Ill THE POISONING OF CHROMOSOMES 939 



{b) Antifolic acids 



These agents cause breakage of chromosomes in certain tissues of some animals. 

 In the intestinal epithelium of the mouse, various 4-aminofolic acids inhibit 

 mitosis and cause a cellular hypertrophy followed by abnormal mitoses with 

 injured chromosomes (Dustin, 1949, 1950b, 1950c). Aminopterin, a-methopterin, 

 and aminoanfol break chromosomes in abnormal normoblast mitoses in man 

 (Thiersch, 1949). Citrovorum factor administered before aminopterin to mice 

 blocks chromosomal rupture and the other observed effects of the aminopterin 

 (Dustin, 1952). Antifolic acids selectively damage intestinal epithelium, bone 

 marrow, the red pulp of spleen and spermatogenic cells, but they do not damage 

 mitoses in lymphoid tissue (Dustin, 1953). Chromosomal breakage has not been 

 reported for cells in tissue culture treated with antifolic agents. 



{c) Purines and pyrimidines 



The discovery of chromosome breakage by caffeine in onions by Kihlman and 

 Levan (1949) was followed by an extensive study of related xanthine derivatives 

 and other purines (Kihlman, 1949). The members of one group of purines, of 

 which 8-ethoxycaffeine is an example, were found to act rapidly, to be more lipoid 

 soluble, and to be able to penetrate the lipid enveloping the resting nuclei of the 

 onion root tip. The members of the other group, including caffeine and 1,3,7,9- 

 tetramethyluric acid, have a greater solubility in water and gain access to the 

 chromosomes only when mitosis exposes them (Kihlman, 195 1). In later work, 

 Kihlman (1952) found that unlike methylxanthines the ethylxanthines do not 

 break chromosomes. The "radiomimetic" activity of the purines tested is correlat- 

 ed with their solubilizing power and with their surface activity. Kihlman also 

 suggested an indirect effect by way of enzyme inhibition, perhaps involving 

 nucleotide coenzymes. 



Studies with the physiological purines and with substances more closely anal- 

 ogous to them lend this suggestion an increased interest. Adenine itself causes 

 structural chromosome changes in onion root tips (Kihlman, 1950a). With an 

 induction of abnormalities in about 20 percent of anaphase figures by concentra- 

 tions of 20 or 40 vaM, adenine is less active than 8-ethoxycaffeine, which at lovuM 

 can produce up to 75% abnormal anaphases in onion roots (Kihlman, 1950b). 



The closely related agent, 2,6-diaminopurine, breaks chromosomes in intestinal 

 mitoses and also damages lymphoid cells of the mouse (Dustin, 1950a). It is also 

 effective in mouse tissue cultures (Biesele, Berger, Clarke and Weiss, 1952). With 

 both mouse sarcoma 180 and embryonic mouse skin in cultures, the incidence of 

 chromosomal bridging and fragmentation produced by treatment with 2,6-diam- 

 inopurine lactate can be decreased by simultaneous treatment with adenine 

 sulfate. However, the chromosome-breaking proclivities of adenine are also dis- 

 played in this system, and there results an optimal relative blocking concentration 

 of adenine. If the concentration of 2,6-diaminopurine just exceeds the threshold, 

 too much as well as too little adenine makes for a higher incidence of chromosomal 

 aberrations. With higher concentrations of diaminopurine, aberrations also in- 

 crease despite maintenance of the otherwise optimal equimolar blocking ratio 

 with adenine. In mouse tissue cultures, chromosomal damage begins with about 



Literature p. 947 



