ABSTRACT
Leukemia L1210 cells with acquired resistance to 1-methyl-1-nitrosourea (MNU) (L1210/MNU) and 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (L1210/BCNU) were developed from leukemia L1210 cells sensitive to these drugs (L1210/0). The modal chromosome number of leukemia L1210/MNU and L1210/BCNU cells increases from 40 (L1210/0) to 41. It was shown that in leukemia L1210/MNU cells the inhibition of DNA synthesis after MNU administration in a therapeutic dose (80 mg/kg) is lasted within 24 hours, while that in leukemia L1210/0 cell--within 96 hours. After administration of BCNU (20 mg/kg) inhibition of DNA synthesis in leukemia L1210/BCNU cells reached of 50% of control in comparison with practically complete inhibition of DNA synthesis in leukemia L1210/0 cells. Centrifugation on alkaline sucrose density gradients revealed no differences in the rate of sedimentation of leukemia L1210/0, L1210/MNU and L1210/BCNU cell lysates. After 1 hour treatment with MNU of mice bearing L1210/MNU and L1210/0 leukemia cells single-strand breaks in DNA were determined. After 4 hours these strand-breaks retained in leukemia L1210/0 cells, but were eliminated in leukemia L1210/MNU cells. Administration of BCNU to mice with leukemia L1210/0 and L1210/BCNU cells resulted in both cases in the production of DNA aggregates. There is no complete cross-resistance between MNU and BCNU which allows a substitution of these drugs providing for the increase in their therapeutic efficiency.
Subject(s)
Carmustine/pharmacology , DNA, Neoplasm/biosynthesis , Leukemia L1210/metabolism , Methylnitrosourea/pharmacology , Nitrosourea Compounds/pharmacology , Animals , Centrifugation, Density Gradient , Chromosome Aberrations/drug effects , DNA, Single-Stranded/analysis , Drug Resistance , Leukemia L1210/drug therapy , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Molecular Weight , Nucleic Acid Conformation/drug effectsABSTRACT
Multiple forms of RNA polymerases (I, II and III) from murine leukemia L1210 cells are solubilized, purified and characterized. Heterogeneity of RNA polymerases I and III is revealed by chromatography on DEAE-Sephadex and Phosphocellulose (P-11). The properties of these forms such as peculiarities of transcription of native and denaturated DNA, metal ion dependence (Mg2+, Mn2+ and (NH4)2SO4) and alpha-amanitin sensitivity resemble those reported for other mammalian RNA polymerases. The level of RNA polymerase I of leukemia L1210 cells increase approximately ten-fold relative to its level in some organs of healthy mice.
