Cellular response to treatment with 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic acid, a water-soluble nitrosourea derivative

The lethal effects of 4-(3-(2-chloroethyl)-3-nitrosoureido)-cis-cyclohexanecarboxylic acid (cis-acid), a water-soluble nitrosourea derivative, were investigated on a human lymphoma cell line. The survival of asynchronous cells exposed to increasing concentrations of the drug was characterized by a threshold exponential curve (Do = 20 microgram/ml; Dq = 20 microgram/ml, 1 hour) similar to that of other nitrosourea derivatives. cis-Acid exerted its main killing effect on cells in early S and in late G2 phase. Cells in mid S and early G1 phase were tenfold more resistant. Changes in survival response as a function of cell cycle stage were reflected primarily by changes in the extent of the shoulder region of the survival curve. In contrast to other nitrosoureas, the lethal effectiveness of cis-acid in solution was stable and the drug could sterilize large numbers of cells in short periods of time. Another important major difference observed for cis-acid with respect to classic nitrosourea derivatives was the capacity of treated cells to recover from sublethal and potentially lethal damage. Our studies have shown that cis-acid is as effective in killing cultured human lymphoma cells as other nitrosoureas, but possibly with a mechanism different from that of these compounds. The major shortcoming noted for cis-acid, namely the capacity of treated cells to recover from drug-induced damage, is offset by the relatively long stability of its killing effect. This, and the fact that cis-acid can be administered in an aqueous solution, make this agent an appealing compound for clinical trials.