946 ANTIMETABOLITES AS MITOTIC POISONS I3 



V. CONCLUSION 



This review has emphasized the mitotic poisoning effects of agents presumably 

 acting on the nucleic acids and nucleoproteins of the chromosomes on one hand, 

 and on the proteins and nucleoproteins of the mitotic apparatus on the other. 

 Many substances which are known to be antimetabolites or which are structurally 

 analogous to precursors of nucleotides, nucleic acids, or proteins may be said to 

 possess a mitotic poisoning action in that they prevent, delay, or disrupt the divi- 

 sions of cells that would otherwise proliferate unimpeded. Various of these anti- 

 metabolites and related compounds poison the several stages of mitosis and pro- 

 duce morphological aberrations in manners reminiscent of the actions of the 

 several groups of better-known, classical mitotic poisons. 



Events in cellular life leading to proliferation and continuing through mitosis 

 may be considered to be complex sets of interlocking phenomena, delicately 

 regulated and easily upset. The presence of an antimetabolite is in some respects 

 equivalent to absence or deficiency of the corresponding metabolite. An antimeta- 

 bolite may not merely inhibit some synthesis, but it may also be incorporated into 

 consequently defective products, whose failure to function properly may be ex- 

 pressed in mitotic inhibitions or aberrations. 



Mitotic poisons may be exogenous or endogenous for given cells. Analysis of 

 the mitotic poisoning action of introduced antimetabolites may provide clues 

 to the normal control of cell division in individual cells and in multicellular or- 

 ganisms. Endogenous mitotic poisons, products of the cell's own metabolism, may 

 include spontaneous mutagens and chromosome-breaking agents (D'Amato and 

 Hoffmann-Ostenhof, 1956) such as putrescine (Marquardt, 1949) or a purine 

 (Kihlman, 1950a; Novick, 1956). 



For use in experimental cancer chemotherapy, antimetabolites possess one 

 possible advantage over the classical mitotic poisons. In particular with anti- 

 nucleic acid antimetabolites, the heterogeneity of nucleic acid anabolism (Ben- 

 dich, 1952) makes it likely that diiferential effects on various cell types may be 

 achieved. Mitotic poisoning action could be used as an indicator of inhibitory 

 effect. A few amino acid analogues evince similar promise. The most useful to 

 date, however, such as azaserine, probably act through their interference in nu- 

 cleic acid metabolism. 



