GROWTH, DEVELOPMENT, AND DIFFERENTIATION 



201 



ship of the accumulation to malonate concentration is not linear for the 

 tumor (Fig. 1-12). As pointed out by Busch and Potter (1952 b), the ac- 

 cumulation of succinate in the tumor may be superficially indistinguishable 

 from that in normal tissues, but there is reason to believe that the succinate 

 in the tumor arises by somewhat different pathways, mainly from gluta- 

 mate and related compounds. There is little reason to believe from the 

 known metabolic characteristics of tumor tissues that malonate would se- 

 lectively depress their growth; indeed, one might expect them to be less 

 sensitive to malonate, except for the fact that tumor cells are often more 

 rapidly proliferating and more active metabolically than normal tissues. 



Neoplastic growth in general seems to be relatively resistant to malonate. 

 Malonate at 30 mM is not toxic to cultures of various tumors but 50 mM 

 is toxic to all types of cells in a few hours (Chambers et al., 1943). It is 

 interesting that no differences in susceptibility of lymphocytes and other 

 wandering cells, whether from normal or neoplastic tissues, are seen. Eagle's 

 KB strain of human carcinoma cells is more sensitive, the 50% inhibitory 

 concentration of malonate being around 4 ml/ (Smith et al., 1959). Malo- 

 nate, like many metabolic inhibitors, is capable of producing acentric blebs 

 on Sarcoma 37 ascites cells (Belkin and Hardy, 1961). Although this indi- 

 cates some alteration of the membrane properties and the permeability to 

 water, the relationship to growth inhibition is unknown. 



Studies of the action of malonate on tumors growing in whole animals 

 are more pertinent to the problem of the possible value of this inhibitor 

 in therapy. The earliest work was done by Boyland (1940) following his 

 investigations of the effects of malonate on tumor respiration. Definite sup- 

 pression of growth was observed with malonate at a dose well below the 

 lethal, the carcinoma being more sensitive than the sarcoma (see accom- 

 panying tabulation). Actual regression of the carcinomata was observed. 



Inhibitor 



Dose 



% Inhibition of growth of 



LD,„ 



(mg/day) Qrafted sarcomata Spontaneous carcinomata 



as indicated by the 131% inhibition. Whether ethylmalonate and malon- 

 amide are metabolized to malonate and are active for this reason is not 

 known, but the lesser potencies compared to malonate do not suggest that 

 these uncharged substances penetrate better. Malonate, fluoride, iodoacetate 



