Chapter 13 



ACTION OF CERTAIN ANTIMETABOLITES 

 AS MITOTIC POISONS 



by John J. Biesele 



I. INTRODUCTION 



Many substances deleterious to living systems injure cell division. When this 

 effect is especially evident, the agent is commonly labeled a "mitotic poison". 

 Efforts have been made to maintain the usefulness of this term by restricting its 

 application to substances acting specifically on dividing cells (Eigsti and Dustin, 

 ^955)5 to agents interrupting mitosis in concentrations without visible effect on 

 interphasic cells (Hughes, 1952a), to agents effective against mitosis by direct 

 action as demonstrated in vitro (Lettre, 1952), and to substances that make mitosis 

 abnormal without killing the cell (Cornman, 1954). 



However, almost any substance may influence cell division in some manner 

 under appropriate conditions (Ludford, 1953). Cell division depends on an inte- 

 gration of many orderly processes and is consequently sensitive to a wide variety 

 of substances, which may include not only foreign material but also certain 

 materials native to the cell's metabolism when present in abnormal concentrations. 

 A substance that influences a cell adversely may also interfere in some sense with 

 the reproduction of the cell. This may occur through a number of different mecha- 

 nisms. Specificity must be borne in mind, and it is not too unusual to find that a 

 substance that poisons mitosis for one cell type does not necessarily exert the same 

 effect on another cell type. Ludford (1953) preferred that a "mitotic poisoning 

 action" be attributed to a substance only with conditions and biological test system 

 specified and the form of effect described. A relative specificity is evident with 

 certain antimetabolites, which in some respects exert mitotic poisoning actions, 

 and it is the fact of their selective activity that is one basis for hope in experimental 

 cancer chemotherapy (Rhoads, 1954). 



It is the purpose of this chapter to discuss the effects on mitosis of structural 

 analogues of normal metabolites. To some extent antimetabolite actions become 

 more intelligible in the light of the activities on mitosis of excesses or deficiencies 

 of normal metabolites. The following sections consider mitotic poisoning actions 

 that (i) are initiated before visible mitosis begins, (2) are expressed in damage 

 to chromosomes, or (3) result in inhibition of spindle formation or function. 



