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Specific Inhibition of Transfer RNA Methylation and Modification in Tissues of Mice Treated with 5-Fluorouracil¹

Departments of Pharmacology [W-C. T., K. R.] and Cell Biology [D. M.], Baylor College of Medicine, Texas Medical Center, Houston, Texas 77030

5-Fluorouracil was administered to normal mice and mice bearing a 7,12-dimethylbenz(a)anthracene-induced, transplantable mammary tumor. Base composition analysis of transfer RNA (tRNA) isolated from liver, normal mammary gland, and tumor showed that only the amounts of uridine and its 5-substituted derivatives (5-methyluridine, pseudouridine, and 5,6-dihydrouridine) were reduced in a dose- and time-dependent manner. The modified uridine derivatives were reduced in excess of the substitution of uridine by 5-fluorouridine. Therefore, we examined the tRNA methyltransferase activities in homologous and heterologous assay systems with DL-ethionine-induced, partially methyl-deficient mouse liver tRNA and Mycoplasma hominis tRNA as substrates. The data showed a very rapid, dose-dependent, and specific inhibition of tRNA uracil-5-methyltransferase in dialyzed enzyme extracts prepared from the liver and tumor of mice treated with 5-fluorouracil.

The reduction in the amounts of pseudouridine and dihydrouridine in tRNA was only partially due to analog incorporation, as shown by base composition analysis. Thus the drug appears to inhibit the biosynthesis of these compounds also.

5-Fluorouracil exhibited a preferential inhibitory effect on tumor tRNA in terms of 5-fluorouridine incorporation and inhibition of uridine modification. This preferential inhibition may in part contribute to the antineoplastic actions of the drug.

¹ Research supported in part by USPHS Grants CA-11944, CA-16840, and CA-10893-P8.

² This work is part of a thesis to be presented to the Graduate School of Baylor College of Medicine in partial fulfillment of the requirements for the Ph.D. degree.

³ Recipient of a Faculty Research Award from the American Cancer Society (PRA-108) while this work was carried out. To whom requests for reprints should be addressed.

Received 9/15/77. Accepted 1/27/78.