Protein binding alters the activity of suramin, carboxyamidotriazole, and UCN-01 in an ex vivo rat aortic ring angiogenesis assay.
Angiogenesis inhibitors are currently in clinical development for cancer. These agents pose unique developmental challenges: (a) determining maximum biological doses versus maximum tolerated doses; (b) defining response criteria other than objective tumor responses; and (c) defining safe regimens for prolonged, chronic administration. The current in vitro angiogenesis assays used in the screening and preclinical development of antiangiogenic agents each have their own advantages and disadvantages, yet all seem to underestimate the importance and impact of in vivo protein-drug interactions. We have developed a human serum rat aortic ring angiogenesis bioassay that highlights protein binding concerns using three anticancer agents that have documented antiangiogenic activity: suramin, carboxyamidotriazole, and 7-hydroxystaurosporine. We have determined that the bioassay concentrations of suramin (100 microg/ml) and 7-hydroxystaurosporine (> 1 microg/ml), but not carboxyamidotriazole (> or = 60 microg/ml), that inhibit microvessel formation are consistent with target plasma levels achievable in the clinic. We conclude that assays such as the human serum rat aortic ring bioassay may prove useful in predicting the concentrations of protein-bound antiangiogenic agents required for free fraction biological activity.
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Medicine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
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D000470:Alkaloids / Q000378:metabolism / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology; D001681:Biological Assay / Q000379:methods; D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000031:analogs & derivatives; D013498:Suramin / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology
D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D001798:Blood Proteins; D014230:Triazoles; D013498:Suramin; C062058:carboxyamido-triazole; C054852:7-hydroxystaurosporine; D019311:Staurosporine