A novel animal model for hemangiomas: Inhibition of hemangioma developmentby the angiogenesis inhibitor TNP-470

Hemangiomas represent the most frequent tumors of infancy. How ever, the pa thogenesis of these tumors is still largely unknown, and current treatment of juvenile hemangiomas remains unsatisfactory. Here we present a novel ani mal model to study proliferating hemangiomas and to evaluate the effect of angiostatic compounds on their growth. Intraperitoneal (i.p,) infection of 4-day-old rats with murine polyomavirus resulted in the development of mult iple cutaneous, intramuscular (i.m.), and cerebral hemangiomas with 100% fr equency. Histological examination of the brain revealed the formation of im mature lesions as soon as 4 days postinfection (p.i.). The subsequent expon ential growth of the hemangiomas, both in number and size, was associated w ith severe hemorrhage and anemia. The cerebral, cutaneous, and i.m, lesions consisted of blood-filled cysts, histologically similar to human cavernous hemangiomas and stained positive for proliferating cell nuclear antigen, u rokinase-type plasminogen activator, and vascular endothelial growth factor . Mature cerebral hemangiomas also expressed von Willebrand factor, Cerebra l lesions caused death of the untreated animals within 19.2 +/- 1.1 days p. i. Remarkably fewer and smaller hemangiomas developed in animals that had b een treated s.c. with the angiogenesis inhibitor TNP-470. Accordingly, TNP- 470 (50 mg/kg), administered twice a week from 3 days p.i., significantly d elayed tumor-associated mortality [mean day of death, 28.2 +/- 3.3 (P < 0.0 01)]. Even if therapy was initiated when cerebral hemangiomas were already macroscopically visible (i.e., 9 days p.i.), a significant delay in hemangi oma-associated mortality was observed, Also. the IFN-inducer polyinosinic-p olycytidylic acid caused a delay of 9 days (P < 0.005) in tumor-associated mortality a hen administered i.p. at 5 mg/kg, twice a week, starting at day 3 p.i. The model described here may be useful for investigating (a) the an giogenic mechanism(s) underlying hemangioma progression; and (b) the effect of anti-angiogenic compounds on vascular tumor growth.