Potentiation of 1‐(2‐Chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea's Toxicity in vitro by Two New Bioreductive Agents

Two new bioreductive compounds, 9‐[3‐(2‐nitro‐1‐imidazolyl)propylamino]acridine hydrochloride (NLA‐1) and 9‐[2‐(2‐nitro‐1‐imidazolyl)ethylamino]acridine hydrochloride (NLA‐2), which behave as hypoxic cytotoxins and radiosensitizers, have been investigated for potentiation of 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea's (CCNU) cytotoxic activity in vitro using V‐79 cells. The preincubation effect as well as conditions of coadministration of CCNU with each sensitizer have been examined. In this latter case, the median‐effect analysis was applied to evaluate whether the phenomenon was additive or synergistic. A clonogenic assay was used to score survival. Both bioreductive compounds, even at very low concentrations, significantly enhance the cytotoxic activity of CCNU under conditions of hypoxic preincubation. The enhancement of CCNU cytotoxicity is dependent upon preincubation time and the concentrations of both CCNU and the specific bioreductive agent. Coincubation of cells under hypoxia with CCNU and each bioreductive agent led to some potentiation, but only at lower survival levels. No chemosensitization was observed under aerobic conditions with either sensitizer.