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

Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

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-(trans-4-hydroxycyclohexyl)-1-nitrosourea, which has strong carbamoylating activity, inhibited the rejoining of drug or X-ray-induced DNA strand breaks in IMR-90 cells, whereas the noncarbamoylating cis-2-hydroxy isomer had little or no effect; 1-(2-chloroethyl)-3-(trans-4-hydroxycyclohexyl)-1-nitrosourea was twice as potent as the cis-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-(trans-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 cis-2-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 suggest that carbamoylation may inhibit the nucleotide excision repair of chloroethylnitrosourea-induced DNA 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 chloroethylnitrosoureas because of a lack of a DNA repair protein (guanine O⁶-alkyltransferase) 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.

¹ This work was presented in part at the 74th Annual Meeting of the American Association for Cancer Research, San Diego, CA, May 1983 (22).

² Recipient of grant from the Rose and Jean Hoguet Foundation. Present address: Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.

³ To whom requests for reprints should be addressed, at Building 37, Room 5D17, 9000 Rockville Pike, Bethesda, MD 20205.

Received 8/ 9/83. Accepted 12/16/83.