Effects of carbamoylation on cell survival and DNA repair in normal human embryo cells (IMR-90) treated with various 1-(2-chloroethyl)-1-nitrosoureas
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.
- Research Organization:
- Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland
- OSTI ID:
- 7096640
- Journal Information:
- Cancer Res.; (United States), Journal Name: Cancer Res.; (United States) Vol. 44:4; ISSN CNREA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
BIOLOGICAL EFFECTS
BIOLOGICAL PATHWAYS
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
CHEMICAL REACTIONS
DNA
NITROSO COMPOUNDS
NITROSOUREAS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
RECOVERY
REPAIR