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In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. Gene silencing of CysLT 1 in HT29-Luc2 cells significantly reduced expression of calpain-2. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. colorectal cancer angiogenesis cysteinyl leukotriene drug discovery xenograftĬolorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries.
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* These authors contributed equally to this workĬorrespondence to: Breandán N. James’s Hospital, Dublin, Irelandģ Department of Histopathology, Trinity College Dublin Central Pathology Laboratory, St James’s Hospital, Dublin, Ireland 1 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, IrelandĢ Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St.