420 Colchicine 



contraction, the role of ATP is well known. Observations of colchi- 

 cine synergists and theoretical considerations led Lettre to suppose 

 that ATP may also be indispensable for spindle contraction and 

 mitosis, and that colchicine acted on the cell by modifying this 

 mechanism. •^'•* 



Experiments in vitro demonstrated that strong concentrations of 

 colchicine inhibited the viscosity fall of complexes of actomyosin and 

 ATP.'" It was further observed that ATP-ase w^as inhibited by col- 

 chicine at concentrations of lO-^ and 10^ M. However, more dilute 

 solutions (lO-'^Af), which arrested mitosis, did not affect the en- 

 zyme. "^^ 



A direct antagonist action of ATP and colchicine was difficult to 

 j^rove, because of the rapid destruction of ATP in fibroblast cultures. 

 Only with very small doses of colchicine was such an antagonism 

 visible. Cultures were grown for 24 hours, and then colchicine, at a 

 concentration of 0.04 mg/ml was added. *58 This arrested, after 24 

 hours, 55 per cent of the cells in mitosis. When 1 mg/ml of ATP was 

 added at the same time, mitotic inhibition did not start until four 

 horns later. The results are given in Table 17.5. It is concluded that 

 the higher the amount of ATP in a cell, the smaller the action of 

 colchicine, and vice versa.*''-' 



ATP may play an important part in the conservation of cell form 

 in cultured fibroblasts. The "resting" cells have been considered to 

 be in a condition of permanent contraction, while cells intoxicated 

 with various drugs, such as Victoria blue, have a lower content in 

 ATP, and display a rounded form with rapidly moving surface blebs. 

 If ATP is added to a fibroblast culture, the cells assume a spindle 

 shape, even when dividing. In this condition, ATP would provide 

 the energy necessary for this contraction, and would also protect the 

 sj)indle against mitotic poisons. ^'^ 



This hypothesis is only a tentative one, and it is not yet proven 

 that colchicine acts by depressing ATP in the cells. Further experi- 

 ments will be needed to explain the relation between cellular respira- 

 tion and the formation of the spindle fibers, and also between ATP 

 and the physiology of the spindle. It is apparent that more funda- 

 mental knowledge about the dynamics of mitosis is needed before the 

 effect of colchicine and its various synergists may become clear. While 

 these effects are still difficult to understand, there is no doubt that 

 the discovery of the colchicine-mitosis has provided a considerable 

 impetus to such fundamental studies. 



17.6: Conclusion: the Singularity of Colchicine 



From this chapter it has been made evident that destruction of 

 the fibrillar properties of the spindle, and mitosis arrest at metaphase 



