Molecular Pharmacology, Vol 17, 111-117, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

The Effect of 5-Azacytidine and Dihydro-5-azacytidine on Nuclear Ribosomal RNA and Poly(A) RNA Synthesis in L1210 Cells in Vitro

¹ Applied Pharmacology Section Laboratory of Medicinal Chemistry and Biology,National Cancer Institute, Bethesda, Maryland 20205
² Drug Design and Chemistry Section, Laboratory of Medicinal Chemistry and Biology, National Cancer Institute, Bethesda, Maryland 20205

The effect of 5-azacytidine (AZC) and 5,6-dihydro-5-azacytidine (DHAZC) on nRNA synthesis was studied in L1210 cells in vitro. AZC produced 50% inhibition of the incorporation of [¹⁴C]uridine into nuclear rRNA and nonpolyadenylic acid and polyadenylic acid-containing heterogeneous nRNA at concentrations of 0.3 µM, 0.4 mM, and approximately 0.6 mM, respectively. The median inhibitory concentrations of DHAZC on these three species of nRNA were 2 mM, 2 mM and approximately 3 mM, respectively. AZC inhibited 2'-O-methylation and DHAZC affected base methylation of rRNA; however, methylation of nonpolyadenylic acid and polyadenylic acid-containing heterogeneous nRNA was not significantly impaired. Measurement of the concentration and specific radioactivity of S-adenosyl-L-methionine and UTP showed that AZC and DHAZC inhibited uridine incorporation into RNA by interference with its cellular uptake, but did not impair methionine transport. AZC and DHAZC did not inhibit [³H]adenosine incorporation into nRNA at 0.1 mM, but inhibited rRNA and poly(A) heterogeneous RNA synthesis by 40% at 1 mM. [¹⁴C]AZC and [¹⁴C]DHAZC were incorporated into all species of nRNA at concentrations that did not impair transcription, with the highest incorporation occurring in polyadenylic acid-containing heterogeneous nRNA. These results suggest that AZC and DHAZC at low concentrations may produce their cytotoxic and antitumor effects via their incorporation into nRNA, and at higher concentrations inhibit the methylation of rRNA, as well as the transcription of rRNA and polyadenylic acid-containing RNA.

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ACKNOWLEDGMENT The authors would like to thank Mrs. Margaret Green for typing the manuscript.

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