Uracil antagonism and inhibition of mammary adenocarcinoma 755.

A revival of interest has taken place in recent years in the possibility of interference with mam malian nucleic acid biosynthesis by means of an tagonists of the free pyrimidines. Early studies appeared to show that, while orotic acid (1, 48) and the sugar derivatives of the pyrimidines (19, 20) are extensively incorporated into both RNA and DNA, the incorporations of free uracil, cytosine, and thymine are insignificant (2, 47). Never theless, later work showed that in certain tissues the nucleic acids are formed from free pyrimidines to an appreciable extent (36, 53). More important, the studies of Rutman et al. (53, 54) demonstrated a significantly greater incorporation of uracil-2-C14 into hepatoma than normal liver. The subsequent investigation by Heidelberger appeared to indi cate that the incorporation of uracil is primarily related to the rate of cell division (40). In addi tion, Canellakis (8) found the incorporation of exogenous uracil to be related inversely to the deg radation of uracil in the specific tissue. Several types of uracil antagonists have shown inhibitory effects in tumor systems. Thus, 5-fluorouracil and 5-fluoroorotic acid (25, 26), 6-azauracil (3, 18, 30, 38, 59), and a number of the other uracil antagonists described here are selective inhibitors of transplantable animal tumors. The purpose of this paper is to examine interference with pyrimidine metabolism as a means of tumor inhibition through the use of a variety of pyrimidine an tagonists and mammary adenocarcinoma 755.