Effect of 5-azacytidine on malignant transformation of a mutant derived from the mouse BALB/c 3T3 cell line resistant to transformation by chemical carcinogens.
BALB/c 3T3 and its derivative MO-5, isolated as a monensin-resistant clone, showed a very low rate of spontaneous malignant transformation. Treatment of BALB/c 3T3 cells with benzo(alpha)pyrene, 4-nitroquinoline-N-oxide, N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, or UV light irradiation significantly enhanced the rate of transformation, whereas the treatment of MO-5 cells with these carcinogens had only a slight if any effect. Exposure of MO-5 as well as BALB/c 3T3 to 5 or 10 microM 5-azacytidine for 3 to 7 days significantly increased the number of transformation foci. The Luria-Delbrück fluctuation test showed that spontaneous mutation frequency (mutants/cell/generation) was 1.2 X 10(-6) for BALB/c 3T3 and 7.1 X 10(-7) for MO-5, respectively, when appearance of cadmium-resistant clones was tested. N-Methyl-N'-nitro-N-nitrosoguanidine enhanced induced mutation frequency of ouabain-resistant and cadmium-resistant mutants of BALB/3T3 but it only slightly enhanced that of MO-5. Methylation status of DNA of MO-5 was compared with that of BALB/c 3T3 by comparing the cleavage patterns generated by the isoschizomeric restriction enzymes HpaII and MspI. DNA of MO-5 was found to be more methylated than that of BALB/c 3T3 in the vicinity of c-myc as well as the metallothionein-I gene. Aberrant DNA methylation in MO-5 and the cellular sensitivity to transformation by chemical carcinogens or 5-azacytidine are discussed.
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology*; D001564:Benzo(a)pyrene; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D008668:Metallothionein / Q000235:genetics; D008745:Methylation; D008769:Methylnitronitrosoguanidine; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D011519:Proto-Oncogenes; D013755:Tetradecanoylphorbol Acetate
D008769:Methylnitronitrosoguanidine; D001564:Benzo(a)pyrene; D015112:4-Nitroquinoline-1-oxide; D004815:Epidermal Growth Factor; D004247:DNA; D008668:Metallothionein; D001374:Azacitidine; D013755:Tetradecanoylphorbol Acetate