Interaction of razoxane and radiation on cultured Chinese hamster cells

Razoxane [(+/-)-1,2-bis(3,5-dioxopiperazine-1-yl)propane] was investigated for its effects on the survival of irradiated Chinese hamster fibroblasts in vitro. Razoxane alone produced cytotoxicity that was dependent upon drug concentration and pulse exposure time, with a preferential lethality for cells treated while in the DNA-synthetic phase. Razoxane enhanced radiation-induced cell killing when used as either a pulse exposure or a continuous treatment. In asynchronous populations of cells, this was expressed as an increase in the slope and a reduction in the shoulder of the radiation dose-survival curve. In synchronous populations of cells, a modest increase in cell killing was observed for those cells treated in G1 and G2, with a greater enhancement for cells treated in the S-phase. Overall, razoxane may potentiate the radiation-induced killing of cultured mammalian cells by a number of mechanisms: 1) a blockade of cell cycle progression causing an accumulation of cells in radiosensitive phases of the cell cycle; 2) selective cytotoxicity of cells in radioresistant phases of the cell cycle; 3) inhibition of the accumulation of sublethal radiation damage; or 4) interaction of the damages induced by each agent so as to produce an enhanced effect. These mechanisms may need to be considered if razoxane and radiation therapy are to be used in combined modality therapeutic approaches.