EFFECTS ON MITOSIS, GROWTH, DIFFERENTIATION 969 



restrict growth of mammalian cells in culture, higher concentrations usually 

 killing the cells directly'. If the mechanism of this growth inhibition is to be 

 elucidated and correlated with metabolic alterations, it will be necessary 

 to work within this range if the conclusions are to be valid. 



Some General Aspects of the Effects of Mercurials on Mitosis and Growth 



A few general comments on the localization of the sites of growth inhi- 

 bition were made on page 1-531 and reference to these will make it evident 

 that at the present time we have little hope of explaining the actions of the 

 mercurials. Essentially nothing is known of the possible effects of mer- 

 curials on protein, nucleic acid, or coenzyme synthesis, or whether the 

 demonstrated inhibitions of active transport are in any way related to the 

 growth depression. We have seen that respiration is not significantly de- 

 pressed during growth inhibition in the few instances in which it has been 

 determined; however, in view of the rather potent inhibition of the cycle, 

 it would be worthwhile to pursue this question further. Mercurials are not 

 efficient uncoupling agents and could scarcely act in this way. The signifi- 

 cance as a possible metabolic mechanism of mercurial action of the obser- 

 vation by Hirashima (1935), that glucose reduces the toxicity of Hg++ for 

 fibroblast cultures, cannot be evaluated. 



A direct action on the sol-gel transformations and protoplasmic move- 

 ments during furrowing, spindle formation, and cleavage has been postulat- 

 ed and discussed briefly in previous sections. Mazia (1959) believes that the 

 mitotic apparatus may be an S — S bonded structure because of the ability 

 of agents splitting S — S bonds to dissolve the structure, and states that 

 p-MB and mersalyl bring about the dissolution of the freshly isolated spindle. 

 The question is whether such an action can be exerted at the concentrations 

 occurring within cells during mitotic inhibition. We have also mentioned 

 that several workers favor a nuclear site for the mercurials but that the 

 evidence is insufficient, as is that of Meyer (1960), who showed that the 

 conidia of Fusarium decemcellnlare incubated with 0.037 mM Hg++ accu- 

 mulate mercury in some form either on or within the nucleus, since there 

 is no necessary correlation between relative intracellular concentrations and 

 the site of action. It is worth noting that p-MB interferes with the synthesis 

 of RNA from nucleosides, as determined by the uptake of cytidine into the 

 nuclear RNA of HeLa cells, and an inhibition of the RNA polymerase was 

 suggested (Srinivasan ct al., 1964). HeLa cells are blocked in metaphase by 

 0.02 mM 7)-MB. In connection with the selective accumulation of mercurials, 

 it is worth noting that merbromin appears to be localized in tumor tissues 

 of both mouse and man, as indicated by fluorescence several days after 

 initiation of intravenous or oral administration (Katsuya et al., 1963). Al- 

 though kidney exhibits the highest concentration of mercurial initially, it 

 and other normal tissues lose the merbromin much faster than tumors. It is 



