Effect of 5-bromodeoxyuridine on deoxyribonucleic acid-thymine synthesis and cell metabolism of lymphatic tissues and tumors.

5-Bromodeoxyuridine (BrUDr) is an effective inhibitor of the growth of E. coli and Lactobacitti, and this growth inhibition can be reversed by thymidine (1-3). There is evidence that this thymidine analog can replace the thymine of both E. coli and bacteriophage deoxyribonucleic acid (DNA) on an equimolar basis (7, 11, 12). In E. coli, nearly 50 per cent of the thymine can be replaced. Whereas the physical properties and appearance of bacteriophage particles containing incorporated 5-bromouracil appeared normal, a proportion were found to be nonviable. Litman and Pardee have observed that T2r2 stocks grown in the presence of 5-bromouracil and sulfanilamide under conditions in which the 5-bromouracil is incorporated into the DNA may contain a high proportion of mutant types (11). The mutagenic effect of 5-bromouracil in the presence of sulfanil amide must certainly be connected with a dis turbance of DNA metabolism or structure. Anoth er instance of mutagenesis resulting from an inter ference with thymine metabolism has been pre sented by Coughlin and Adelberg (6), who ob served that specific thymine starvation is muta genic in an E. coli strain which has a double re quirement for thymine and histidine. A hundred fold proportional increase of histidine-independent mutants appeared among the survivors of 185 minutes of thymine starvation. These facts prompted a study of the potential role of BrUDr as an inhibitor of thymine bio synthesis by tumors. The effect of the analog on the incorporation of formaldehyde-C14 into thymine compounds under in vivo or in vitro conditions was investigated. Inhibition was ob served in the labeling of DNA-thymine, but the labeling of DNA-adenine or guanine was reduced only at high concentrations of BrUDr. Other analogs of thymidine had no significant effect