The angiogenesis inhibitor TNP-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease

Tumor vascularity is highly correlated with disease outcome in neuroblastom a, Thus, novel therapeutics that target the vascular endothelium are candid ates for incorporation into clinical trials. We therefore examined the effe ct of TNP-470 on human neuroblastoma growth in mouse models reflecting both clinically evident and minimal disease. Mice were inoculated s.c. or by ta il vein injection with 10(7) human neuroblastoma-derived CHP-134 cells and treated with TNP-470 (100 mg/kg/dose s.c. three times a week or by continuo us infusion) or saline, Treatment was given as a single agent in establishe d xenografts, 10 days after 450 mg/kg of cyclophosphamide, or 12 h after tu mor inoculation. Tumor growth rate was markedly inhibited in mice receiving TNP-470 administered alone both s.c. and by continuous infusion with a tre atment to control ratio (T:C) at day 16 of 0.3 (P < 0.001) and a T:C at day 30 of 0.4 (P = 0.029) for each dosing method, respectively. TNP-470 also s ignificantly inhibited tumor growth when administered following cyclophosph amide (T:C at day 30 = 0.2, P < 0.001) and inhibited disease establishment when given shortly after xenograft inoculation (T:C at day 30 = 0.1, P < 0. 001) or tail vein injection. TNP-470 was shown to directly inhibit angiogen esis by Matrigel assay (P = .010) and to increase the apoptotic index in tr eated tumors. These data show that TNP-470 is a potent inhibitor of human n euroblastoma growth rate and tumorigenicity. We speculate that TNP-470 may be a useful adjuvant therapy for high-risk neuroblastoma patients, particul arly when used in settings of minimal disease status.