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

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.

• Authors: Hala Gali-Muhtasib, Mazen Sidani, Fady Geara, Assaf-Diab Mona, Josianne Al-Hmaira, Makhluf J Haddadin, Ghazi Zaatari
• Journal: International journal of oncology (Int J Oncol) Vol. 24 Issue 5 Pg. 1121-31 (May 2004) ISSN: 1019-6439 [Print] Greece
• PMID: 15067333 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Drug Combinations
• Hypoxia-Inducible Factor 1, alpha Subunit
• Laminin
• Proteoglycans
• Quinoxalines
• Radiation-Sensitizing Agents
• Transcription Factors
• Vascular Endothelial Growth Factor A
• matrigel
• Collagen
• quindoxin

Topics

• Adenocarcinoma (blood supply, metabolism, radiotherapy)
• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Blotting, Western
• Carcinoma, Lewis Lung (blood supply, metabolism, radiotherapy)
• Cell Hypoxia (drug effects)
• Cell Survival (drug effects)
• Collagen (chemistry, metabolism)
• Combined Modality Therapy
• Drug Combinations
• Female
• Hypoxia-Inducible Factor 1, alpha Subunit
• Laminin (chemistry, metabolism)
• Mammary Neoplasms, Experimental (blood supply, metabolism, radiotherapy)
• Mice
• Mice, Inbred C57BL
• Necrosis
• Neovascularization, Pathologic (prevention & control, radiotherapy)
• Proteoglycans (chemistry, metabolism)
• Quinoxalines (therapeutic use)
• Radiation Tolerance
• Radiation, Ionizing
• Radiation-Sensitizing Agents
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• Tumor Stem Cell Assay
• Vascular Endothelial Growth Factor A (genetics, metabolism)