TFT and 6TG resistance of mouse lymphoma cells to analogs of azacytidine

Abstract

5-Azacytidine (5-aza-CR) and six of its analogs were examined for their ability to induce trifluorothymidine (TFT) and/or 6-thioguanine (6TG) resistance in L5178Y mouse lymphoma cells. These analogs were 5-aza-2'-deoxycytidine (5-aza-CdR), 5-fluoro-2'-deoxycytidine (5-FCdR), 5,6-dihydro-5-azacytidine (dH-aza-CR), 6-azacytidine (6-aza-CR), cytidine (CR) and 1-b-D-arabinofuranosylcytosine (ara-C). 5-Aza-CR and 6-aza-CR were examined for their ability to induce 6TG-resistant colonies and results demonstrated no effect. At least a 5-fold increase in TFT resistance was observed for 5-aza-CR, 5-aza-CdR, 5-FCdR, dH-aza-CR and ara-C. The concentration at which these compounds induced TFT resistance correlated well with the potential of the nucleoside analogs to induce differentiation in C3H10T1/2 cells as determined by Constantinides et al. (Nature, 267, 364-366, 1977). In L5178Y mouse lymphoma (MOLY) cells, 5-aza-CR induced TFT resistance and produced both small and large colonies. Previous studies using mammalian cells showed the absence of mutagenic activity with 5-aza-CR and some of its analogs at the ATPase and hgprt loci. However, the different spectrum of DNA lesions detected at the tk locus may be responsible for the response of MOLY cells to 5-aza-CR.