COMPARISON OF BIOCHEMICAL AND BIOLOGICAL EFFECTS OF 4-NITROSOUREAS WITH DIFFERING CARBAMOYLATING ACTIVITIES

Abstract

Four chloroethylnitrosoureas with differing degrees of carbamoylating activity were compared for their effects on incorporation of radioactive precursors into macromolecules [in mouse L1210 leukemia cells in culture]. The comparison werecomparisons were made with concentrations that, for each drug, produced a defined biological effect, a 0.5 log or a 2 log reduction in cloning efficiency from a 1 h drug exposure. Dose-dependent inhibition of incorporation of labeled precursors into nucleic acids and incorporation of labeled precursors into nucleic acids and proteins was observed during the 1 h drug exposure with either of the 2 strongly carbamoylating nitrosoureas, 1-3-bis(2-chloroethyl)-1-nitrosourea [BCNU] and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea [CCNU]; the most extensive inhibition involved incorporation into DNA. No inhibitions were observed during exposure to a weakly carbamoylating nitrosourea (chlorozotocin) or during exposure to 1-(2-chloroethyl)-1-nitrosourea, a compound the carbamoylating activity of which is not agreed upon. By 4 h after removal of BCNU or CCNU from the extracellular medium, the cells partially recovered from the earlier inhibition of radioactive thymidine incorporation. This recovery was dependent on an undefined factor present in serum. The inhibitions that were observed during the 1 h drug exposure are clearly not essential to the cytotoxic effect of chloroethylnitrosoureas since no inhibitions occurred with 2 of the 4 compounds studied.