260 1. lODOACETATE AND lODOACETAMIDE 



mality in the pliitei, and this can be mainly counteracted by pyruvate. The 

 bilateral determination during the early development of Dendraster excen- 

 tricus is altered by iodoacetate at concentrations around 0.05-1 mM when 

 applied in a gradient (Pease, 1941). Chick embryos explanted to Ringer- 

 glucose medium undergo morphogenesis and differentiation up to the for- 

 mation of the primitive nervous system and the heart. Iodoacetate at 0.1 

 mM causes almost immediate cessation of development and complete de- 

 generation, but at 0.02-0.05 mM the effects are more selective, the head 

 fold being the the most sensitive region, as in glucose deficiency (Spratt, 

 1950). Eventually the entire neuraxis undergoes degeneration, while the 

 heart remains unaffected and continues to beat. Pyruvate counteracts these 

 effects very effectively, indicating that the block may be on the EM path- 

 way. As might be expected, those regions undergoing the greatest differ- 

 entiation are in general the most sensitive. In connection with the processes 

 of differentiation, the effects of iodoacetate on posterior regeneration in the 

 annelid Tubifex tubifex are interesting, and in addition provide an instance 

 of extreme sensitivity (Anderson, 1956). Although regeneration aerobically 

 is not disturbed by concentrations up to 0.01 mM (indeed some accelera- 

 tion of later regeneration may be observed), aneaerobically a concentration 

 of 0.00001 mM kills all the worms. 



EFFECTS ON NEOPLASTIC GROWTH 



Tumors as a whole have a characteristic metabolic pattern, although 

 deviations from this are well known, and for this reason their response to 

 iodoacetate is interesting. This characteristic pattern can be briefly sum- 

 marized as follows: (a) a high glycolytic rate, both aerobic and anaerobic 

 (Table 1-36), (b) a normal respiratory rate, despite deficiencies in mito- 

 chondrial enzymes such as succinate oxidase, pyruvate oxidase, a-ketoglu- 

 tarate oxidase, and cytochrome oxidase, (c) a rather low respirator}^ quo- 

 tient, (d) a high hexokinase activity (perhaps due to deficiency of the nor- 

 mal control) and an efficient mechanism for the utilization of glycolytically 

 generated ATP for glucose phosphorylation, (e) a frequent exhibition of the 

 Crabtree effect, (f ) low levels of glucose-6-phosphatase and phosphogluco- 

 mutase with high levels of phosphohexoisomerase, all of which directs the 

 sequence along the EM pathway and away from glycogen formation and 

 other pathways, (g) perhaps a deficiency in phosphorylase, (h) a slightly 

 more active pentose-P pathway than in normal tissues, (i) somewhat low 

 levels of NAD and NADP (which may alter susceptibility of some enzymes 

 to iodoacetate), and (j) a high incorporation rate of amino acids into pro- 

 tein. Many of these characteristics, such as the high glycolytic rates, are 

 not necessarily seen in all proliferating tissues. The responses of certain 

 systems to iodoacetate have been given for tumors in previous tables: 



