Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms.

Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon cancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). Mice were sacrificed when they became moribund as determined by a blinded observer. In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time. SU6668 increased median survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time. In addition, pericyte vessel coverage and tumor vascularity were significantly decreased in mice treated with SU6668. Based on current knowledge of endothelial cell survival, these data suggest that SU6668 may prevent tumor endothelial cell survival directly (vascular endothelial growth factor) and indirectly (pericyte coverage) by affecting endothelial cell survival mechanisms.

Monoclonal antibodies against Pseudomonas aeruginosa outer membrane antigens: isolation and characterization.

Hybridomas secreting monoclonal antibodies specific for Pseudomonas aeruginosa outer membrane antigens were isolated. One of the antibodies was highly specific for the O antigen of the lipopolysaccharide of International Antigen Typing Scheme serotype 5 strains, reacting only weakly with a serotype 17 strain and failing to react with the outer membranes of strains representing 15 other serotypes. This monoclonal antibody was able to agglutinate heat-killed bacterial cells as well as lipopolysaccharide-coated sheep erythrocytes. Two other monoclonal antibodies were able to interact with the outer membranes of strains representing all 17 serotypes, although they were unable to agglutinate heat-killed bacterial cells. One of these was shown to be specific for the major outer membrane lipoprotein H2. The antigenic site against which this monoclonal antibody reacted was present in the outer membranes of two Pseudomonas fluorescens strains, two Pseudomonas putida strains, a Pseudomonas anguilliseptica strain, and an Azotobacter vinelandii strain, but not in the outer membranes of five other bacterial species.