Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation - PubMed (original) (raw)

Comparative Study

. 2004 May;24(5):1121-31.

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Comparative Study

Quinoxaline 1,4-dioxides are novel angiogenesis inhibitors that potentiate antitumor effects of ionizing radiation

Hala Gali-Muhtasib et al. Int J Oncol. 2004 May.

Abstract

We have recently shown that quinoxaline 1,4-dioxides (QdNOs) are potent hypoxia selective cytotoxins that modulate hypoxia inducible factor-1alpha (HIF-1alpha) expression. In this study, we evaluated the cytotoxicity, anti-angiogenic, and radiosensitization activities of the two quinoxaline 1,4-dioxides (QdNOs), BPQ and DCQ. Clonogenic survival, Matrigel, and radiosensitization assays were performed in vitro and in vivo using Lewis lung carcinoma (LLC) and EMT-6 mammary adenocarcinoma cells. Transcript and protein levels of HIF-1alpha and VEGF were determined using RT-PCR and Western blotting, respectively. DCQ showed cytotoxic effects under hypoxic conditions for both cell lines. Treatment with either drug inhibited HIF-1alpha and VEGF secretion, with DCQ being more potent than BPQ. DCQ also inhibited the formation of tube-like structures of ECV-304 endothelial cells in Matrigel by 60-80% and significantly reduced neoangiogenesis in vivo. When combined with radiation (200-1000 cGy), DCQ resulted in the death of 100% of LLC or EMT-6 cells. Using the C57BL/6 mouse model, combined treatment with DCQ and radiation delayed the growth of LLC tumors for 17 days and reduced mean tumor volume by 80% at day 20. However, BPQ combined with radiation did not induce significant tumor regression. Histological analyses revealed a significant increase in tissue necrosis in tumors treated by DCQ and radiation. These results indicate a potent anti-angiogenic and radiation modification effect of two quinoxaline dioxides. These findings should stimulate further research in other tumor models as these compounds could have potential clinical applications in cancer therapy.

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