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

• Published in: Clinical cancer research 1999-10, Vol.5 (10), p.2726-2734
• Main Authors: SLATON, J. W, PERROTTE, P, INOUE, K, DINNEY, C. P. N, FIDLER, I. J
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Dose-Response Relationship, Drug; Down-Regulation; Fibroblast Growth Factor 2 - genetics; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunotherapy; Interferon-alpha - pharmacology; Male; Matrix Metalloproteinase 9 - genetics; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Recombinant Proteins; Tumor Cells, Cultured; Urinary Bladder Neoplasms - blood supply; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism
• ISSN: 1078-0432; 1557-3265

The purpose of this study was to identify and optimize the antiangiogenic activity of IFN-alpha against human bladder cancer cells growing in the bladder of nude mice. 253J B-V IFN(R) cells (resistant to antiproliferative effects of IFN-alpha or IFN-beta) were implanted into the bladder wall of nude mice. Three days later, the mice were treated with s.c. injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, 3, or 7 times/week). Daily therapy with IFN-alpha produced the most significant inhibition of tumor growth, tumor vascularization, and down-regulation of basic fibroblast growth factor and matrix metalloprotease-9 mRNA and protein expression. Changing dose and schedule of IFN-alpha administration had minimal effects 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 produced maximal inhibition of bFGF and MMP-9 expression (mRNA and protein), maximal reduction in tumor vessel density, and maximal reduction in serum levels of bFGF. Daily administration of higher doses of IFN-alpha failed to produce significant antiangiogenic effects. These data suggest that the antiangiogenic activity of IFN-alpha is dependent on frequent administration of optimal biological dose and not maximal tolerated dose.