EFFECTS OF 2-DEOXY-D-GLUCOSE 401 



activity in vivo has thus been demonstrated but there should be much more 

 work to establish if sufficient differential depression can be achieved, and 

 other types of neoplasm should be studied. 



Effects of 2-DG on Whole Animals 



The intravenous infusion of 2-DG at doses of 50-200 mg/kg in cancer 

 patients produces a feeling of warmth, flushing, diaphoresis, headache, 

 drowsiness, tachycardia, a rise in blood glucose, and a fall in white cell 

 count (Landau et al., 1958). Hyperglycemia has been noted in all studies 

 and might be attributed to a reduced utilization of glucose brought about 

 by glycolytic inhibition. However, other factors must be considered. Brown 

 and Bachrach (1959) showed that the rise in blood glucose from 2-DG can 

 be partially prevented by demedullation of the adrenals, indicating that 

 2-DG may stimulate the release of epinephrine. Increases in urinary cate- 

 cholamines during 2-DG infusion have also been noted (Laszlo et al., 1961). 

 Hokfelt and Bydgeman (1961) felt that this epinephrine release is the 

 primary cause of the hyperglycemia and showed that 2-DG can deplete 

 the adrenals of half their epinephrine. Spinal transection reduces the 2-DG 

 effect, indicating epinephrine release to be mediated through the central 

 nervous system. Pretreatment with dihydroergotamine, which blocks the 

 effects of epinephrine, abolishes the 2-DG hyperglycemia (Altszuler et al., 

 1963; Sakata et al., 1963). It is interesting in connection with the possible 

 effects of 2-DG on the central nervous system that 2-DG is transported from 

 the blood into the cerebrospinal fluid faster than glucose; there is also com- 

 petition between glucose and 2-DG for the carrier (Fishman, 1964). Landau 

 et al. (1958), on the other hand, were inclined to discount the role of epine- 

 phrine since no rise in blood pressure is observed during maximal hyper- 

 glycemia. The hyperglycemia probably is responsible for the decreased 

 stainability and degranulation of pancreatic islet cells produced by 2-DG, 

 indicating increased activity of these cells, rather than a direct action 

 (Hokfelt and Hultquist, 1961). The symptoms listed above must be due 

 in part to the restricted glucose utilization caused by 2-DG. The rise in 

 blood glucose must tend to counteract this inhibition, since glucose in- 

 fusions reduce mortality from 2-DG, but not sufficiently. It is interesting 

 that the anaphylactoid reaction to dextran and ovomucoid in rats is 

 inhibited by 2-DG at 200 mg/kg intravenously, although the response to the 

 histamine releasers is not affected, indicating an important role of glucose 

 uptake and metabolism in certain inflammatory reactions (Goth, 1959). 

 The LD50 in mice is around 2.5 g/kg for single intravenous injections and 

 5 g/kg subcutaneously or intraperitoneally (Laszlo et al., 1960). The animals 

 survive several hours to a day in most cases but may die within 10 min af- 

 ter intravenous injection. The major toxic effects are related to the central 

 nervous system and are weakness, convulsions, and coma. 



