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Inhibition of Ribosomal RNA Maturation in Novikoff Hepatoma Cells by Toyocamycin, Tubercidin, and 6-Thioguanosine¹

McArdle Laboratory for Cancer Research, The Medical School, University of Wisconsin, Madison, Wisconsin 53706

The purine nucleoside analogs, toyocamycin, tubercidin, and 6-thioguanosine, all inhibit ribosomal RNA maturation in cultured Novikoff hepatoma cells. While processing of the 45 S RNA to the 38 S RNA continues, formation of the mature 28 S RNA and the mature 18 S RNA is markedly inhibited by the addition of any of the analogs. Labeling of the 32 S RNA intermediate precursor is inhibited to a lesser degree. The pattern of inhibition observed is similar to that previously reported for other base and nucleoside analogs (5-fluoroorotic acid, 5-fluorouridine, 5-azacytidine, and 8-azaguanine), suggesting that inhibition of ribosomal RNA maturation may be a phenomenon common to those base analogs incorporated into RNA.

6-Thioguanosine not only affects the incorporation of ³H-labeled uridine into RNA, but it also decreases the size of the acid-soluble uridine pool. Thus the monitoring of RNA synthesis in the presence of the analog with uridine as the labeled precursor must be interpreted in the light of changes in the precursor pool size.

Tubercidin and 6-thioguanosine have demonstrated clinical value in cancer chemotherapy. The mechanism of action of these and other chemotherapeutically useful analogs has not as yet been definitively elucidated. The finding that purine and pyrimidine analogs can inhibit ribosomal RNA maturation is discussed as a possible mode for their cancerostatic activity.

¹ The work reported herein was supported by Grant CA-07175 from the National Cancer Institute and Grant E-588 from the American Cancer Society.

² Trainee in Biochemical Pathology of the National Institute of General Medical Sciences (GM-00130). These studies comprised a portion of the thesis submitted to the Graduate School of the University of Wisconsin in partial fulfillment of the requirements of the Ph.D. degree.

Received 8/24/73. Accepted 12/ 3/73.

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