200 1. MALONATE 



energy for mitosis is derived from cycle oxidations. Malonate at 20 mM 

 prevents the cell from entering mitosis for 3 hr but evidence of recovery is 

 seen after this time. However, at 4 hr, although some cells are progressing 

 through mitosis, the number of mitoses is definitely less than in the controls. 

 There is no evidence that malonate can stop mitosis once it has begun. 

 Epidermal cells adjacent to the wound show a higher number of mitoses 

 than normal epidermis and malonate depresses both strongly (see accom- 

 panying tabulation). (Bullough and Laurence, 1957). Malonate can thus 



Malonate 



Average number of mitoses 



(milf) Epidermis adjacent to wound Normal epidermis 



8.20 0.96 



10 1.23 0.22 



20 0.05 0.18 



30 0.05 0.01 



inhibit healing without significant damage to the tissue, since no necrosis 

 is seen following incubation with malonate. Similar results were obtained 

 by Gelfant (1960) and concentrations as low as 0.5 mM are definitely inhi- 

 bitory. After 4 hr 50 m M malonate produces some necrosis. The mitotic 

 rate in the germinal epithelium of rat ovaries is also suppressed by malo- 

 nate, 2 mM having variable effects but inhibiting 21% on the average and 

 10 mi/ inhibiting 59% (Weaver, 1959). The relatively high sensitivity of 

 mammalian tissue mitosis to malonate would implicate the cycle as an 

 important source of energy for this process. 



Growth of Neoplastic Tissues 



The respiration of various types of tumor cells is inhibited by malonate 

 (Table 1-26) but comparisons with the appropriate normal tissues have 

 seldom been made. Amino acid uptake is also inhibited (Kit and Greenberg, 

 1951) and high-energy phosphate compounds reduced (Greaser and Schole- 

 field, 1960), but whether tumor tissue is more or less sensitive than normal 

 tissue to malonate is not known. Fishgold (1957) obtained evidence that 

 hepatoma succinate oxidase is inhibited more readily than the enzyme from 

 normal mouse liver, but it is not certain if this is a true difference in the 

 affinities of the dehydrogenase active center for malonate or the result of 

 other factors. Other than this, there is no demonstrated metabolic difference 

 between tumor and normal tissues with respect to inhibition by malonate. 

 The time course of the accumulation of succinate in the Flexner-Jobling 

 tumor is essentially the same as in other tissues (Fig. 1-11), but the relation- 



