39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 523 



incorporation of uracil is increased by tenfold, as compared to that seen in 

 normal liver. 554 



Results which would suggest more specific interference with nucleic acid 

 synthesis have been observed with several antimicrobial agents (in addi- 

 tion to azaserine and DON). Thus, mitomycin C, an antibiotic with car- 

 cinostatic activity, has been reported to interfere with the synthesis de novo 

 of purine nucleotides by E. cofo', 555 and, more recently, a selective inhibition 

 by this antibiotic of the formation of DNA as compared to the synthesis of 

 RNA or protein, was demonstrated in this same organism. 556 Extensive in- 

 vestigations of the mode of action of D-erythrochloramphenicol as an anti- 

 microbial agent have recently been reviewed. 557 It appears that this com- 

 pound causes the formation of an RNA which is abnormal in both physical 

 properties 558 and biological stability, 559 an effect which has been related to 

 the profound influence of this antibiotic on protein synthesis in many bac- 

 terial species. Although the L-threo-isomer of this compound is inactive as 

 an antibacterial agent, it reduced by about two-thirds the incorporation of 

 adenosine-5'-phosphate into the nucleic acids of cell suspensions of Ehrlich 

 ascites carcinoma; however, the incorporation of adenine under these same 

 conditions was unimpaired. 143 



Another pair of compounds, ethidium bromide and antrycide, which are 

 potent trypanocidal agents, exhibit apparently selective actions on the syn- 

 thesis of nucleic acids in Strigomonas oncopelti. Thus, ethidium bromide, a 

 phenanthradinium derivative, causes an almost instantaneous inhibition of 

 the production of DNA, while protein and RNA synthesis continue un- 

 changed for some time. 560 In contrast to these results, antrycide, a pyrimi- 

 dine derivative of a substituted quinoline, interferes with the production of 

 RNA, with only delayed effects on DNA synthesis. 561 More specifically, 

 antrycide prevents the utilization of preformed adenine or guanine without 

 interfering with the synthesis de novo of purines from glycine or the utiliza- 

 tion of uracil. 



The nicotinamide antimetabolite, 2-ethylamino-l ,3,4-thiadiazole, has 



564 A. Cantarow, T. L. Williams, I. Melnick, and K. E. Paschkis, Cancer Research 



18, 818 (1958). 

 555 H. C. Reilley, J. G. Capuccino, and D. M. Harrison, Proc. Am. Assoc. Cancer 



Research 2, 338 (1958). 



656 S. Shiba, A. Terawaki, T. Taguchi, J. Kawamata, Nature 183, 1056 (1959). 



657 E. F. Gale, in "The Strategy of Chemotherapy" (S. T. Cowan and E. Rowatt, 

 eds.), p. 212. Cambridge Univ. Press, London and New York, 1958. 



658 A. B. Pardee, K. Paigen, and L. S. Prestidge, Biochim. et Biophys. Acta 23, 162 

 (1957). 



559 F. C. Neidhardt and F. Gros, Biochim. et Biophys. Acta 25, 513 (1957). 



560 B. A. Newton, J. Gen. Bacteriol. 17, 718 (1957). 



561 B. A. Newton, J. Gen. Bacteriol. 19, ii (1958). 



