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Effect of 5-Azacytidine on Malignant Transformation of a Mutant Derived from the Mouse BALB/c 3T3 Cell Line Resistant to Transformation by Chemical Carcinogens¹

Departments of Biochemistry [C. Y., Y. K., M. O., M. K.] and Orthopedics [S. M.], Oita Medical School, Hazama-cho, Oita 879-56, Japan

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(a)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 µM 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.

¹ This work was supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture of Japan.

² To whom requests for reprints should be addressed.

Received 7/28/86. Revised 1/12/87. Revised 6/18/87. Accepted 6/24/87.