50(3 R. E. HANDSCHUMACHER AND A. D. WELCH 



metabolism of this analog to the corresponding uridine ribonucleotides 

 could be demonstrated. 398 Like orotic acid, fluoroorotic acid is relatively 

 immune to catabolic attack in mammalian systems; however, a small 

 amount of what appears to be 2-fluoro-3-ureidosuccinic acid was excreted 

 in the urine following injection of fluoroorotic acid-2-C 14 . 392 Fluoroorotic is 

 reduced at a faster rate than orotic acid by dihydroorotic acid dehydro- 

 genase isolated from Zymobacter oroticum. 399 



Although 5-fluorocytosine has relatively little biological activity, fluoro- 

 cytidine and fluorodeoxycytidine 400 have been shown to reduce the rate of 

 growth of experimental tumors. 395 ' 401402 Studies in vitro with Ehrlich 

 ascites tumor cells indicate that fluorocytidine does not appear to act pri- 

 marily as an inhibitor of incorporation of pyrimidines into nucleic acid 

 cytosine; rather, a predominant effect on the incorporation of uracil or 

 cytidine into the thymine of DNA is indicated. 374 Such a result suggests 

 that fluorocytosine functions primarily through deamination to the cor- 

 responding uracil derivative; this reaction could occur after conversion to 

 a deoxyribose derivative, since a very active deoxycytidylic acid deaminase 

 has been demonstrated in certain neoplastic and normal tissues. 403 



2. Other Halogenated Pyrimidines 



The members of this group of pyrimidines, in which the hydrogen in 

 position 5 is replaced by chlorine, bromine, or iodine, may be considered 

 primarily as analogs of thymine. Their synthesis was accomplished by the 

 direct halogenation of uracil or its corresponding ribonucleoside or deoxy- 

 ribonucleoside; however, preparation of the corresponding derivatives of 

 the cytosine nucleosides required photocatalysis of the reaction. 



The inhibitory nature of chloro-, bromo-, and iodouracil was first demon- 

 strated with L. casei, the growth of which was limited by the supply of 

 thymine. 404 In this first report, the stimulatory nature of these compounds 

 on growth under certain conditions was also noted, an observation which 

 has since been of considerable theoretical interest; confirmation of this 

 result has been obtained in other bacterial systems with bromouracil. 239, 



398 R. E. Parks, Jr., J. L. Way, J. L. Dahl, Proc. Am. Assoc. Cancer Research 2, 333 

 (1958). 



399 H. C. Friedman and B. Vennesland, J. Biol. Chem. 233, 1398 (1958). 



400 J. J. Fox, I. Wempen, and R. Duschinsky, Abstr. 4th Intern. Congr. Biochem., 

 Vienna p. 6 (1958). 



401 J. H. Burchenal, E. A. D. Holmberg, and J. J. Fox, Abstr. 4th Intern. Congr. 

 Biochem. , Vienna p. 185 (1958). 



402 M. L. Eidinoff, M. A. Rich, and A. G. Perez, Proc. Am. Assoc. Cancer Research 3, 

 18 (1959). 



403 F. Maley and G. F. Maley, Federation Proc. 18, 280 (1959). 



404 G. H. Hitchings, E. A. Falco, and M. B. Sherwood, Science 102, 251 (1945). 



