ANTIMITOTIC ACTIONS 527 



Inhibition of Mitosis in Tissue Cultures 



The numerous reports of the Cambridge group represent perhaps the 

 most thorough investigation of any aspect of quinone action, and the 

 appHcation of these findings to cancer therapy has begun (see page 541). 

 On the basis of the work of Lehmann on Tuhifex eggs, Mitchell in 1946 

 began a study of the effects of menadione on chick fibroblast mitosis 

 Initially he used menadiol-diP because it is water-soluble and felt the action 

 might be more selective if the active groups were blocked and released 

 later within the cells. Exposure of the cultures to menadiol-diP for 24 hr 

 leads to inhibition of mitosis (see accompanying tabulation) (Mitchell and 



Simon-Eeuss, 1947). However, it was soon found (Friedmann et al., 1948 a) 

 that 1,4-naphthohydroquinone-diP is much more potent, being approxi- 

 mately 1000 times more active than the methyl derivative, and has an ef- 

 fective threshold concentration of 0.0000005 mM. Mitosis is almost com- 

 pletely blocked at 0.0005 mM. No toxic effects are seen at 0.000001 mM 

 but at 0.00001 mM there are some vacuolized and exploded cells. Exten- 

 sive comparisons of the actions of various quinones were made later and 

 some of the results are summarized in Table 5-7. Before considering the 

 relationships between structure and activity, it will be necessary to discuss 

 some of the cytological changes induced by these agents since there are 

 some qualitative differences in their actions. 



Mitotic inhibition by the quinones may or may not be associated with 

 disturbances in the phase distribution, abnormal mitoses (clumping of 

 chromosomes at metaphase, anaphase bridges, and chromosomal frag- 

 mentation and deletions), and toxicity to the cells (cytoplasmic bubbling, 

 enlargement, and rounding up), and quite certainly more than a single 

 mechanism of action is involved. Menadiol-diP, for example, first causes 

 temporary cell enlargement, this occurring within 2 min at 0.005 mM, and 

 cytoplasmic bubbling accompanied by swelling of mitochondria and nuclei 

 (Mitchell and Simon-Reuss, 1952 b). These changes reach a maximum at 

 20 min and then disappear slowly. Mitotic inhibition is obvious after 80 min 

 and persists for 24-36 hr, the commonest abnormality being a clumping 



