This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chou, T.-C. Articles by Philips, F. S. Search for Related Content PubMed PubMed Citation Articles by Chou, T.-C. Articles by Philips, F. S.

Metabolism and Effects of 5-(ß-D-Ribofuranosyl)isocytosine in P815 Cells¹

Laboratories of Pharmacology [T-C. C., F. S. P.], Applied Therapy [J. H. B.], and Organic Chemistry [J. J. F., K. A. W., C. K. C.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

5-(ß-D-Ribofuranosyl)isocytosine (ICyd), a C-nucleoside, has been shown to be active against P815 leukemia in mice. In P815 cells treated with [2-¹⁴C]ICyd, we have detected radioactivity in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to ICyd. Half-saturation concentrations for the incorporation of [2-¹⁴C]ICyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280, and 94 µg/ml, respectively, which were >100-fold higher than those for tritiated cytidine. The incorporation of ICyd was competitively inhibited by cytidine. Phosphorylation and incorporation of ICyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-ß-D-arabinofuranosylcytosine are about 2- to 20-fold higher than in P815 sublines resistant to ICyd or to both 5-azacytidine and 1-ß-D-arabinofuranosylcytosine. These data suggest that the phosphorylation of ICyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that ICyd and 5-azacytidine are cross-resistant and that P815 cells resistant to ICyd are collaterally sensitive to 1-ß-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.

¹ This study was supported in part by American Cancer Society Grant CH 36 A, National Cancer Institute Grants 16534 and 08748, and by the Elsa U. Pardee Foundation.

Received 6/ 9/78. Accepted 11/14/78.

This article has been cited by other articles:

				J. C. Cheng, C. B. Matsen, F. A. Gonzales, W. Ye, S. Greer, V. E. Marquez, P. A. Jones, and E. U. Selker Inhibition of DNA Methylation and Reactivation of Silenced Genes by Zebularine J Natl Cancer Inst, March 5, 2003; 95(5): 399 - 409. [Abstract] [Full Text] [PDF]