520 5. QUINONES 



ANTIMITOTIC ACTIONS 



Despite the fact that the quinones have long been known to inhibit the 

 growth of various microorganisms, invertebrates, and plants, direct demon- 

 stration of a true antimitotic action was first made by Lehmann in 1942. 

 Since that time the principal streams of work may be designated as follows: 

 Lehmann and his collaborators at Bern from 1942 to 1949 using Tuhifex 

 eggs: Meier and his collaborators at Basel from 1945 to 1947 using tissue 

 cultures; the Cambridge school of Mitchell, Friedmann, Simon-Reuss, 

 Hughes, and others from 1947 to 1956 using fibroblasts and tumor cells; 

 Parmentier and Dustin at Brussels from 1948 to 1953 on in vivo antimitotic 

 effects; and Druckrey and his colleagues at Freiburg from 1952 to 1954 

 using sea urchin eggs. By antimitotic action is meant at least a partially 

 selective inhibition or blockade of some step in the mitotic cycle without 

 simultaneously killing the cells or obviously damaging them. Many quinones 

 undoubtedly have an antimitotic effect in this sense, and this selective 

 toxicity on dividing cells has stimulated interest in the quinones as of 

 possible clinical value in the suppression of tumors. Thus the most com- 

 prehensive, quantitative, and interesting data we have on the quinones 

 relate to their antimitotic activity. We shall see that the basis for this ac- 

 tivity has been postulated to be an action on metabolic systems, but the 

 mechanisms involved are debatable. 



Inhibition of Egg Cleavage 



Lehmann introduced the eggs of the fresh-water oligochaete Tuhifex as 

 an experimental object in 1942, and in succeeding reports (Lehmann, 

 1945, 1947, 1949; Lehmann and Hadorn, 1946; Lehmann and Bretscher, 

 1951) has shown their cleavage to be very sensitive to many quinones, the 

 effect being selective in that no gross nuclear damage can be observed. 

 This action was analyzed and compared with the actions of other antimi- 

 totic agents in a thorough manner, and we shall attempt to present the sa- 

 lient features of this work. 



The effects exerted by the quinones can usually be classified into three 

 categories depending on the concentration and the total time of exposure. 

 In the lowest concentration range, cleavage is not inhibited but develop- 

 ment is disturbed so that abnormal blastulas are formed; at somewhat 

 higher concentrations, cleavage itself is blocked; and finally, at still higher 

 concentrations, damage to the cells occurs as shown by cytolysis. It is 

 true that cytolysis does not occur at very high concentrations, the eggs 

 being presumably killed in a fixed or gel state, but this is far above the an- 

 timitotic range in which we are interested. These changes are plotted in 

 Fig. 5-6 for p-benzoquinone; initially there is a rapid drop in normal em- 

 bryos, with a simultaneous rise in defective blastulas; it is only after this 



