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Effects of Structure and Chemical Activity on the Ability of Nitrosoureas to Inhibit DNA Repair¹

Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30303

Nitrosoureas with different chemical properties were compared in this study for their ability to inhibit DNA repair. The objectives were to obtain a clearer definition of the extent of inhibition that can occur and to assess the relative contributions of alkylating and carbamoylating activities to repair inhibition. L1210 cells in culture were prelabeled with radioactive thymidine and exposed to ionizing radiation, after which the rate of rejoining of radiation-induced strand breaks was assessed, in control and drug-incubated cultures, by alkaline elution of the prelabeled DNA through membrane filters. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, a compound with strong alkylating and carbamoylating activities, is a strong inhibitor of repair, significantly slowing the rate of rejoining of the radiation-induced strand breaks. The repair-inhibiting action of the drug is most evident when the cell lysate is treated with proteinase K immediately prior to alkaline elution. This proteinase digestion removes DNA-protein cross-links, which can retard the rate of elution and obscure the presence of unrejoined strand breaks. Chlorozotocin, which has the same alkylating moiety as 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea but which lacks carbamoylating activity, has no discernible effect on repair. 1,3-Bis-(cyclohexyl)-1-nitrosourea, which has the same carbamoylating moiety as 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea but which lacks all alkylating activity, is shown to be a potent inhibitor of repair. The main findings, then, are that nitrosoureas can be strong inhibitors of repair, that alkylating activity is unrelated to repair inhibition, and that strong carbamoylating activity is the essential requirement for inhibition.

¹ This investigation was supported by Grants CA-16620 and CA-16255, awarded by the National Cancer Institute, Department of Health, Education, and Welfare. A preliminary report of this work was presented at the 69th Annual Meeting of the American Association for Cancer Research, 1978 (11).

² To whom requests for reprints should be addressed, at Department of Medicine, Emory University School of Medicine, 69 Butler St., S.E., Atlanta, Ga. 30303.

Received 9/22/79. Accepted 10/ 5/79.

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