II PREPROPHASIC INHIBITION 937 



media. Aspartic acid produces chromosomal abnormalities and delays in meta- 

 phase (Kieler, 1953c). Methionine and tryptophan also stimulate cell division, but 

 not cystine and proline. 



The presence of an effective amino acid analogue may be equivalent to a de- 

 ficiency of the corresponding normal amino acid and prevent the incorporation 

 of the latter into protein and of other amino acids as well (Halvorson and Spiegel- 

 man, 1952). Francis and Winnick (1953) observed that fluorophenyl alanines, 

 P-3-thienylalanine, and ethionine inhibit protein synthesis, nucleic acid synthesis, 

 and growth in cultures of chick heart cells. The syntheses of protein and the corre- 

 sponding ribonucleic acid may be closely related. In pea extracts (Webster, 1956), 

 amino acid antagonists inhibit ribonucleic acid formation as well as protein syn- 

 thesis, and nucleic acid antimetabolites also inhibit protein synthesis. It is of 

 interest that the more active analogues of physiological amino acids studied in 

 tissue culture by Biesele and Jacquez (1954) produce mitotic aberrations similar 

 to those caused by some purines. In cultures of mouse sarcoma T241 and newborn 

 mouse heart cells, [3-(/)-fluorophenyl)-DL-alanine at i.o mA/ for 24 h. completely 

 suppresses mitosis, but 0.25 mM permits a few cell divisions. The inhibition is 

 partly reversed by l- phenylalanine. In cultures of mouse sarcoma 180 and mouse 

 embryo skin, mitotic inhibitions greater than 50 percent are caused by 0.5 mM 

 of^the para isomer of fluorophenylalanine, by i.o mA/of the ortho, and by 2.0 mM 

 of the meta isomer. 



III. THE POISONING OF CHROMOSOMES 



Among the antimetabolites that hinder the syntheses necessary to permit a cell 

 to enter mitosis are some whose adverse effect is also expressed in damage to the 

 chromosomes of cells that do manage to divide. Perhaps the chromosomal damage 

 is mediated by errors in reduplication of nucleoprotein. 



Although the structure of chromosomes is not fully understood, it is known that 

 they contain, in addition to deoxyribonucleic acids, their quota of ribonucleic 

 acids, histones or protamines, and more complex proteins. The last vary in 

 amount in accordance with metabolic activity (Mirsky, 1947). It is perhaps im- 

 possible to assign a primary role in chromosome structure to any one component 

 (Kaufmann, McDonald and Bernstein, 1955), although histone is less important 

 than the combination of DNA and residual protein, which may include RNA, in 

 maintaining morphological integrity of isolated chromosomes (Mirsky and Ris, 

 1 951). It is therefore perhaps incorrect to ascribe all chromosome breaks and other 

 aberrations to a primary effect on the integrity or reproduction of DNA alone. 



Thus the production of "stickiness" in chromosomes by treatment with ribo- 

 nuclease (Kavifmann and Das, 1954), which has been compared to the primary 

 effects of radiation (Kaufmann, McDonald and Bernstein, 1955), may result 

 from a dissociation of nucleoprotein by the ribonuclease. Chromosomal "stickiness" 

 may occur "spontaneously" (D'Amato, 1948), as in mitotic cells near the necrotic 

 center of tumors, whose chromosomes probably agglutinate because of toxic 

 materials liberated by dying cells (Koller, 1949). Some tissue extracts have 



Lileralure p. 9^7 



