88b METABOLISM OF THE CANCER CELL 12 



of rat thymus, mouse spleen, appendix, Ehrlich and Gardner lymphosarcomas 

 or lymphatic leukemia with glucose- i-'^^C, glucose-2-''*C, glucose-6-^'*C or 

 vmiformly labeled glucose. It was observed that the hexose monophosphate shunt 

 was active in intact tumor and spleen cells. All of the tissues utilized glycolysis to 

 the extent of 60-80%. On the basis of the differential oxidation of glucose- i-'^^G 

 and glucose-6-^'*C to ''*CO-, it was calculated that the intact tumor cells formed 

 two to five times as much pentose from the glucose as did the normal lymphatic 

 cells. The growth of implanted tumors was suppressed in severely diabetic rats 

 and these animals excreted less than half of the glucose excreted by force-fed, non- 

 tumor bearing diabetic controls (Ingle, 1956). 



Picco and Dogliotti (1952) in studies on human tumors have provided further 

 information that tumors contain more glucose, pyruvic acid, and lactic acid than 

 homologous normal tissues. The original demonstration of a lowered pH in ani- 

 mal tumors (Greenstein, 1954) has been confirmed and extended by Eden et al. 

 ( ^ 955) • Using large numbers of several varieties of rat tumors they reported an 

 average pH of 6.99 for the neoplastic tissues. Following the injection of glucose, 

 the pH dropped to 6.55 within three to four hours. Normal muscle and hepatic 

 tissues did not exhibit any pH decrease. Naeslund and Swensen (1953) and 

 Naeslund (1954) attempted to find compounds that would precipitate at this 

 lowered pH and thereby accumvilate in the malignant tissue. Benzoylsulpha- 

 methylpyrimidine has a solubility three times as high at pH 7.5 than at pH 6.51. 



The addition of glucose, mannose, or fructose inhibits the respiration of ascites 

 tumor cells (Brin and McKee, 1956). Within 2-3 hour this inhibition is 

 released. Just prior to the release of inhibition the glucose has disappeared and 

 the lactate concentration is maximal. The addition of inorganic phosphate re- 

 duced this inhibition, indicating that the diffusion or entry of inorganic phosphate 

 into the tumor cell may not be adecjuate to support the metabolic requirements. 

 McKee et al. (1953) also found that glucose added in amounts greater than 1.5 

 millimoles inhibited oxidation in mouse ascites carcinoma cells. They concluded 

 that a shunting of the metabolism from oxidative to glycolytic may be of impor- 

 tance in the abnormal growth and the non-differentiation of the tumor cells. Roitt 

 (1956) has observed an inhibition of carbohydrate metabolism in ascites tumor 

 cells by the ethyleneimines. The analog, 2-deoxy-D -glucose inhibits aerobic and 

 anaerobic glycolysis in slices of rat tumors, rat brain and diaphragm. This compound 

 did not inhibit endogenous respiration in any of the tissues (Woodward and Hud- 

 son, 1954). Tri- and tetra-iodothyroacetic acid accelerated glycolysis in several 

 ascites tumors (Heimberg et al., 1955). Lettre (1952, 1952a) reported that pyocanin 

 decreased considerably the number of mitoses in cultures of fibroblasts and of 

 mouse ascites tumor. This effect was attributed to the stimulatory effect of pyo- 

 canin on respiratory metabolism. A relationship was proposed between mitosis 

 and the glycolytic metabolic state. The anaerobic consumption of glucose and 

 also lactate production was stimulated by dinitrocresol in ascites tumor cells 

 (Clowes and Keltch, 1954). However, the consumption of fructose and mannose 

 was not stimulated by this compound, suggesting that the amounts and types of 

 hexokinase in the ascites cells may differ from that of brain and other normal cells. 

 El'Tsina (1953), in ascertaining the role of glycolytic and oxidative processes in 



