tivity in this tumor was reduced by 50 per cent, maximum inhibition of tumor growth. Associated and, concomitantly, the rate of growth of the tu- with reduced tumor growth, there were significant

TABLE 2

EFFECT OF CORTICOSTEROIDS ON THE ALANINE TRANSAMINASE ACTIVITY AND GROWTH OF WALKER CARCINOSARCOMA 256

TREATMI~NT* TUMOR GROWTHt ALANI2~E TRANSAMINASEACTIVITY

Per cent mMoles substrate utilized/ Treated/ Compound (mg/kg/day) Grams control gm protein/hr at 38~ C. control

None ...... 4.~ +l.sJ; 0.32+ .06 Cortisol 10 1.5 + .45 36 1.4 4-1.0 4.4 30 0.35+ .07 8 4.7 _+1.6 14.8 g 50 0.414- .07 10 4.6 4-1.2 14.4 DOCA 30 6.2 _+1.7 (P>0.05) 148 0.154- .06 0.47

None 2.6 4-1.3 0.374-0.05 DOCA 80 7.6 4-4.6 (P>0.05) 293 0.124-0.04 0.32

* Compounds were injected S.C. for 14 days; treatment began 24 hours after the tumor was transplanted. t The animals were sacrificed and the tumors weighed 15 days after transplantation. :~ Average values + standard deviation. There were five rats in each group.

TABLE 3 EFFECT OF HIGH LEVELS OF DIETARY PROTEIN ON ALANINE TRANSAI~INASE ACTMTY AND GROWTH OF WALKER CARCINOSARCOMA ~6

TuuoR GaOW~ AI~NINE TRANSAMINA8~ ACTIVITY PROTEIN CHANGE (CASmN) IN BODY IN DIET* WEIGHT t Per cent mMoles substrate utilized/ Treated/ (PER CENT) Grams (oM.) control gm protein/hr at 38 ~ C. control

18 57 3.1 +1.1w 0.29+ .13w 50 83 1.5 4- .96 (P

* Animals were started on the diets 1 week before the tumor was unplanted. t Total weight gain during the 15-day period of tumor growth. :~ Tumors were removed and weighed 15 days after transplantation. wAverage values + standard deviation. There were four to six animals in each group.

increases in the alanine transaminase activity in or food withheld on day 15 following implantation the tumors of the animals fed the high protein of the tumor. In both conditions, tumor inhibition diets. In the groups receiving the highest levels of was not as great as when these treatments were protein (75 and 95 per cent), a moderate depres- begun on day 8. Furthermore, the transaminase sion in the rate of growth was noted. In the group activity was not increased in the tumors. Thus, the receiving the 50 per cent casein diet, an optimal several-fold increase in alanine transaminase ac- rate of body growth was maintained. tivity observed in the animals fed high protein Since liver alanine transaminase activity is in- diets or in rats treated with cortisol did not occur creased by cortisol administration, as well as by in the diabetic or fasted rats, even though marked other conditions which initiate an enhanced rate of inhibition of tumor growth was observed in each gluconeogenesis (17), it was of interest to study the case. activity of this transaminase in the Walker tumor The effects of cortisol administration on the growing in diabetic or fasted rats (Table 4). A1- growth and alanine transaminase activity of estab- loxan diabetes has been reported to cause a reduc- lished Walker tumors was compared with the re-

TABLE 4 ALANINE TRANSAMINASE ACTIVITY AND GROWTH OF WALKER CARCINOSARCOMA ~56 IN DIABETIC OR FASTED RATS

ALANINE TRANSAMINASE ACTIVITY TUMOR GROWTH (MMoLES SUBSTRATE UTILIZED/GM PROTEIN/HR AT 38 ~ C.) No. CONDITION ,, ANIMALS Per cent Grams Liver Tumor control , Experiment 1" Control 2.0 8.9+1.75 0.33_+ 08~; Diabetic 0.09 4.5 38.6-+9.0 0.63_+ .08 Fasted 0.16 8.0 39.1+6.5 0.80+_ .39 Experiment 2t Control 27.2 5.9_+1.2 0.23+ .05 Diabetic 8.8 32 29.4_+8.1 0.31• .24 Fasted 7.6 28 15.7• 0.23_+ .19

* Alloxan (200 mg/kg body weight) was injected I.P., and food was withheldbeginnin~on the 8th day following transplantation. The fasted animals were sacrificed on day 13. t Alloxan (200 mg/kg body weight) was injected I.P. and food withheld on the 15th day following transplantation. The fasted animals were sacrificed on day 20, or after food was withheld for 5 days. ~/Average values + standard deviation. tion in growth of Walker careinosarcoma 256 and sults obtained when treatment was started on the Novikoff hepatoma (5), in the growth of a di- day after implantation. The results are summar- methylaminoazobenzene-induced hepatoma (18) ized in Table 5. The rats used ranged in weight in the rat, and to decrease the number of Ehrlich from 75 to 100 gm. In all groups treatment with ascites cells in C57/6BL mice (20). In our experi- the two levels of cortisol inhibited tumor growth ments, data were included only from animals with significantly. The extent of tumor inhibition, how- at least S00 rag. of sugar per 100 ml. of blood and ever, was related to the day on which injection 4-plus sugar in their urine. In experiment 1, al- with cortisol was started. Tumor growth was sup- loxan was injected on day 8, and the tumor was pressed maximally when cortisol was given on days removed and weighed on day 15. In the animals 1 to 14; minimum inhibition occurred when treat- that were fasted, food was withheld beginning on ment began on day 14. Although started at differ- day 8, and the animals were sacrificed after 5 days ent periods of tumor growth, daily injections of 1.0 of starvation. Marked inhibition of tumor growth mg. of cortisol caused about the same increase in was observed in each condition. The ratio of ala- tumor alanine transaminase activity. In each pe- nine transaminase activity in the tumors of dia- riod the alanine transaminase response of the tu- betic or fasted animals to that of the control group mor, following treatment with 2.5 rag. of cortisol, was about 2. In experiment 2, alloxan was injected was greater than that obtained with the 1.0-mg.

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1961 American Association for Cancer Research. 624 Cancer Research Vol. 21, June 1961 amount. The greatest increase in the activity of with a 70-90 per cent inhibition of tumor growth this enzyme was found in the tumors of animals following treatment with cortisol (10-50 mg/kg treated with ~.3 rag. of cortisol daily on days 1-14; daily for 14 days). On the other hand, treatment maximal inhibition of growth was associated with with DOCA decreased the activity of alanine the marked increase in transaminase activity ob- transaminase, and, concurrently, a moderate con- served in these tumors. sistent stimulation of tumor growth occurred. Thus, an inverse relationship between the activity DISCUSSION of alanine transaminase and the growth of the Lymphoid tissues are remarkably sensitive to Walker tumor could be demonstrated with respect treatment with corticosteroids. The observation to both inhibition and stimulation of tumor growth that dissolution of the thymus gland of young rats in rats treated with cortisol or DOCA. following treatment with cortisol was associated Further correlation between this enzymatic re- with a markedincrease in the activity of alanine-a- sponse and changes in the rate of tumor growth ketoglutarate transaminase in this tissue (16) indi- can be obtained by the study of tumors naturally cated that a correlation might exist between in- sensitive or refractory to treatment with corti-

TABLE 5 RELATIONSHIP BETWEEN TIME OF CORTISOL ADMINISTRATION, INHIBITION OF GROWTH, AND ALANINE TRANSAMINASE ACTIVITY OF WALKER CARCINOSARCOMA 256

TUMOR GROWTH ALANINE TRANSAMINASE ACTIVITY TRF~ TMEN T EXPEmMF.NT CORTISOL PERIOD (MG/RA T/DAY) (DAYS) NO, Per cent mMoles substrate utilized/ Treated/ Grams control gm protein/hr at 38~ C. control

1-14 5.0 0.33 +. 08" 1.0 1.1 22 0.55+ .08 1.7 5.4 0.17+ .01 2.5 O. 27 5 2.5+1.0 14.7

7-21 22.5 0.81+ .11 1.0 5.8 26 0.60+ .25 1.9 9.88 0.29+ .02 2.5 1.28 13 0.87+ .88 3.0

14-28 87.0 0.22+ .11 1.0 16.0 48 0.89+ .11 1.8 19.4 0.22 + .09 gt 2.5 6.7 35 0.76 + .58 3.5

* Average values _+ standard deviation. There were three rats in each control group and from four to six rats in the cortisol-treated groups.

creases in the activity of this enzyme and inhibi- costeroids or sublines selected for resistance to tion of growth of cortisol-sensitive tumors. The drugs of this class. In preliminary studies, lympho- activity of this enzyme in rat liver was increased sarcoma P1798, a transplantable mouse tumor by the administration of corticotrophin or corticos- which is sensitive to corticosteroids (8), was re- teroids and by treatments which induce gluco- duced in size by 85 per cent and showed a fivefold neogenesis--namely, feeding high protein diets, rise in alanine transaminase activity following withholding food, or producing an alloxan diabetes treatment with 50 rag. of cortisol per kg. daily for 4 (17). In contrast, the administration of deoxycor- days; neither the growth nor the alanine trans- ticosterone acetate consistently lowered the activ- aminase activity of a cortisone-resistant subline of ity of alanine transaminase in liver, owing, most this tumor was affected by the same treatment likely, to suppression of hypophyseal function re- with this hormone, a Also, the growth of the Mur- suiting in lowered secretion of corticotrophin. phy-Sturm lymphosarcoma and the Novikoff The growth of Walker carcinosarcoma ~56 was hepatoma was not markedly affected by treatment suppressed, and the activity of alanine transami- with cortisol, and the transaminase activity of nase was increased significantly in animals receiv- these tumors was only slightly increased. 3 ing cortisol. The several-fold increase in the activ- 3 F. Rosen, M. Potter, and C. A. Nichol, unpublished obser- ity of this enzyme in the tumor was associated vations.

al - treatment with eorticosteroids has been variable in nine transaminase activity in both liver and tumor different laboratories (19, 31). In addition to other of the rats which were treated with cortisol or fed differences in experimental technics, the route of high levels of casein in the diet might be associated administration of the hormone can influence the with higher levels of circulating amino acids than response observed. The data in Table I indicate would occur in animals in which the liver is con- clearly that subcutaneous injection was much verting amino acids to carbohydrates that are re- more effective than either intraperitoneal or oral quired by the diabetic or fasted animals. In each administration both with respect to inhibition of case, however, marked inhibition of tumor growth tumor growth and to the relative increase in the occurred consistently. Goranson and Tilser (5) activity of alanine transaminase. In contrast, the noted a reduction in the size of Novikoff hepatoma adaptive responses of hepatic tyrosine and trypto- and Walker 256 tumors which were implanted in- phan transaminases are most marked following the traperitoneaIly in rats treated with diabetogenic intraperitoneal administration of cortisol (9, 10). doses of alIoxan; the effect of alloxan diabetes was Feeding diets containing a high proportion of less pronounced when the tumors were grown sub- protein may cause changes in protein and amino cutaneously. The relatively small changes in the acid metabolism that directly influence the rate of activity of alanine transaminase in the Walker tumor growth, or such effects may result from in- tumor when grown in diabetic or fasted rats sug- ereased secretion of eortieosteroids due to a re- gests that capacity for growth of the neoplasm sponse to this metabolic stress. An effect of amino may be limited by the changes in liver metabolism. acids on adrenal function was indicated by the On the other hand, suppression of tumor growth comparable response of tryptophan peroxidase in may result from impairment of a number of differ- rat liver following injection of histidine, tyrosine, ent metabolic functions, each critically involved or cortisone, whereas these amino acids were inef- with capacity for growth. In each instance studied fective in this respect in adrenalectomized rats to date, however, an increase in the activity of ala- (7). A direct effeet on the tumor must also be con- nine transaminase in Walker carcinosarcoma ~56 sidered, since increased levels of dietary protein has been consistently associated with inhibition of protein resulted in higher activikv of hepatic ala- the growth of this tumor. nine transaminase in both intact and adrenalec- In liver and pancreas, as well as in the tissues tomized rats (17). Although it is not clear whether sensitive to the corticosteroids, such as thymus high dietary protein affects the growth of the gland and certain tumors, the rise in aspartie acid Walker tumor in a direct or an indirect manner, it transaminase activity was not greater than ~0 per is noteworthy that when half of the diet consisted cent in any instance. Thus, it is unlikely that the of casein inhibition of tumor growth occurred at marked increase (up to 1500 per cent) in alanine the same time that a rapid rate of body growth transaminase activity is a nonspecific effect associ- was maintained; no significant increase in alanine ated with reduction in size of the tissue. Among transaminase actbr was observed under these the steroids that have been studied to date, with- conditions. The greater suppression of tumor out exception all the compounds known to have growth observed with the two highest levels of pronounced glycogenic activity have increased protein was associated with a threefold increase in alanine transaminase activity in the liver of alanine transaminase activity. treated rats. Two biologically inactive analogs of An enhanced rate of gluconeogenesis in the rat cortisol did not elicit an alanine transaminase re- occurs in response to the metabolic or physical sponse (16). stress associated with diabetes or starvation. Al- In only a few instances can changes in enzy- though each of these conditions must involve mul- matic activity be correlated with the rate of tiple and different effects on metabolism, one com- growth of normal or neoplastic tissues (3). The mon change which oce~rs in the liver of diabetic or activity of alanine transaminase does appear to fasted rats, and also in animals receiving cortisol or reflect one change in metabolism associated with high protein diets, is a marked increase in the ac- growth (1, 3). The activity of this transaminase is tivity of alanine transaminase (17). In each of relatively low in the liver of immature, rapidly these conditions, the changes in this hepatic en- growing rats. In adult rats, however, the hepatic zyme could result from increased levels of circulat- level of alanine transaminase is considerably ing amino acids which are substrates of this trans- higher. Furthermore, adrenalectomy lowers the aminase. In contrast to the hepatic changes, the hepatic level of this enzyme in adult but not in im- activity of alanine transaminase was only slightly mature rats, indicating that the level of the en- increased in the tumors which were grown in al- zyme in the adult animal is partly under the con-

trol of adrenal secretions (6). In the present study, Sensitive Lymphosarcoma of the Mouse. J. Nat. Cancer a similar relationship between the activity of ala- Inst., 20:1091-1115, 1958. nine transaminase and the growth of the Walker 9. LIN, E. C. C.; CXVEN, M.; and KNOX, W. E. Effects of Vitamin Be Deficiency on the Basal and Adapted Levels of tumor has been observed. Thus, in the rapidly Rat Liver Tyrosine and Tryptophan Wransaminases. J. growing tumor, the level of this enzyme is espe- Biol. Chem., 233:1183-85, 1958. cially low, whereas an increase in alanine trans- 10. LIN, E. C. C., and KNOX, W. E. Specificity of the Adaptive aminase activity induced by treatment with cor- Response of Tyrosine-a-ketoglutarate Transaminase in the tisol was associated with inhibition in the growth Rat. J. Biol. Chem., 233:1186-89, 1958. 11. LowRy, O. H.; ROBERTS, S. R.; and KAPPHAHN, J. I. The of this neoplasm. Fluorometric Measurement of Pyridine Nucleotides. J. The manner in which changes in transaminase Biol. Chem., 224:1047-64, 1957. activity can influence capacity for growth and the 15. LowRy, O. H.; ROSEBROUGH, N. R.; FARR, A. L.; and effect of increased transamination on the comple- RANDALL, R. J. Protein Measurement with the Folin ment of amino acids required for protein synthesis Phenol Reagent. J. Biol. Chem., 193:565-75, 1951. deserve further study. Other transaminase en- lS. NELSON, N. A Photometric Adaptation of the Somogyi Method for the Determination of Glucose. J. Biol. Chem., zymes in rat tumors are being examined to deter- 153: 375-80, 1944. mine whether treatment with cortisol stimulates 14. ROSEN, F.; BVDNXCK,L. E.; KLEIN, D.; and NICHOL, C. A. activity as in the case of alanine transaminase or Relationship of Glutamic-Pyruvic Transaminase Activity has little effect as in the case of aspartic acid to the Growth of Walker Carcinoma 256. Proc. Am. Assoc. Cancer Research, 3: 58, 1959. transaminase. 15. Ros~, F.; ROBEaTS, N. R.; BUDNICK, L. E.; and NIcaoL, REFERENCES C. A. An Enzymatic Basis for the Gluconeogenic Action of Hydrocortisone. Science, 127: 587-88, 1958. 1. BEATON, G. H.; Cvm~Y, D. M.; and VEEN, M. J. Alanine- Glutamic Transaminase Activity and Protein Metabolism. 16. ~. Corticosteroids and Transaminase Activity: The Arch. Biochem. & Biophys., 70: 588-90, 1957. Specificity of the Glutamic-Pyruvic Transaminase Re- $. BraN, M., and McKEE, R. W. Effects of X-Irradiation, sponse. Endocrinology, 65:556-64, 1959. Nitrogen Mustard, Fasting, Cortisone and Adrenalectomy 17. ROSEN, F.; ROBERTS, N. R.; and NIC~OL, C. A. Glucocor- on Transaminase Activity in the Rat. Arch. Biochem. & ticosteroids and Transaminase Activity. I. Increased Ac- Biophys., 61: 384-89, 1956. tivity of Glutamic-Pyruvic Transaminase in Four Condi- 3. COHEN,P. P., and HEKHUIS, L. G. Transamination in Tu- tions Associated with Gluconeogenesis. J. Biol. Chem., mors, Fetal Tissues and Regenerating Liver. Cancer Re- 234: 476-80, 1959. search, 1: 650-56, 1941. 18. SALZBERG, D. A., and GRIFFIN, A. C. Inhibition of Azo 4. GAVOSTO,F.; PILERI, A.; and BBUSCA,A. Increased Trans- Dye Carcinogenesis in the Alloxan-Diabetic Rat. Abstracts aminase Activity in the Liver after Administration of Cor- of Scientific Proceedings, Cancer Research, 12:594, 1955. tisone. Biochim. et Biophys. acta, 24:550-54, 1957. 19. TALALAY,P.; TAKANO, G. M.; and HUOGINS, C. Studies on 5. GORANSON,E. S., and TILSER, G. J. Studies on the Rela- the Walker Tumor. II. Effects of Adrenalectomy and Hy- tionship of Alloxan-Diabetes and Tumor Growth. Cancer pophysectomy on Tumor Growth in Tube-fed Rats. Can- Research, 15: 626-31, 1955. cer Research, 12: 838-43, 1956. 6. HARDING,H. R.; ROSEN, F.; and NICHOL, C. A. Relation- 50. VANGEROV, M., and McKEE, R. W. Metabolism of Glu- ships between Corticosteroids and Transaminase Enzymes, cose, Lactate, and Alanine by Ehrlich's Ascites Carcinoma p. 817. Fifth International Congress of Endocrinology, Cells from Normal and Alloxan-Diabetic Mice. Fed. Proc., Copenhagen, 1960. 14: 596, 1955. 7. KNox, W. E. Two Mechanisms Which Increase in Vivo the ~1. WALPOLE,A. L. The Walker Carcinoma ~56 in the Screen- Liver Tryptophan Peroxidase Activity: Specific Enzyme ing of Tumor Inhibitors. Brit. J. Pharmacol., 6:135-43, Adaptation and Stimulation of the Pituitary-Adrenal Sys- 1951. tem. Brit. J. Expel Path., 31:465-69, 1951. 55. WROBLEWSKI,F., and LADuE, J. S. Serum Glutamic Py- 8. LAMPKIN,J. McC., and POTTER, M. Response to Cortisone ruvic Transaminase in Cardiac and Hepatic Disease. Proc. and Development of Cortisone Resistance in a Cortisone- Soc. Exper. Biol. & Med., 91:569-71, 1956.

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1961 American Association for Cancer Research. Corticosteroids and Transaminase Activity III. A Relationship between Changes in Alanine Transaminase Activity and the Growth of Walker Carcinosarcoma 256

Fred Rosen, Louis E. Budnick, Dolores K. Solomon, et al.

Cancer Res 1961;21:620-626.

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