400 2. ANALOGS OF ENZYME REACTION COMPONENTS 



Effects of 2-DG on Cell Division and Growth 



The growth rate of E. coli is depressed at least 50% by 10 mM 2-DG 

 but the differential rate of inducible /5-galactosidase synthesis is not altered 

 (Cohn and Horibata, 1959). Although Neurospora and Aspergillus can 

 grow slowly on 2-DG alone, the growth is inhibited when the usual sugars 

 are present (Sols et al., 1960 b). The mutiplication of influenza virus in 

 chick embryos is markedly inhibited by 2-DG but in preliminary studies 

 there was no evidence that the development of lesions in mice is altered 

 (Kilbourne, 1959). Glucose and, to some extent, pyruvate are able to 

 counteract this depression. Sea-urchin egg cleavage is delayed by 2-DG 

 and development is stopped at various stages, depending on the concen- 

 tration: 1-10 mM prevents gastrulation and the eggs reach swimming 

 blastulae, 100 mM delays first cleavage but the early blastula stage is 

 eventually reached, 200 mM causes greater cleavage delay and develop- 

 ment stops before the blastula stage (Bernstein and Black, 1959). Glucose 

 can counteract the cleavage delay. The most sensitive tissue investigated 

 appears to be chick embryo heart fibroblasts, since the mitotic index is 

 reduced from 2.65 to 0.15 by 1.52 mM 2-DG (Ely et al, 1952). Glucose at 

 approximately equimolar concentration is not able to reverse this inhibition 

 significantly. The migration of cells in the 2-DG-treated cultures is also 

 limited and the cells become vacuolated. These observations all point to a 

 general growth-inhibiting action of 2-DG, which is not unexpected, but 

 there has been little study of differential growth effects. 



The ability of tumors to derive a good part of their energy for growth 

 from glycolysis prompted the original study of 2-DG as a possible carcino- 

 static agent, but surprisingly little work has been done on this aspect. 

 It has been established that glycolytic inhibition of tumors in vivo is pos- 

 sible, in that patients with chronic myelogenous leukemia infused with 

 60 mg/kg 2-DG show 35-40% inhibition of glycolysis in the leukemic cells 

 (Laszlo et al., 1958). The growth of cultured HeLa cells from human carci- 

 noma is inhibited readily by 2-DG, 5 mM producing essentially complete 

 depression which is reversible up to 3 days but not afterward (Barban 

 and Schulze, 1961). Glucose or mannose will counteract the growth inhibi- 

 tion. Cells in a fructose medium are inhibited more readily than when 

 grown on glucose or mannose, which corresponds to the greater inhibition 

 of fructose utilization discussed previously. When 2-DG is added at 2-5% 

 to the diet of rats, the growth of carcinoma G-175 in reduced (Sokoloff et al., 

 1956). Adult rats tolerate this dosage well but the growth of young rats is 

 retarded. The 2-DG can also be injected subcutaneously at 2-4 mg/kg/day. 

 Mouse sarcoma is similarly affected. The inhibition in either case is not 

 very marked. Solid, transplanted, and ascitic tumors in mice grow more 

 slowly when 2-DG is administered (Laszlo et al., 1960). A modest prolonga- 

 tion of the survival time of the animals was noted. Definite carcinostatic 



