376 GEORGE BOSWORTH BROWN AND PAUL M. ROLL 



the agent and the increased synthesis. Nevertheless, a number of experi- 

 ments have been reported in which experimentally created conditions have 

 resulted in alterations of a "normal" pattern of nucleic acid synthesis. 



Two methods have been used most frequently to assay the effect of an 

 agent upon the biosynthesis of nucleic acids. In one the differences between 

 the amounts of nucleic acids in the tissues of experimental and control 

 animals are determined. In some investigations the amounts of nucleic acid 

 per unit weight of tissue are determined, but such changes are not neces- 

 sarily a sufficient indication of a modification of nucleic acid synthesis since 

 they can arise from an alteration in amounts of the other cellular constit- 

 uents alone. A change in the nucleic acid content per cell is a much more 

 reliable indication of an alteration of nucleic acid synthesis. On the basis of 

 the widely accepted hypothesis of a constant DNA content per nucleus 

 (Chapter 19), an observation of an altered PNArDNA ratio is a good in- 

 dication of a change in PNA synthesis. In the other method differences in 

 the extent of incorporation of labeled compounds into the nucleic acids of 

 experimental and control animals are determined. If a difference is ob- 

 served, it can be assumed that the agent had an effect, either direct or in- 

 direct, upon nucleic acid biosynthesis. 



1. Role of Vitamins 

 a. Folic Acid 



It has been demonstrated in a number of microorganisms that folic acid 

 and p-aminobenzoic acid are involved in the introduction of carbons 2 and 

 8 in the purines and the methyl group of thymine*" (Chapter 23). In mam- 

 mals, folic acid is one of the few agents which has been demonstrated to 

 have a specific function in nucleic acid synthesis. Drysdale et al}"^ found, in 

 rats made deficient in folic acid by means of a diet containing succinylsul- 

 fathiazole, that there was a considerably lower incorporation of formate-C*^ 

 into the purines of liver nucleic acid than into the corresponding purines of 

 rats made deficient and then treated with folic acid. No difference was ob- 

 served in the extent of incorporation of formate into the purines of the re- 

 maining viscera in the deficient and the treated animals. 



Skipper et alP^ found that, following the treatment of mice with either 

 of the fohc acid antagonists, aminopterin or A-methopterin, there was a 

 14-fold decrease in incorporation of formate-C'^ into the visceral nucleic 

 acids but only a 0.25-fold decrease of incorporation into the total visceral 

 homogenate, which indicates that the inhibitors were definitely affecting 



1" W. Shive, Vitamins and Hormones 9, 75 (1951). 



138 H. E. Skipper, J. H. Mitchell, Jr., and L. L. Bennett, Jr., Cancer Research 10, 510 

 (1950). 



