500 E. E. HANDSCHUMACHER AND A. D. WELCH 



into DNA thymine of Ehrlich ascites tumor cells in vivo resulted from the 

 administration of fluorouracil at a dosage level which did not interfere 

 with incorporation of formate into nucleic acid purines or proteins. 367,370 

 Similarly, the incorporation of orotic acid and uracil into DNA thymine 

 of Ehrlich ascites cells was depressed to a degree resembling that of for- 

 mate, while the incorporation of thymidine per se was markedly increased, 

 a finding which suggests localization of the primary metabolic inhibition 

 at the conversion of uracil derivatives to thymine deoxy ribonucleotides. 

 However, this same level of fluorouracil also caused up to G8% inhibition 

 of the conversion of uracil-2-C 14 to the uracil or cytosine of the RNA of 

 ascites cells, and the incorporation of orotic acid into the pyrimidine bases 

 of RNA was depressed up to 68% under these conditions. 



The preferential inhibition of the incorporation of formate-C 14 into the 

 thymine of DXA of Ehrlich ascites tumor cells, as compared to that of 

 spleen, liver, or intestine, suggested that the greater capacity of Ehrlich 

 ascites cells for the anabolic utilization of uracil has an enhancing effect 

 on the ability of fluorouracil to cause inhibition. Although the inhibitor 

 was injected intraperitoneally, and came into direct contact with the tu- 

 mor cells, it will become evident that this 5-fluoropyrimidine exerts a selec- 

 tive effect on tumors, while the 5-fluoro derivative of orotic acid does not 

 exhibit such selectivity. Substantiation of these statements is to be found 

 in the specific concentration of fluorouracil derivatives in a number of ex- 

 perimental tumors of mice and in human cancer tissues following the ad- 

 ministration of fluorouracil, whereas such concentration was not apparent 

 following the administration of fluoroorotic acid to tumor-bearing ani- 

 mals. 366 This blockade of pyrimidine metabolism by fluorouracil results in 

 a depression of DXA synthesis, as evidenced by a sharp reduction of phos- 

 phate-P 32 uptake into DXA. 370 An interesting extension of this finding was 

 made through the use of cytochemical techniques. It was noted that the 

 administration of fluorouracil for 7 days to mice bearing Ehrlich ascites 

 cells, in doses sufficient to cause 85% inhibition of tumor growth, caused a 

 comparable reduction in mitotic index and marked alterations in cellular 

 components. 371 ' 372 Cells from treated animals were considerably larger and 

 contained increased amounts of protein and RXA. The DXA content per 

 cell, however, was reduced to approximately 50% of that found in control 

 cells with little or no change in the average ploidy of the cell. Examination 

 of interphase cells with Feulgen stain disclosed irregular, coarse clumps, 

 and strands of DXA around vacuoles, a phenomenon regarded as charac- 



370 P. Danneberg, B. J. Montag, and C. Heidelberger, Cancer Research 18, 329 

 (1958). 



371 A. Lindner, Proc. Am. Assoc. Cancer Research 2, 322 (1958). 



372 A. Lindner, Cancer Research 19, 189 (1959). 



