Abstract CCL2, (CC-chemokine ligand 2 or monocyte chemoattractant protein-1 (MCP-1)), is overexpressed in many human tumors and is believed to exert pro-tumor effects by recruiting monocytes to the tumor, where these cells become tumor associated macrophages (TAMs). TAMs secrete growth factors that stimulate angiogenesis and tumor growth, as well as proteases to promote tumor invasion and metastasis. CCL2 expression levels in primary breast tumors have been correlated with macrophage infiltration and blood vessel density, which in turn is correlated with disease stage and prognosis. These correlations indicate that CCL2 is a key player in tumor macrophage infiltration and/or tumor growth/invasion, and suggest that neutralizing CCL2 could be an effective form of therapy for breast cancer patients.The objective of these studies was to investigate whether CCL2 blockade could inhibit tumor growth in mice bearing human breast tumors. The human breast tumor cell lines MDA-MB-231 (ER-, PR-, Her2-) and MDA-MB-361 (ER+, PR+, Her2+) were implanted orthotopically in immunocompromised mice, and in both models the primary tumors metastasized to lungs and brain. Neutralizing antibodies to human CCL2 (CNTO 888) and to the mouse orthologs, MCP-1 and MCP-5, were administered therapeutically, either as a cocktail (termed CCL2 blockade) or individually to study the relative roles of host vs tumor derived CCL2 in promoting tumor growth.In both tumor models, CCL2 blockade significantly inhibited the growth of established primary tumors in the mammary fat pad. In addition, CCL2 blockade inhibited metastasis to distant sites. As measured by Taqman, visual inspection and immunohistochemistry, mice with MDA-MB-361 tumors treated with CCL2 blockade showed significantly reduced metastasis to lungs and brain, while mice bearing MDA-MB-231 tumors showed significantly reduced metastasis to lungs.To define the relative roles of human tumor-derived CCL2 vs mouse host-derived MCP-1/MCP-5, in vivo monotherapy tumor studies were conducted using the individual neutralizing antibodies. These studies included the mammary fat pad model and a tail vein metastasis model. In both cases, only the treatment with the anti-mouse MCP-1 antibody significantly inhibited primary tumor growth and distant metastasis, indistinguishable from the effect of CCL2 blockade treatment. In the tail vein metastasis model, the antibody treatment resulted in significantly fewer detectable lesions with these lesions showing a significant reduction in both tumor size and growth fraction, suggesting antibody treatment inhibits tumor seeding and growth. Mechanistic studies are in progress to further understand the basis of the anti-tumor effect mediated by the antibody treatment. These results demonstrate that host-derived MCP-1, produced from the tumor microenvironment, plays the critical role in tumor growth and metastasis in these models of human breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6095.

Objective: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin) as treatment for choroidal neovascularisation (CNV) associated with angioid streaks Methods: A non-randomised, interventional case series conducted on eyes with subfoveal CNV associated with angioid streaks. Intravitreal bevacizumab (1.25 mg in 0.05 ml) was injected into nine eyes of six patients between August 2005 and December 2007. Treatment efficacy was assessed based on pre- and post-treatment visual acuity and optical coherence tomography (OCT). Results: With a mean follow-up of 19 months (range 10 to 28 months), the best corrected visual acuity improved by three or more lines in four eyes (44.4%), remained within two lines of baseline in four eyes (44.4%) and decreased by three or more lines in one eye (11.1%). Central foveal thickness (CFT) measured by OCT decreased an average of 67.7 μm (range +11 to −175 μm) with an average improvement in standardised change in macular thickening of 46.6% (range −12% to +84.5%). No injection-related complications or drug-related side effects were observed. Conclusions: Intravitreal bevazicumab for the treatment of subfoveal CNV secondary to angioid streaks mildly reduced central foveal thickness with a trend toward stabilisation of visual acuity. Additional follow-up and a larger patient cohort are needed to evaluate the long-term effects of this treatment.

Developing novel antibiotics is urgently needed with emergency of drug resistance. Vancomycin, the last resort for intractable Gram-positive bacterial infections, is ineffective against Gram-negative bacteria and vancomycin resistant bacteria. Herein, we report a series of novel vancomycin derivatives carrying LPS binding peptides, vancomycin-LPS binding peptide conjugates (VPCs). The LPS binding peptides were conjugated onto 4 sites of vancomycin via CuAAC or maleimide- sulfydryl addition, and the formed VPCs were screened against VISA/VRE and Gram-negative strains. VPCs exhibited enhanced activity against vancomycin resistant bacteria and obtained the activity against Gram-negative bacteria in vitro, providing a novel strategy for vancomycin modification and glycopeptide antibiotics synthesis.

Abstract Matrix metalloproteinases (MMPs) are endopeptidases that play pivotal roles in promoting tumor disease progression, including tumor angiogenesis. In many solid tumors, MMP expression could be attributed to tumor stromal cells and is partially regulated by tumor-stroma interactions via tumor cell–associated extracellular matrix metalloproteinase inducer (EMMPRIN). The role of EMMPRIN during tumor angiogenesis and growth was explored by modulating EMMPRIN expression and activity using recombinant DNA engineering and neutralizing antibodies. In human breast cancer cells, changes in EMMPRIN expression influenced vascular endothelial growth factor (VEGF) production at both RNA and protein levels. In coculture of tumor cells and fibroblasts mimicking tumor-stroma interactions, VEGF expression was induced in an EMMPRIN- and MMP-dependent fashion, and was further enhanced by overexpressing EMMPRIN. Conversely, VEGF expression was inhibited by suppressing EMMPRIN expression in tumor cells, by neutralizing EMMPRIN activity, or by inhibiting MMPs. In vivo, EMMPRIN overexpression stimulated tumor angiogenesis and growth; both were significantly inhibited by antisense suppression of EMMPRIN. Expression of both human and mouse VEGF and MMP, derived from tumor and host cells, respectively, was regulated by EMMPRIN. These results suggest a novel tumor angiogenesis mechanism in which tumor-associated EMMPRIN functionally mediates tumor-stroma interactions and directly contributes to tumor angiogenesis and growth by stimulating VEGF and MMP expression.

s for the 19th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer, San Francisco, California, November 4-7, 2004: Antibody Therapy

s for the 19th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer, San Francisco, California, November 4-7, 2004: Antibody Therapy

s for the 19th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer, San Francisco, California, November 4-7, 2004: Antibody Therapy

Proc Amer Assoc Cancer Res, Volume 45, 2004 2998 Increased expression and activity of urokinase and its receptor, uPAR, has been associated with tumor growth and metastasis, and blockage of the interaction between urokinase and uPAR by peptide antagonists or antisense methods has been demonstrated to decrease tumor growth, angiogenesis and metastasis. Using a monoclonal rat antibody against murine uPAR that interferes with the binding of uPA to its receptor, we found significant inhibition of bFGF-stimulated angiogenesis in a mouse subcutaneous Matrigel model. In vitro, antibody blockage of the uPA/uPAR interaction reduced the invasion of murine Lewis lung carcinoma cells through reconstituted basement membrane, as well as the adhesion of these cells to vitronectin. In an in vivo tumor model, nude mice bearing subcutaneous murine Lewis lung tumors were treated with anti-uPAR via i.p. injection three times weekly (10 mg/kg). Although primary tumor growth was not affected, the number of lung metastases was significantly reduced by antibody treatment, consistent with the involvement of uPA/uPAR in the early steps of the metastatic cascade. These observations suggest that blockage of the uPA/uPAR interaction by an antibody can inhibit multiple processes involved in tumor progression.