ANTIANGIOGENIC THERAPY OF TRANSGENIC MICE IMPAIRS DE-NOVO TUMOR-GROWTH

Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have te sted the proposition that treatment with angiogenesis inhibitors can i nhibit the progression of tumorigenesis after the switch to the angiog enic phenotype. In this model, islet cell carcinomas develop from mult ifocal, hyperproliferative nodules that show the histological hallmark s of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycl ine, and interferon alpha/beta. The treatment regimen markedly attenua ted tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The prolifer ation index of tumor cells in treated and control mice was similar, wh ereas the apoptotic index was doubled in treated tumors. This study sh ows that de novo tumor progression can be restricted solely by antiang iogenic therapy. The results suggest that angiogenesis inhibitors repr esent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangioge nic agents.