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The Effect of 2-Desoxy-D-Glucose on Glycolysis and Respiration of Tumor and Normal Tissues

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The Effect of 2-Desoxy-D-Glucose on Glycolysis and Respiration of Tumor and Normal Tissues The Effect of 2-Desoxy-D-glucose on Glycolysis and Respiration of Tumor and Normal Tissues GLADYSE. WOODWARDANDMARIET. HUDSON (Biochemical Research Foundation, Newark, Delaware) Inhibition of metabolism by structural analogs end of each experiment. Reaction rates are expressed of metabolites is one of the newer concepts of of dry tissue/hour, and are based on the initial steady rate. chemotherapy. It seems possible that this concept The symbols, QCOJ.Qco2>an<l Q<v are used to express, re spectively, the rates of anaerobic glycolysis, aerobic glycolysis, might be applied to cancer by use of structural and respiration. The Q values as given in the tables are from analogs of glucose to inhibit the glycolysis of the single or duplicate determinations. tumor cell, since tumor tissue in contrast to most normal tissues possesses the ability to glycolyze RESULTS glucose at a high rate both anaerobically and EFFECTop 2DG ONGLYCOLYSIS aerobically (7). It was found that 2DG in the maximum concen 2-Desoxy-D-glucose (2DG) is a structural ana tration used with each tissue did not significantly log of glucose, differing from glucose only at the affect the endogenous glycolysis of any of the tis second carbon atom by the absence of one oxygen sues studied. Calculation of the degree of inhibi atom. This analog has been shown (2) to compete tion of glucose or fructose utilization, therefore, is with glucose in the yeast fermentation system and, based on the Q values from which the correspond thereby, to inhibit fermentation of glucose. In a ing blank Q value has been subtracted. preliminary report (8) 2DG was also shown to Tumor.—The anaerobic glycolysis of glucose inhibit the anaerobic glycolysis of rat tumor (glucolysis) by both Flexner-Jobling and Walker slices. The present report deals with further stud 256 carcinoma was inhibited 72-91 per cent, as ies on the effect of 2DG on the metabolism of tu shown in Table 1, when 2DG was present in a 1:1 mor tissue. Studies have been included on the ef molar ratio with 0.015 M glucose, a concentration fect produced on the metabolism of a few normal of glucose which was sufficient for maximum glu tissues by 2DG. colysis in the absence of 2DG. The extent of the inhibition was less as the proportion of 2DG :glu MATERIALS AND METHODS cose was decreased. Usually the inhibition was The transplantable rat tumors, Flexner-Jobling carcinoma (FJ) and Walker 256 carcinoma (W256), were grown sub- 50 per cent or greater when the ratio was 0.5:1. cutaneously in male rats of the Wistar strain which weighed When the ratio was as low as 0.067:1 the degree 125-150 gm. at the time of transplantation. When the tumors of inhibition was insignificant. The extent of in were of sufficient size for slicing, usually 7-12 days after implan hibition produced by 2DG at any one concentra tation, the rats were decapitated and the tumors excised. Brain, tion varied from tumor to tumor even among tu liver, and diaphragm were taken from the tumor-bearing rats and from normal rats of the same size and strain. Tumor, mors of the same type. brain, and liver were sliced to a thickness of about 0.5 mm. Tumor glucolysis was inhibited aerobically as with a Stadie-Riggs microtome. The diaphragm was cut into well as anaerobically (Table 1). The extent of in quarters. Only those tumor slices were used which were rela hibition appears to be slightly less aerobically tively free of necrosis. than anaerobically at the same level of 2DG con The usual Warburg technics (9) were followed, the direct methods for measurement of glycolysis and respiration of tissue centration. slices being used. In the glycolytic studies, the tissue slice was The competitive nature of the inhibition is suspended in 2 ml. of Krebs-Ringer bicarbonate solution shown by the data in Table 2. As the glucose con in a Warburg flask, while in the respiration studies the slice was suspended in 2 ml. of Krebs-Ringer phosphate solution centration was increased in the presence of a con from which calcium had been omitted. Glucose, fructose, and stant amount of 2DG, the extent of inhibition 2DG (1) were included in the 2 ml. of medium in concentra caused by 2DG was decreased, indicating that tions as indicated in the tables. 2DG inhibits by competing with glucose as sub The amount of tissue used in each flask was determined as strate for the glycolytic system. dry weight after removal from the suspending medium at the The anaerobic glycolysis of fructose (fructoly- Received for publication May 24, 1954. sis) by tumor tissue slices also was found to be 599 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1954 American Association for Cancer Research. TABLE 1 INHIBITION OF GLUCOLYSISOFRAT TUMORSLICESBY2DG (Glucose concentration, 0.015 M) GLDCOLTSISRATE GlucoseTonos»FJFJW256FJFJFJW256FJW256FJFJW256W256IDGCONC.U0.0150.00750.003750.0150.00750.003750.0150.00750.003750.00750.00750.003750.0020.0010.0010.0150.0150.0150.0075+2DG Glucose2DG:GLDCO8EBATIÓ1:1.5:1.25:11:1.5:1.25:11:1.5:1.25:1.5:1.5:1.25:1.133:1.067:1.067:11:11:11:1.5:1addrd added<&10.017.624.67.412.417.87.418.225.010.312.823.432.223.728.6Qco,6.74.89.815.2o1*'Qco,(anaerobic)31.031.023.627.132.432.042.727.629.3(aerobic)20.512.124.622.7NoadditionQNl2.05.25.44.03.53.84.52.53.8Qco,-1.3-1.5-3.00INHIBITIONorOLOCOLTSIS(per cent)724«i*ill7251893007808SO2715363545433 * FJ —Flexner-Joblingcarcinoma. W256—Walker 256 carcinoma. TABLE 2 REVERSALOF2DG INHIBITIONOFANAEROBICGLUCOLYSISOFRATTUMOR SLICESBYINCREASEDGLUCOSE <; r I . i .1.1.-IM BATI TUMOB*FJW256W256FJFJW256GLUCOSECONC.M0.0150.030.060.0150.030.060.0150.030.0450.060.0150.030.060.0150.030.060.0150.030.06Glucose+2DGaddedONzyco¡8.418.018.411.cent)7100556007447372578482064412838110 2DG)17.220.133.2(with0.015 H S10.421.411.819.822.626.08.618.625.210.215.618.627.638.448.6GlucoseaddedQN««cot(with 0.00752DG)30.825.042.9NoadditionQ&4.84.04.42.42.03.0INHIBITIONorGLOCOLTSIS(perH *For abbreviations, see footnote to Table 1. Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1954 American Association for Cancer Research. WOODWARDANDHUDSON—2-Desoxy-D-glucose and Tissue Metabolism 601 inhibited by 2DG (Table 3). A concentration of Brain.—Brain tissue, which can glycolyze glu 0.06 Mfructose was used in these studies, since this cose at a considerable rate anaerobically, although concentration was found necessary for maximum not aerobically (7), was chosen as a normal tissue fructolysis. In this medium, 2 DG in concentra upon which to test the effect of 2DG on glucolysis. tions of 0.0005 M or higher produced inhibition. The data in Table 4 show that the anaerobic glu On the basis of the 2DG ¡fructoseand 2DG ¡glucose colysis of brain slices was very susceptible to in ratios required for equal inhibition, it is apparent hibition by 2DG. With brain tissue, as with tu that fructolysis is at least 50 times more sensitive mor tissue, the extent of the inhibition produced to 2DG than is glucolysis. by 2DG at any one concentration varied from TABLE 3 INHIBITIONOFANAEROBICFRUCTOLYSISOFRATTUMORSLICESBY2DG (Fructose concentration, 0.06 M) FBDCTOLTSIBHATE FRUCTOSERATIO0. TUMOR*FJFJFJW256FJ«DGCONC.M0.0150.00750.003750.003750.0018750.0010.0010.00050.0010.00050.000250.0010.000250.000062DG:cent)10010010082878679488083207520 25:10.125:10.062:10.062:10.031:10.016:10.016:10.008:10.016:10.008:10.004:10.016:10.004:10.001:1Fructose+ÕDGaddedQCÔ4.84.87.26.05.25.48.010.87.67.215.97.819.420.6Fructoseadded«S,18.818.815.318.619.8NoadditionOS,7.23.26.04.88.7INHIBITIONOFFRUCTOLYSII(per * For abbreviations, see footnote to Table 1. TABLE 4 INHIBITIONOFANAEROBICGLUCOLYSISOFRATBRAINSLICESBY2DG (Glucose concentration, 0.015 M) GLUCOLYBIBBATE RATUSEDAS SOURCEOF :OLUCOSERATIO0.25:10.25:10.125:10.125:10.067:10.125:10.067:10.125:10.067:10.033:10.017:10.067:10.067:10.033:10.017:1Glucose+*DGadded0N,^COJ1.72.04.113.213.85.45.73.35.810.610.87.66.46.312.0GlucoseaddedQNl12.111.99.911.710.810.013.49.49.79.511.6NoadditionQCO.1.41.68.84.22.71.53.21.21.91.52.7INHIBITIONorGLUCOLYBIS(per TISSUE*W256-bearingNormalFJ-bearingW256-bearingW256-bearingNormalFJ-bearingFJ-bearingNormalFJ-bearingFJ-bearing«DGCONC.If0.003750.003750.0018750.0018750.0010.0018750.0010.0018750.0010.00050.000250.0010.0010.00050.000252DGcent)979588006763797528252242400 For abbreviations, see footnote to Table 1. Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1954 American Association for Cancer Research. 602 Cancer Research animal to animal. The variation, however, did not therefore, at least 100 times less sensitive to 2DG appear to depend upon whether the brain tissue than is tumor fructolysis. was from a normal or tumor-bearing rat. It should be noted that the brain slices from one Walker 256- EFFECTOF2DG ONRESPIRATION bearing rat (fourth rat, Table 4) were entirely re 2DG did not significantly affect the endogenous sistant to 2DG in concentrations at which a high respiration of rat tissues, as shown in Table 8. The degree of inhibition was produced with the brain respiration of tumor, liver, and diaphragm is de slices from other rats. pendent mainly upon endogenous material. With 2DG at a concentration of 0.001 M in the pres these tissues, Qo, in the presence of added glucose ence of 0.015 M glucose produced an average in was no greater than in the absence of glucose. In hibition of about 50 per cent with brain tissue, fact, the addition of glucose, as had been observed whereas with tumor tissue 2DG at a concentra by many workers, at times brought about a slight tion of 0.0075 M was required for a similar extent lowering of Qo,.
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