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Mutagenicity of 5-Azacytidine and Related Nucleosides in C3H/10T Clone 8 and V79 Cells¹

Cancer Research Laboratory and Department of Pathology, School of Medicine, University of Southern California, Los Angeles 90033 [J. R. L.], and Division of Hematology-Oncology, Childrens Hospital of Los Angeles, Los Angeles, California 90027 [P. A. J.]

To determine whether 5-azacytidine (5-AzaCR)-induced transformation and/or differentiation of C3H/10T clone 8 (10T) cells might have a mutational basis, we studied whether 5-AzaCR and structurally related nucleoside analogs could mutate 10T and Chinese hamster V79 cells.

In an assay for mutation to ouabain resistance in 10T cells, which detects base substitution mutations but not frameshift mutations, 5-AzaCR and 6-azacytidine were not significantly mutagenic. 5-Aza-2'-deoxycytidine, 5-fluoro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine, 5-fluoro-2'-deoxyuridine (FUdR), 5-bromo-2'-deoxyuridine (BUdR), and 1-ß-D-arabinofuranosylcytosine (ara-C) were only weakly mutagenic. In an assay for mutation to ouabain resistance in V79 cells, which also detects base substitution mutations but not frameshift mutations, 5-AzaCR, 5-aza-2'-deoxycytidine, FUdR, and ara-C were not detectably mutagenic, and BUdR was moderately mutagenic at highly cytotoxic concentrations. In an assay for mutation to 8-azaguanine resistance in V79 cells, which detects base substitution and frameshift mutations, 5-fluoro-2'-deoxycytidine and ara-C were weakly mutagenic, BUdR was moderately mutagenic at very cytotoxic concentrations, and 5-AzaCR, 5-aza-2'-deoxycytidine, FUdR, 6-azacytidine, and 5,6-dihydro-5-azacytidine were not significantly mutagenic.

Therefore, 5-AzaCR and related cytosine analogs can be considered as negligibly mutagenic. This study does not provide support for a mutational basis for 5-AzaCR-induced differentiation in 10T cells. Further, there was no correlation between the mutagenicity of the nucleosides 5-AzaCR, ara-C, BUdR, and FUdR studied here and their previously reported abilities to transform 10T cells. The mutagenicities of 5-AzaCR and FUdR were so low that the biological significance of these effects is uncertain. Hence, it is not clear to what extent, if any, mutation contributes to the transformation caused by these two compounds, and other possible mechanisms of transformation should also be investigated.

¹ This Investigation was supported by Grants CA-21,036, CA-14,089, and GM-25,739 from the NIH.

Received 6/ 3/81. Accepted 11/18/81.

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