Abstract
Previous studies have suggested that 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl) -3-nitrosoureahydrochloride (ACNU) and 1,(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) bind specifically to the nucleosomal DNA of murine bone marrow and L1210 leukaemia cells whereas the glucose nitrosoureas, 2-(3-(2-chloroethyl)-3-nitrosoureido)-2-deoxy-D-glucopyranose, (chlorozotocin, CLZ) and 1-(2-chloroethyl)-3-(-D-glucopyranosyl)-1-nitrosourea (GANU), bind preferentially to the linker DNA of bone marrow but not tumour cell chromatin. In order to provide an explanation for this differential, the DNA repeat and linker lengths in murine bone marrow and L1210 leukaemia cells were measured using electrophoresis of micrococcal nuclease-digested DNA. The linker length of bone marrow chromatin was approximately 22% longer than that in L1210 leukaemia cells from mouse ascites. The linker length of L1210 cells maintained in suspension culture was 27% less than in those from ascites fluid. The tissue-specific toxicity of sugar nitrosoureas and the differential binding of these drugs to chromatin does not appear to correlate quantitatively with differences in DNA linker length.
Highlights
The use of nitrosoureas in cancer chemotherapy has been seriously limited by their acute myelotoxicity, (Wasserman et al, 1975; Osband et al, 1977). This problem led to the development of the glucosenitrosourea analogues, 2-(3-(2-chloroethyl)-3-nitrosoureido)-2-deoxy-D-glucopyranose, and 1-(2-chloroethyl)-3-(-D-glucopyranosyl)1-nitrosourea (GANU) which were less myelotoxic than the more traditional chloroethylnitrosoureas, 1,(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU) yet retained comparable antitumour activity in experimental tumours as well as in man (Panasci et al, 1977, 1979; Hoth et al, 1980)
Efforts to determine why the glucose-nitrosoureas were less toxic to bone marrow have considered the binding of drugs to chromatin and chromatin constituents
We report measurements of the DNA repeat and linker lengths in chromatin from murine bone marrow and L1210 leukaemia cells
Summary
L1210 mouse leukaemia cells were grown as suspension cultures in RPMI 1640 (M.A. Bioproducts, Walkerville, MD) supplemented with 100 U ml-1 penicillin, 100 jug ml- streptomycin, 4mM L-glutamine (all from M.A. Bioproducts, Walkerville, MD) and 10% fetal calf serum (K.C. Biologicals, Lenexa, KS). L1210 cells were maintained in vivo by serial passage in CDF1 mice and obtained for experimentation by aspiration from ascites fluid 7 days after i.p. innoculation with 105 cells. Bone marrow cells were obtained by expression with medium from femurs and tibias from normal CDF1 mice
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