39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 505 



action of fluorouracil, since the incorporation of lysine into proteins, under 

 the conditions studied, was not significantly depressed. 374 



In common with uracil, fluorouracil is extensively degraded by mam- 

 malian liver. 392 The first two degradative reactions apparently are cata- 

 lyzed by the .same enzymes which catabolize uracil; this results in the for- 

 mation of 5 , 6-dihydrofluorouracil and a-fluoro-/3-ureidopropionic acid; in 

 man, further degradation of fluorouracil-2-C 14 is indicated by the excretion 

 of urea-C 14 , whereas mice excrete much of the radioactivity from carbon 2 

 as respiratory carbon dioxide. A unique metabolite, believed to be 2-fluoro- 

 3-guanidopropionic acid, has also been isolated from the ascitic fluid of 

 mice bearing Ehrlich ascites carcinoma. More recently, a-fluoro-j8-alanine 

 has been identified as a major urinary excretion product of human sub- 

 jects. 393 Although the first two degradation products, dihydrofluorouracil 

 and a-fluoro-jS-ureidopropionic, do not inhibit the growth of microorgan- 

 isms inhibited by fluorouracil, 384 it seems probable that certain of the toxic 

 effects of fluorouracil in mammals are related to the formation of a flu- 

 orinated aliphatic acid which is probably fluoroacetic acid. 394 It is significant 

 that, as with uracil, sarcoma-180 and Ehrlich ascites tumors do not degrade 

 fluorouracil to any significant extent; this finding may account in part for 

 the higher levels of this analog found in tumors, as compared to normal 

 tissues. 392 Furthermore, the toxicities of fluorouracil, fluorodeoxyuridine, 

 and fluorodeoxycytidine (see below) are sharply increased when nontoxic 

 amounts of thymidine are administered with these analogs, a result which 

 suggests inhibition of the degradation of these fluorinated compounds. 395 



5-Fluoroorotic acid has properties somewhat similar to those of fluoro- 

 uracil, particularly with respect to effects on the synthesis of DNA in mi- 

 croorganisms and mammalian systems. 367 However, as indicated previously, 

 it does not localize preferentially in tumors, but appears in highest concen- 

 tration in the kidneys, 366 a circumstance which may reflect active secretion 

 by the renal tubular epithelium, as has been observed with orotic acid. 396 

 Fluoroorotic acid, unlike fluorouracil, inhibits the synthesis of orotidine- 

 5'-phosphate from orotic acid and pyrophosphorylribose-5-phosphate by a 

 particle-free supernatant of rat liver. 397 In this same system, extensive 



392 N. K. Chaudhuri, K. L., Mukherjee, and C. Heidelberger, Biochem. Pharmacol. 

 1, 328 (1959). 



393 C. Heidelberger, personal communication (1959). 



394 F. S. Philips, R. Duschinsky. and S. S. Sternberg, Proc. Am. Assoc. Cancer Re- 

 search 3, 51 (1959). 



395 J. H. Burchenal, E. A. D. Holmberg, H. F. Oettgen, S. C. Hemphill, and J. A. 

 Reppert, Proc. Am. Assoc. Cancer Research 3, 10 (1959). 



396 L. Peters, personal communication (1959). 



397 J. E. Stone and V. R. Potter, Cancer Research 17, 800 (1957). 



