Mechanism of Colchicine-Mitosis 415 



tures at a concentration of 0.1 mg/ml, and the antifolic drug-, niiiino- 

 pterin (^-amijiopteroylglutamic acid) arrests mitoses in tissue cul- 

 ture.-^2 Tfhis is a remarkable fact, for this antimetabolite when in- 

 jected into mice, behaves as a strong and typical poison of the "radio- 

 mimetic" tvpe, inducing chromosome breakages.'''^ 



77.^-7; Colchicine compared witJi other spindle poisons. The 

 spindle structure, which can be destroyed by purely physical means, 

 is evidently adversely influenced by a series of substances which appear 

 to act through their chemical reactivity. Arsenic, the heavy metals 

 (mercur\ and cadmium) , and the sulfhydryl poisons of the iodoacet- 

 amide type indicate that -SH groups may play an important role in 

 metaphase dynamics. Some more complex substances, such as the 

 antibiotic patulin, and protoanemonin, may owe their antimitotic 

 properties to the lactone structure, and perhaps also to interference 

 with sulfhydryl. Podophyllotoxin may possibly belong to the same 

 group, but the difficulties of understanding clearly the action of such 

 complex molecules are formidable. There is no indication that colchi- 

 cine may fit in this type of chemical theory, though the facts gathered 

 by the protagonists of the "narcosis" hypothesis, as well as the study 

 of colchicine derivatives, point towards a chemical combination of 

 the alkaloid ^vith some intracellular receptor. 



The comparison of colchicine with other spindle poisons makes 

 clear t^\'o facts: the great amount of work which is still necessary to 

 understand the action of this drug, and the notable specificity of 

 colchicine. For, if several chemicals have been quoted as acting 

 similarly, fe^v have been capable of inducing polyploidy, and still 

 none has pro\ed comparable in the practical work on polyploidy in 

 plants. The extraordinary fact is the great efficiency and activity of 

 colchicine, which will lemain active when highly diluted, but con- 

 centrated solutions of which will not kill the cells. This points to 

 some singular relation between the alkaloid and the spindle. 



Further research about the biological activity of the tropolone 

 compounds should help to understand better the chemical action of 

 colchicine in the cell. Thus far, it has not been possible to "simplify" 

 the molecule and obtain spindle poisoning. The few^ reports on trop- 

 olone derivatives indicate some action on mitosis, in Tradescantia 

 staminal hair cells, far weaker than colchicine. ^-^ The necessity for 

 such a complex molecule to achieve with the utmost efficiency what 

 can be done by such simple agents as cold, arsenic, and ethylcarbyl- 

 amine, is most puzzling. The solution of this problem should bring 

 some important new insight on the submicroscopic and (hemical 

 mechanics of mitosis. 



Often the mechanism of thug adivity has been solved when a 

 proper antagonist could be found, for instance p-aminobenzoic acid 



