132 1. lODOACETATE AND lODOACETAMIDE 



than iodoacetate, stimulates the pentose-P pathway strongly and was pos- 

 tulated by Birkenhager (1959) possibly to inhibit phosphohexokinase, this 

 bringing about a greater accumulation of glucose-6-P. However, there is 

 very little evidence that iodoacetate can in general increase the utilization 

 of glucose through the pentose-P pathway. 



The pentose-P pathway is present in most tumor tissues and may actually 

 be slightly more active than in normal tissues (Aisenberg, 1961, p. 88). In 

 addition to the two carcinomas in Table 1-20, several tumors have been 

 studied less intensively. Villavicencio and Barron (1957) found iodoacetate 

 to inhibit aerobic glucose utilization less readily in lymphosarcoma than in 

 lymphatic cells, and concluded that the pentose-P cycle is more important 

 in the tumor, while Racker (1956) attributed the failure of iodoacetate to 

 inhibit glucose respiration in ascites cells to some alternate pathway for 

 glucose oxidation. Iodoacetate at concentrations completely blocking gly- 

 colysis inhibits 50-75% the formation of C^^Og from glucose-u-C^^ and glu- 

 cose-6-C^* in a variety of tumors, so that an alternate pathway is likely, 

 although one cannot be certain that aerobically the EM pathway is fully 

 blocked (van Vals et al., 1956; van Vals and Emmelot, 1957). 



Another type of evidence for the operation of alternate pathways is the 

 differential effects sometimes observed on the oxidation of glucose, hexose 

 monophosphates, and hexose diphosphate. Some of the results and the dif- 

 ficulties involved have been described (page 125) and here we shall note 

 only briefly some data obtained aerobically. If the pentose-P pathway is 

 operative, the oxidation of fructose- 1,6-diP may be inhibited more readily 

 than that of glucose or glucose-6-P. This has been found in Sarcina lutea 

 (Barron and Friedemann, 1941), tobacco leaves (Clayton, 1959), sea urchin 

 eggs (Lindberg and Ernster, 1948), and adrenal tissue (Kelly et al., 1955). 

 In other instances the oxidation of hexose monophosphates is inhibited by 

 iodoacetate completely, as in grasshopper embryos (Bodine and West, 1953) 

 and pea seeds (Hatch and Turner, 1958), so that a normal EM pathway with 

 no pentose-P cycle is indicated. The oxidation of fructose-l,6-diP in Strep- 

 tomyces coelicolor is inhibited only 22% by 2 milf iodoacetate, whereas 3- 

 PGDH is blocked completely by 1 milf (Cochrane, 1955). In this case, 

 fructose-l,6-diP may be hydrolyzed to the monophosphate which can pro- 

 ceed through the pentose-P pathway. However, another possibility is the 

 phosphorolytic cleavage of fructose-6-P by a phosphoketolase, such as 

 was found in Acetobacter xylinum by Schramm et al. (1958), acetyl-P being 

 formed along with erythrose-4-P, 



Fructose-6-P + P, -> acetyl-P + erythrose-4-P + H2O 

 which can be metabolized to acetyl-P or acetate. 



