Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule

The purpose of this study was to identify and optimize the antiangiogenic a ctivity of IFN-alpha against human bladder cancer cells growing in the blad der of nude mice, 253J B-V IFNR cells (resistant to antiproliferative effec ts of IFN-alpha or IFN-beta) were implanted into the bladder wall of nude m ice, Three days later, the mice were treated with s.c. injections of IFN-al pha (70,000 units/week) at different dosing schedules (1, 2, 3, or 7 times/ week), Daily therapy with IFN-alpha produced the most significant inhibitio n of tumor growth, tumor vascularization, and down-regulation of basic fibr oblast growth factor and matrix metalloprotease-9 mRNA and protein expressi on. Changing dose and schedule of IFN-alpha administration had minimal effe cts on the expression of vascular endothelial growth factor or interleukin 8. The daily s.c. administrations of 5,000 or 10,000 units IFN-alpha-2a pro duced maximal inhibition of bFGF and MMP-9 expression (mRNA and protein), m aximal reduction in tumor vessel density, and maximal reduction in serum le vels of bFGF, Daily administration of higher doses of IFN-alpha failed to p roduce significant antiangiogenic effects. These data suggest that the anti angiogenic activity of IFN-alpha is dependent on frequent administration of optimal biological dose and not maximal tolerated dose.