262 1. lODOACETATE AND lODOACETAMIDE 



to iodoacetate in tumors, especially those more characteristic of neoplastic 

 tissue and possibly relating to the inhibition of growth. Glucose often de- 

 presses respiration in tumors (Crabtree effect) and this is apparently due to 

 compartmentalization of ATP formed from glycolysis, and the replacement 

 of the ATP lost in the inhibited respiration by ATP generated glycolytically. 

 The basis for this may be some competition between reactions for ADP or 

 P(. This phenomenon is seen well in Ehrlich ascites carcinoma cells. If iodo- 

 acetate prevents ATP generation during glycolysis, one might expect it to 

 stimulate respiration in such cells at low concentrations and in the presence 

 of glucose. The results reported are not consistent. Ibsen et at. (1958) stated 

 that iodoacetate does not stimulate the respiration under these circum- 

 stances; slight stimulation was observed in a few cases, but it is questionable 

 if the change is significant. Kvamme (1958 b) found only a 17% inhibition 

 of respiration by 0.05 mM iodoacetate. Laws and Stickland (1962), how- 

 ever, obtained a 14% increase in the respiration by 1 n\M iodoacetate. To 

 add further complication, Seelich and Letnansky (1960) reported definite 

 respiratory stimulation by 0.5 mM iodoacetate in phosphate buffer, but 

 only an inhibition in bicarbonate buffer. The interrelationships in this field 

 are so complex that it is perhaps not surprising that variable results are 

 often obtained. Another factor which must be considered in interpreting 

 the Crabtree effect and the action of iodoacetate is the role that NADP 

 reduction and the pentose-P pathway play in determining the respiratory 

 rate. In any event, it is clear that iodoacetate markedly reduces the levels 

 of ATP and total adenine nucleotides in ascites cells in the presence of 

 glucose (Kvamme, 1958 a; Thomson et al., 1960). The marked fall in the 

 pH, brought about in tumor cell suspensions by the addition of glucose, is 

 not only abolished by low concentrations of iodoacetate, but a rise in the 

 pH is observed, e.g., from 6.95 to 7.48 (Racker, 1956) or 5.92 to 7.07 (Kvam- 

 me, 1958 b), the magnitude depending on the glucose concentration and the 

 incubation time. The effects of such pH changes intracellularly on neo- 

 plastic growth are not known. The ratio of C^^Og formed from glucose- 1-C^* 

 to that from glucose-6-C^^ is markedly reduced in ascites cells (Table 1-20) 

 (Wenner, 1959) and, as was described (page 131), this is due here to an 

 indirect depression of the pentose-P pathway through the block of pyru- 

 vate formation, since the principal oxidizer of NADPH in these cells is 

 pyruvate. Finally, it may be recalled that 0.54 mM iodoacetate inhibits 

 the incorporation of acetate-1-C^^ into proteins, fatty acids, and cholesterol 

 in slices of a variety of tumors (van Vals and Emmelot, 1957), although 

 there is marked variation between the different tumors, e.g., incorporation 

 into fatty acids being inhibited 85% in adrenal carcinoma and not at all 

 in hepatoma. Such interferences in biosynthesis, whatever the mechanisms 

 involved, must be important in the effects of iodoacetate on neoplastic 

 growth. The inhibition of inward transport and accumulation of amino 



