For patients with solid
tumors, the tolerance of surrounding tissues often limits the dose of radiation that can be delivered. Thus, agents that preferentially increase the cytotoxic effects of radiation toward
tumor cells would significantly alter the therapeutic ratio and improve patient survival. Using a high-throughput, unbiased screening approach, we have identified
4'-bromo-3'-nitropropiophenone (NS-123) as a radiosensitizer of human
glioma cells in vitro and in vivo.
NS-123 radiosensitized U251
glioma cells in a dose-dependent and time-dependent manner, with dose enhancement ratios ranging from 1.3 to 2.0. HT-29
colorectal carcinoma and A549
lung adenocarcinoma cells were also radiosensitized by
NS-123 in vitro, whereas
NS-123 did not increase the radiation sensitivity of normal human astrocytes or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos,
NS-123 enhanced the
tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse
tumor xenograft model in which
NS-123 sensitized U251
tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with
NS-123 resulted in accumulation of unrepaired IR-induced
DNA strand breaks and prolonged phosphorylation of the
surrogate markers of DNA damage H2AX,
ataxia telangiectasia mutated
protein,
DNA-dependent protein kinase, and CHK2 after IR, suggesting that
NS-123 inhibits a critical step in the DNA repair pathway. These results show the potential of this cell-based, high-throughput screening method to identify novel radiosensitizers and suggest that
NS-123 and similar
nitrophenol compounds may be effective in antiglioma modalities.