II ANTIMETABOLITES AS MITOTIC POISONS 927 



II. PREPROPHASIC INHIBITION 



•Certain syntheses must occur before the visible mitotic stages in order to prepare 

 a cell for its division into two viable daughter cells. Poisons that interfere with 

 mitosis by acting during the period of essential synthesis before the prophase are 

 known as preprophase poisons (D'Amato, 1949a, 1949b). The sensitive period 

 before prophase has also been termed the antephase; poisons acting then need not 

 interfere with mitoses already in progress (Bullough and Johnson, 195 1). 



Of the greatest importance for the mitosis itself and for the daughter cells is 

 the reproduction of the hereditary material, which appears to be either deoxy- 

 ribonucleic acid or deoxyribonucleoproteins. It is now established that the repro- 

 duction of the hereditary material in ordinary somatic cells occurs during inter- 

 phase and not during any strictly mitotic phase. This conclusion has been reached 

 by means of a number of complementary techniques, including photometric deter- 

 mination of the amount of stain combined with nucleus or chromosomes after the 

 Fevdgen nucleal reaction (Alfert, 1950; Seshachar, 1950; Patau and Swift, 1953; 

 Roels, 1954), studies of ultraviolet absorption (Walker and Yates, 1952; Walker, 

 1953; Davies, Deeley, Richards and Walker, 1954; Richards, Walker and Deeley, 

 1956), and radioautographic determination of the uptake of ^^P (Howard and 

 Pelc, 1 951; Howard and Pelc, 1953; Marshak, 1955) or of ^"^C-labeled thymidine 

 into DNA (Plant and Mazia, 1956). 



Chromosomal histone is also doubled when DNA is synthesized before cell 

 division (Bloch and Godman, 1955; Alfert, 1955). This finding is related to that 

 made by Vendrely ( 1 954) of a constant relation between the amounts of arginine 

 and DNA in nuclei of a number of animal species. Inorganic radiosulfur is incor- 

 porated into chromosomes, probably into their proteins, at about the same time 

 before division as phosphorus is taken up into new DNA (Pelc and Howard, 1952). 

 It may be necessary that histone or other protein be reproduced in order to per- 

 mit reduplication of the DNA, for it has been suggested (Friedrich-Freksa, 1940; 

 Kacser, 1956; Mazia, 1956) that protein intervenes as a mold in the synthesis of 

 each strand of DNA. Perhaps other materials must also be synthesized in prepara- 

 tion for cell division. The lipid content of rapidly growing cells, for example, may 

 be high, in agreement with their nucleotide content (Berg, 195 1). 



Although the reduplication of all the chromosomal constituents appears to be 

 essential to cell division, it still may not be sufficient. Perhaps the old and the new 

 strands of DNA or nucleoprotein must be separated by an uncoiling process 

 (Schwartz, 1955). It seems that synthesis of DNA is not alone sufficient to trigger 

 cell division (Moses and Taylor, 1955; Mazia, 1956). Nevertheless, the metabolic 

 processes which Potter (1956) sees as the prerequisites of mitosis are: the formation 

 of thymine and 5-methylcytosine by methylation of the pyrimidine ring, as well as 

 the formation of deoxyribotides by a reductive process. 



Some of the syntheses preparatory to cell division make use of energy derived 

 from carbohydrate metabolism. This is obligatorily aerobic respiration for some 

 cells, such as those of mouse ear epidermis (Bullough, 1952). Some eggs require 

 oxygen for cleavage, while others can act as facultative anaerobes (Brachet, 1947). 

 In general, the metabolism may be partly aerobic and partly anaerobic (Boy- 



JLiterature p. 9^7 



