Thomas Richard Kasser

Emerging Role of Apelin as a Therapeutic Target in Cancer: A Patent Review

Since tumors cannot grow or spread without forming new blood vessels, inhibiting angiogenesis is an excellent approach for the treatment of cancer. Further, inhibitors of angiogenesis have mild side effects since they act on endothelial cells, which eliminate the possibility of developing resistance or tolerance in tumor cells, unlike that seen with chemotherapy drugs. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab acts by preventing new blood vessel formation in solid tumors and is approved by FDA to treat colorectal, lung, breast, glioblastoma and kidney cancers. The registration of this drug and its ongoing success in the clinic has validated the targeting of angiogenesis as an important approach to the treatment of solid tumors. Apelin is a novel angiogenic factor and recent studies indicate that apelin promotes angiogenesis, lymphangiogenesis and tumor growth in vivo and the angiogenic potential of apelin is similar to that of VEGF. Also, apelin expression is upregulated and has been shown to be associated with clinical outcome in certain human cancers. Thus, inhibition of apelin activity might lead to a new class of anti-angiogenesis drugs which should be more efficacious than those currently on the market due to their ability to be both anti-angiogenic as well as anti-lymphangiogenic. There are very few patents on the angiogenic effects of apelin and this review article focuses on these patented claims related to inhibiting apelin signaling and sheds more light on how blocking apelin signaling might open doors to a new class of angiogenic inhibitors.

A method for the determination of glucose synthesis in isolated bovine hepatocytes.

A simple method for determining glucose synthesis from radiolabeled precursors in isolated bovine hepatocytes using ion exchange resins is presented. This method allows processing of multiple small volume samples using suspensions of anion and cation exchange resins rather than traditional stacked column separation methods. Hepatocytes were isolated from calf liver by collagenase perfusion of the caudate lobe and were incubated with (14)C-labeled lactate or propionate as gluconeogenic substrates. Glucose synthesis was determined in an aliquot of cell suspension that was vortexed with a slurry of anion exchange (acetate form) resin, followed by a slurry of cation exchange resin. Newly synthesized, labeled glucose was recovered in the supernatant after centrifugation and quantitated by scintillation counting. Using this procedure, more than 98% of the unused labeled precursor was bound to the ion exchange resin and essentially 100% of a labeled glucose tracer was recovered in the supernatant. Pretreatment of hepatocyte suspensions with glucose oxidase was shown to eliminate the accumulation of radioactivity in the supernatant, thus confirming the specificity of this technique for measurement of newly synthesized glucose. This method was sensitive to changes in the rate of hepatic gluconeogenesis that resulted from changes in substrate concentration or the addition of glucagon or fatty acids to the hepatocyte incubations.