This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lally, B. E. Articles by Koumenis, C. Search for Related Content PubMed PubMed Citation Articles by Lally, B. E. Articles by Koumenis, C.

Identification and Biological Evaluation of a Novel and Potent Small Molecule Radiation Sensitizer via an Unbiased Screen of a Chemical Library

Departments of ¹ Radiation Oncology, ² Cancer Biology, and ³ Pathology/Comparative Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina; ⁴ Department of Biology, East Carolina University, Greenville, North Carolina; and ⁵ Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Constantinos Koumenis, Department of Radiation Oncology University of Pennsylvania School of Medicine 185 John Morgan Building 3620 Hamilton Walk Philadelphia, PA 19104-6072. Phone: 215-898-0076; Fax: 215-898-0090; E-mail: koumenis{at}xrt.upenn.edu.

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. [Cancer Res 2007;67(18):8791–9]

This article has been cited by other articles:

				G. A. Geiger, W. Fu, and G. D. Kao Temozolomide-Mediated Radiosensitization of Human Glioma Cells in a Zebrafish Embryonic System Cancer Res., May 1, 2008; 68(9): 3396 - 3404. [Abstract] [Full Text] [PDF]

				H. Feitsma and E. Cuppen Zebrafish as a Cancer Model Mol. Cancer Res., May 1, 2008; 6(5): 685 - 694. [Abstract] [Full Text] [PDF]