title: Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule.
abstract: 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.
authors.affiliation: Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Slaton
authors.forename: P
authors.initials: P
authors.lastname: Perrotte
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: C P
authors.initials: CP
authors.lastname: Dinney
authors.forename: I J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D020780:Matrix Metalloproteinase 9