IN-VIVO DNA-DAMAGE INDUCED BY A NEW SUGAR DERIVATIVE OF N-NITROSOUREACRC-0510375 ARANOSE IN SENSITIVE AND RESISTANT TO THE DRUG L1210 LEUKEMIA-CELLS

In vivo effect of 3-alpha-L-arabinopyranosyl-1-methyl-1-nitrosourea (a ranose, CRC-0510375) on DNA synthesis, formation of O-6-methylguanine adducts (O-6-MeG) and single-strand breaks (SSB) in DNA, activity of D NA polymerases alpha, beta and O-6-methylguanine-DNA methyltransferase (MGT) in parent L1210 leukemia cells and L1210 cells with acquired re sistance to aranose (L1210/A) were studied. The extent of aranose-indu ced inhibition of DNA synthesis, amount of SSB and their rate of repai r in both strains were similar. The cells of L1210/A strain contained the elevated level of sulfhydryl (SH) groups in comparison with L1210. Aranose induced formation and long-term persistance of a conciderable amount of O-6-MeG in DNA of L1210 in contrast to that in L1210/A. MGT activity was 9 times higher in L1210/A then in L1210. Administration of aranose to mice bearing L1210/A leukemia resulted in rapid decline of MGT activity which has been completely recovered by 72 hours after administration of the drug. The data presented suggest that the resist ance mechanisms to aranose appear to involve the enhancement of MGT ac tivity, which resulted in the loss of cytotoxic effect of the drug.