Significance of DNA cross-links on 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3- nitrosourea (ACNU)-induced cytotoxicity against ACNU-sensitive and -resistant lines of 9L rat glioma cells.

The formation and removal of DNA cross-links caused by treatment with 1-(4-amino-2-methylpyrimidin-5-yl)-methyl-3-(2-chloroethyl)-3-nitr osourea (ACNU) were assayed by the technique of alkaline elution for DNA in comparison with the cytotoxicities in ACNU-sensitive rat 9L cells or ACNU-resistant subclones of 9L cells (9L/R cells). The ACNU-resistant 9L/R cells appeared to be about 16 times more resistant against ACNU than were the 9L cells. The DNA cross-links immediately after the treatment with ACNU were not detectable in 9L or 9L/R cells. Although the level of cross-links for 9L cells had reached a maximum at 6 hours and then persisted at almost the same level as that at 24 hours after the treatment with ACNU, the level for 9L/R cells was very low at 6 hours and then gradually decreased at 24 hours after treatment with ACNU. Inhibition of the formation of DNA interstrand cross-links caused by the treatment with ACNU might be a factor for the ACNU resistance in 9L/R cells. Also, the capacity for the repair of DNA interstrand cross-links might participate in the mechanisms of the ACNU resistance in 9L/R cells.