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Studies on the Mechanism of Action of 6-Uracil Methyl Sulfone in Mouse Ehrlich Ascites Tumor Cells in Vitro^*

( Department of Pharmacology, Yale University School of Medicine, New Haven, Conn.)

6-Uracil methyl sulfone inhibited the utilization of radioactive formate for the biosynthesis of the methyl group of DNA-thymine by Ehrlich ascites tumor cells in vitro. This inhibition was diminished markedly in the presence of deoxyuridine and, even more markedly, by deoxycytidine; in this respect, the corresponding ribosides were less efficient. In the absence of the inhibitor, the utilization of formate for DNA-thymine biosynthesis was equally enhanced by these pyrimidine ribosides and deoxyribosides.

Orotic acid, in the absence of UMS, was as effective as uridine and deoxyuridine in increasing the utilization of radioactive formate for the biosynthesis in vitro of the methyl group of DNA-thymine of Ehrlich ascites cells, but was ineffective in reversing the inhibition by UMS. Although the utilization of radioactive orotic acid for the biosynthesis of RNA-pyrimidines was not impaired by UMS, the incorporation of orotic acid into DNA-thymine was markedly reduced by the inhibitor.

The utilization of radioactive thymidine was not curtailed at even a 1,000-fold excess of UMS; hence, the prime mechanism of inhibition by UMS in the Ehrlich ascites tumor system appears to be at a stage of the conversion of the precursor to a methyl-containing compound on the pathway to DNA-thymine.

^* This study was supported by grants from the American Cancer Society, as recommended by the Committee on Growth, National Research Council, and from the National Institutes of Health, U.S. Public Health Service.

Received 1/24/58.