502 R. E. HANDSCHUMACHER AND A. D. WELCH 



ditions employed ranged from 0.5% to 6% of the normal uracil content of 

 the RNA of various tissues; as yet, however, it cannot be said with cer- 

 tainty that fluorouracil specifically replaces any particular base in the RNA. 

 In tobacco mosaic virus a much greater incorporation of fluorouracil into 

 the RNA occurs, despite a reduced rate of synthesis. In this case it can be 

 said with some certainty that up to 30 % of the uracil is replaced by fluoro- 

 uracil with retention of infectivity, despite reduced production of the 

 virus 377 ; in another laboratory, a marked decrease in the rate of prolifera- 

 tion of this virus also was noted. 378 No significant incorporation of fluoro- 

 uracil in the form of fluorocytosine has been detected in either the RNA 

 or the DNA of mammalian or bacterial cells. 



The evidence for extensive anabolism of fluorouracil to ribonucleotide 

 and deoxyribonucleotide derivatives, as well as other evidence cited below, 

 prompted a search for methods of preparing the corresponding ribonucleo- 

 side and deoxyribonucleoside. Thus, a chemical synthesis of 5-fluorouracil- 

 /3-D-ribofuranoside was devised 379 in which techniques similar to those used 

 for the preparation of thymine riboside 380 were employed. Formation of the 

 deoxyribonucleoside of fluorouracil 379 was first accomplished by transdeoxy- 

 ribosidation from thymidine with resting cell suspensions of Streptococcus 

 faecalis, as has been described 381 for the formation of azathymidine (i.e., 

 the deoxyribonucleoside of 3,5-dioxo-6-methyl-l ,2,4-triazine). The trans- 

 fer of deoxyribose from thymidine to fluorouracil by extracts of E. coli 

 resulted in a more efficient conversion and is currently employed for the 

 production of the deoxyribonucleoside. 38 ' 2 



With a few notable exceptions, the ribonucleoside and deoxyribonucleo- 

 side of fluorouracil exhibit in vivo many of the biological properties observed 

 with the parent analog. 374 ' 375383 Localization of the deoxyribonucleoside 

 in tissues showed an even greater affinity for tumor (sarcoma- 180) than 

 did fluorouracil, whereas the ribonucleoside was found in higher concen- 

 tration in various tissues other than tumor. 374 Intensive metabolic degrada- 

 tion of the deoxyribonucleoside to fluorouracil occurred in ascites cell sus- 

 pensions 374 and in bacterial systems, 382 but the ribonucleoside appeared to 

 be much more stable. 374 Comparisons of host-toxicity in mice indicate that 

 fluorouridine is considerably more toxic than fluorouracil, whereas the 



377 M. P. Gordon and M. Staehelin, /. Am. Chem. Soc. 80, 2340 (1958). 



378 C. I. Davern and J. Bonner, Biochim. et Biophys. Acta 29, 205 (1958). 



379 R. Duschinsky, E. Pleven, J. Malbica, and C. Heidelberger, Abstr. 132nd Meet- 

 ing Am. Chem. Soc, New York, p. 19C (1957). 



380 J. J. Fox, N. Yung, J. Davoll, and G. B. Brown, J. Am. Chem. Soc. 78, 2117 (1956). 



381 W. H. Prusoff, J. Biol. Chem. 215, 809 (1955). 



382 S. S. Cohen, J. G. Flaks, H. D. Barner, M. R. Loeb, and J. Lichtenstein, Proc 

 Natl. Acad. Sci. U. S. 44, 1004 (1958). 



383 C. Heidelberger, L. Griesbach, O. Cruz, R. J. Schnitzer, and E. Grunberg, Proc. 

 Soc. Exptl. Biol. Med. 97, 470 (1958). 



