202 1. MALONATE 



and azide were administered to patients with advanced neoplasia and tem- 

 porary suppressive effects were noted (Black and Kleiner, 1947; Black et at., 

 1947). Sodium malonate was given orally at doses of 1-1.5 g/day. It is 

 difficult to state clearly the effects of malonate, since the inhibitors were 

 usually given sequentially or together, but it was stated that hematological 

 remissions occurred in acute myeloblastic leukemia and that shrinkage of 

 solid tumors, with relief of pain, was evident. The tumor cells usually be- 

 come refractory to these inhibitors. After resistance to fluoride and iodo- 

 acetate has developed, a beneficial effect is seen with malonate. It would 

 seem that these results are encouraging enough to warrant further study, 

 particularly with combinations of the inhibitors to prevent or reduce the 

 development of resistance. Several derivatives of malonate were tested 

 against mammary Carcinoma 755 in mice and suppressive action was dem- 

 onstrated (Freedlander et al., 1956). Malonic acid at 1.2% in the diet did 

 not affect either the tumor size or the growth of the mice. The most active 

 ethyl ester was diethylethoxymethylenemalonate (the group =CH — — 

 — CH2CH3 on C-2), which at 1.2% in the diet reduces the surface area of 

 the tumors 83% while causing minimal loss of body weight. This substance 

 is as effective as 8-azaguanine and is less depressant on the total body 

 growth. Some diamides are also active, iV-dimethylmalondiamide being the 

 most active, reducing tumor area 68% with no effects on body growth. 

 It was thought that these substances may be inhibitory to succinate de- 

 hydrogenase, probably after hydrolysis, but there is no evidence at present 

 for this and it is quite possible that the mechanism is entirely different. 

 Despite the lack of evidence for a high susceptibility of the metabolism or 

 growth of isolated neoplastic cells to malonate, the in vivo work has brought 

 out interesting effects that deserve more thorough investigation. 



CELLULAR AND TISSUE FUNCTION 



Many studies of the effects of malonate on physiological function with 

 the object of relating the cellular activity to succinate oxidase or the cycle 

 have been reported, but in only a few instances have the necessary data 

 been obtained and a relationship adequately established. The general rela- 

 tions between enzyme inhibition and changes in cellular function were 

 discussed in Chapter 1-9, and several methods for demonstrating correla- 

 tions were presented. The complexities of such studies were emphasized 

 and the difficulties commonly encountered are well illustrated in the results 

 of malonate inhibition. In addition to the various possible metabolic effects 

 of malonate, one must bear in mind that malonate, or the cations added 

 with it, can directly alter functional processes, actions which can be dis- 

 tinguished by the proper controls. 



