Effects of Carbamoylation on Cell Survival and DMA Repair in Normal Human Embryo Cells (IMR-90) Treated with Various 1-(2-Chloroethyl)-1-nitrosoureas1

The possibility was examined that the carbamoylating activity of some chloroethylnitrosoureas could interfere with the activity of normal human cells to survive treatment with these drugs; 1-(2-chloroethyl)-3-(frans-4-hydroxycyclohexyl)-1 -nitrosourea, which has strong carbamoylating activity, inhibited the rejoining of drug or X-ray-induced DMA strand breaks in IMR-90 cells, whereas the noncarbamoylating c/s-2-hydroxy isomer had little or no effect; 1-(2-chloroethyl)-3-(frans-4-hydroxycyclohexyl)-1nitrosourea was twice as potent as the c/s-2-hydroxy isomer in reducing colony survival. The moderate or high carbamoylating drugs 1,3-bis(2-chloroethyl)-1 -nitrosourea and 1-(2-chloroethyl)3-(cyclohexyl)-1-nitrosourea had effects resembling those of 1(2-chloroethyl)-3-(frarts-4-hydroxycyclohexyl)-1 -nitrosourea. The low carbamoylating drug 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1 -nitrosourea had effects resembling those of the c/s2-hydroxy isomer. 1-(2-chloroethyl)-1-nitrosourea, although a strong carbamoylator in chemical systems, behaved biologically as if it were a low carbamoylator. This can be rationalized on the basis of limited cellular uptake of cyanate ion. The results sug gest that carbamoylation may inhibit the nucleotide excision repair of chloroethylnitrosourea-induced DMA damage that may be crucial to the ability of normal human cells to recover from the action of these drugs. Previous work has indicated that susceptible human tumor cells are sensitive to chloroethylnitro soureas because of a lack of a DNA repair protein (guanine O6alkyltransferase) that is not involved in nucleotide excision repair. On the basis of these findings and other evidence, further clinical trials of appropriate noncarbamoylating chloroethylnitrosoureas would be justified.