Open-i Logo
Submit this form
Results 1-1   << Back

 
In vivo efficacy of CXCR7 antagonist. Efficacy of CCX754 was evaluated in syngeneic or xenograft mouse models engrafted with (A) human B lymphoma IM9 cells, (C) human A549 lung carcinoma cells, or (D) mouse LL/2 Lewis lung carcinoma cells. Control groups receiving vehicle alone were included in all experiments. Horizontal bars in C indicate means, and error bars in D represent SEM. Images in A show peritoneal cavity of mice bearing IM9 tumor cells and receiving either CXCR7 antagonist (right) or vehicle alone (left). (B) Immunohistochemical analysis of CXCR7 expression on a human biopsy sample of a malignant lung carcinoma. n = 8 in all groups. Statistical differences between treatment groups were calculated using survival curve statistics and the Student's t test using GraphPad Prism software.
© Copyright Policy

fig9: In vivo efficacy of CXCR7 antagonist. Efficacy of CCX754 was evaluated in syngeneic or xenograft mouse models engrafted with (A) human B lymphoma IM9 cells, (C) human A549 lung carcinoma cells, or (D) mouse LL/2 Lewis lung carcinoma cells. Control groups receiving vehicle alone were included in all experiments. Horizontal bars in C indicate means, and error bars in D represent SEM. Images in A show peritoneal cavity of mice bearing IM9 tumor cells and receiving either CXCR7 antagonist (right) or vehicle alone (left). (B) Immunohistochemical analysis of CXCR7 expression on a human biopsy sample of a malignant lung carcinoma. n = 8 in all groups. Statistical differences between treatment groups were calculated using survival curve statistics and the Student's t test using GraphPad Prism software.

Mentions: The role of CXCR7 on cell survival and adhesion, coupled with the pronounced expression of the receptor on transformed cells and activated endothelial cells, prompted us to examine its role in mammalian models of tumor formation. To this end, we tested the CXCR7 antagonist CCX754 (14), an analogue of CCX451 that has superior in vivo pharmacokinetic properties, in mouse models engrafted with various tumors. CCX754's pharmacokinetic properties permitted once daily dosing (Fig. 8 A), bound to CXCR7 with low nM affinity (Fig. 8 B), and demonstrated high selectivity for CXCR7 over other CXCRs (Table I). Efficacy of CCX754 was evaluated in immunodeficient or syngeneic mice engrafted with either human B lymphoma IM9 (Fig. 9 A), human lung carcinoma A549 (Fig. 9 C), or mouse lung carcinoma LL/2 (Fig. 9 D). Each of these tumors was shown to express CXCR7 by both the signature 125I SDF-1 binding profile and flow cytometric staining with the anti-CXCR7 mAb (unpublished data).

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ - J. Exp. Med. (2006)

Bottom Line: This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11).However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties.Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.

Affiliation: ChemoCentryx, Inc., Mountain View, CA 94043, USA.

ABSTRACT
The chemokine stromal cell-derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.

View Similar Images In: Results Collection              View Article: Pubmed Central PubMed      Show All Figures 
getmorefigures.php?pmc=2118398&rFormat=json&query=null&fields=all&favor=none&it=none&sub=none&sp=none&coll=none&req=5
Show MeSH

Lister Hill National Center for Biomedical Communications
U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894
National Institutes of Health, Department of Health & Human Services
Privacy, Accessibility, Frequently Asked Questions, Contact Us, Collection
Freedom of Information Act, USA.gov