II PREPROPHASIC INHIBITION 93 1 



adenine (Hultgren, Kihlman and Fries, 1955) ; antagonism of caffeine by means 

 of tryptophan, aniline, or procaine suggests that caffeine does not necessarily 

 inhibit by competing for purine-specific enzymes. 



Benzimidazole is also conventionally regarded as an antagonist of adenine 

 (Woolley, 1952). Benzimidazole at 300 ppm inhibits mitosis in onion roots, not 

 only preventing nuclei with doubled DNA from entering mitosis but also prevent- 

 ing new DNA synthesis in younger nuclei. These inhibitions can be blocked for 

 some hours with 800 ppni adenine sulfate (Duncan and Woods, 1953). However, 

 Slonimski (1954) concluded that the reversal by salts of adenine or guanine of the 

 benzimidazole-induced inhibition of yeast growth results from a lowering of the 

 pH and consequent movement of benzimidazole from the cells into the medium. 



8-Azaguanine furnishes an example of a more specific relation between physio- 

 logical purine (guanine) and antagonist (Kidder and Dewey, 1949). 8-Azaguanine 

 specifically inhibits entry into mitosis of cells of the Brown-Pearce tumor in rabbits 

 but does not affect mitosis in jejunal crypts and testes (Shapiro, Weiss and Gell- 

 horn, 1950). In the mouse, 8-azaguanine restricts mitotic rates in carcinomas 755 

 and EO771 but not in the tumors C954, C1300, Si 80, and S91, nor in the jejunum, 

 ileum, or testis (Woodside, Kidder, Dewey, and Parks, 1953). The differential 

 susceptibility of various tumors to 8-azaguanine inhibition is inversely related to 

 their ability to deaminate 8-azaguanine to noninhibitory 8-azaxanthine (Hirsch- 

 berg, Kream and Gellhorn, 1952). Tumor EO771 gives anomalous results. 



8-Azaguanine may inhibit because of its incorporation into ribonucleic acid 

 (Kidder, Dewey, Parks and Woodside, 1949). However, more azaguanine was 

 found to be incorporated into visceral RNA than into tumor RNA (Mitchell, 

 Skipper and Bennett, 1 950) . No solution to this dilemma was seen by Parks ( 1 950) . 

 Nevertheless, RNA of the susceptible mouse leukemia L1210 incorporates 8- 

 azaguanine-2-^'*C at 100 times the rate of its incorporation into RNA of the 

 derivative azaguanine-dependent leukemia (Bennett, Skipper and Law, 1953). 



The incorporation of 8-azaguanine probably makes RNA defective. Mandel 

 (1955) considered the action of 8-azaguanine as an antimetabolite to lie at the 

 polynucleotide level rather than at the free purine level. 8-Azaguanine seems to 

 occupy positions in tobacco mosaic virus normally held by guanine (Matthews, 

 1954). 8-Azaguanylic acid can be recovered from the RNA of such virus (Mat- 

 thews, 1953) much as thiouridylic acid can be recovered from TMV grown in the 

 presence of thiouracil (Jeener and Rosseels, 1953). W^hen one-fifth of the RNA 

 uracil in Bacillus megatherium is replaced with thiouracil, the growth rate changes 

 from exponential to linear (Hamers, 1956). Incorporation may well proceed by 

 way of the riboside of thiouracil, which Strominger and Friedkin (1954) made 

 with the aid of phosphorylase. This and a similarly catalyzed reaction between 

 8-azaguanine and ribose-i -phosphate or deoxyribose-i -phosphate (Friedkin, 

 1954) supported the suggestion made by Kalckar (1953) that unnatural purines 

 and pyrimidines might trap ribose or deoxyribose. 



It is the fate of 8-azaguanine to be incorporated into the ribonucleic acids of 

 various microorganisms and animal tissues but not into their deoxyribonucleic 

 acids (Lasnitzki, Matthews and Smith, 1954). These avithors pointed out that a 

 defective bonding between 8-azaguanine and cytosine might be expected in RNA, 



Literature p. Q4y 



