936 ANTIMETABOLITES AS MITOTIC POISONS 13 



purines and sometimes display a different selectivity of action against different 

 cell types (Biesele, 1957). The ribofuranosyl derivative of 6-chloropurine has 

 much the same pattern of relative inhibition of mitosis in sarcoma 180 cells and 

 the fibroblasts and epithelial cells of mouse skin as the free purine. The ribofur- 

 anosyl derivative of 6-methylpurine is even more inhibitory than the very toxic 

 free base, and the sensitivity of fibroblasts is increased to equal that of the sarcoma 

 180 cells. 6-Furfurylamino-9-[3-D-ribofuranosylpurine is hundreds of times more 

 inhibitory than its free base, kinetin, and especially so to fibroblasts. A similar 

 effect is seen with the ribofuranosyl derivative of 6-methylmercaptopurine. 



In general, purine nucleosides are not as effective precursors of nucleic acid 

 as are the free purines or their nucleotides, but the reverse is often true for pyrimid- 

 ine nucleosides compared with the free pyrimidines [cf. Schlenk, 1955). Conse- 

 quently, the nucleosides of abnormal pyrimidines are better antimetabolites than 

 the free bases (Visser, 1955). In mouse tissue cultures, pyrimidine nucleosides are 

 more likely to exhibit activity than are the pyrimidines themselves (Biesele, 

 unpublished). With some, such as 5-bromocytidine, a differential mitotic suppres- 

 sion occurs in mouse embryo skin cells rather than in sarcoma 180 cultures. 



The four nucleosides of ribonucleic acid inhibit growth in vitro of Trichomonas 

 vaginalis, apparently by acting as antimetabolites against the free bases and the 

 ribonucleotides. In a sense, the ribonucleosides act as metabolic regulators of cell 

 division in this organism (Sprince, Goldberg, Kucker and Lowy, 1953). In other 

 cells, the nucleotides may serve this purpose. 



{e) Nucleotides 



Despite their incorporability into nucleic acids (Roll, Weinfeld and Brown, 

 1954; Brown and Roll, 1955; Goldwasser, 1955), the natural ribonucleotides 

 individually suppress growth in some systems. Adenylic acids prevent chick cells 

 in vitro from entering prophase (Hughes, 1952c). Adenylic, guanylic, and cytidylic 

 acids inhibit mitosis in the germinal epithelium of rat ovaries cultured in vitro, 

 but uridylic acid is without effect (Berrian and Dornfeld, 1950). Growth of 

 certain mouse tumors is inhibited by adenylic acid and guanylic acid and pro- 

 moted by uridylic acid, while cytidylic acid has little effect (Parsons, Gulland 

 and Barker, 1947). Perhaps these inhibitory effects are related to the upset of a 

 certain balance in availability of the nucleotides needed for orderly nucleic acid 

 synthesis. 



(/) Amino acids and analogues 



This concept of balance among precursors is seen to possess special validity for 

 the amino acids needed for protein synthesis. Kieler (1954b) has pointed out 

 not only that the necessary amino acids must be present in order to promote 

 mitotic activity in chick fibroblast cultures, but also that they should be present 

 in the correct relative concentrations. Using dialyzed medium, Kieler (1953a) 

 has found that addition of arginine, histidine, or lysine to a medium deficient in 

 that amino acid stimulates mitosis. Prophases accumulate in lysine-deficient 

 medium. Excesses of any of these three amino acids depress mitotic activity 

 (Kieler, 1953b). Glutamic and aspartic acids greatly stimulate mitosis in deficient 



