ANTIMITOTIC ACTIONS 529 



of the chromosomes with some fragmentation, but no anaphase bridges 

 are evident. Mitoses can be inhibited without marked mitotic abnormalities 

 at the proper concentration. Some compounds, such as 2-bromo-l,4-naph- 

 thohydroquinone-diP, 2,3-dicarboxyl-l,4-naphthohydroquinone-diP, or tri- 

 methyl-p-QHo-diP, are quite toxic to resting cells whereas other compounds 

 show a much more selective action on cells in mitosis. Some compounds 

 seem to alter phase distribution markedly so that, in one case, there is an 

 acumulation of metaphase cells; others do not alter this pattern and in- 

 stead prevent entrance into mitosis. As in eggs, some compounds act more 

 on cytoplasmic and others on nuclear processes. The three principal types 

 of action with respect to fibroblast division are: (1) blockade of entry into 

 mitosis, (2) metaphase arrest with spindle abnormalities, and (3) chromo- 

 somal breakage and clumping. An interesting point, as yet unsettled, is 

 the possible role of cell edema in causing the alterations in spindle and chro- 

 mosome structure and behavior. That is, do the quinones act directly 

 on the mitotic apparatus or indirectly affect it through disturbances in 

 cell permeability, active transport, and water balance? It may perhaps be 

 important to remember that 2,4-dinitrophenol at 0.005 mM produces cell 

 swelling, clumped metaphases, and chromosomal fragmentation, so that 

 an interference with the energy metabolism of the fibroblasts can bring 

 about many of the changes seen with the quinones. 



It is difficult to discuss structure-action relations in view of the different 

 types of action, and the following general remarks must be taken as being 

 only tentative. 



(A) Phosphorylation. The phosphorylated compounds are usually 2-5 

 times more potent antimitotically than the corresponding hydroquinones. 

 The reason for this is unknown. If the phosphates are hydrolyzed in the 

 cell by phosphatases to the active compounds, one would not expect the 

 phosphates to be more potent unless penetration into the cells is facilitated. 

 There are no data on relative penetration rates, but one would expect the 

 phosphates to enter the cells less readily, due to the introduction of negative 

 charges onto the molecules. The question as to whether the phosphates 

 can act directly cannot be answered because no work has been done with 

 isolated systems and under conditions in which the phosphates are assuredly 

 stable. The suggestion by Mitchell and Simon-Reuss (1952 b) that the di- 

 phosphates may react with polypeptide chains, particualry with the basic 

 amino acids such as arginine in chromosomal histones, because of a cor- 

 responding phosphate-to-phosphate distance of around 10 A, is interesting 

 but requires confirmation. If this occurs, it might interfere with the union 

 of nucleic acids to proteins. But if the phosphates are indeed active, then 

 how do the nonphosphorylated compounds act to produce similar anti- 

 mitotic effects? 



(B) Methylation. Methylation of both benzo- and naphthoquinones re- 



