title: A novel animal model for hemangiomas: inhibition of hemangioma development by the angiogenesis inhibitor TNP-470.
abstract: Hemangiomas represent the most frequent tumors of infancy. However, the pathogenesis of these tumors is still largely unknown, and current treatment of juvenile hemangiomas remains unsatisfactory. Here we present a novel animal 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 multiple cutaneous, intramuscular (i.m.), and cerebral hemangiomas with 100% frequency. Histological examination of the brain revealed the formation of immature lesions as soon as 4 days postinfection (p.i.). The subsequent exponential growth of the hemangiomas, both in number and size, was associated with 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, urokinase-type plasminogen activator, and vascular endothelial growth factor. Mature cerebral hemangiomas also expressed von Willebrand factor. Cerebral 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 been 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 delayed tumor-associated mortality [mean day of death, 28.2 +/- 3.3 (P < 0.001)]. Even if therapy was initiated when cerebral hemangiomas were already macroscopically visible (i.e., 9 days p.i.), a significant delay in hemangioma-associated mortality was observed. Also, the IFN-inducer polyinosinic-polycytidylic acid caused a delay of 9 days (P < 0.005) in tumor-associated mortality when 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 angiogenic mechanism(s) underlying hemangioma progression; and (b) the effect of anti-angiogenic compounds on vascular tumor growth.
authors.affiliation: Rega Institute for Medical Research, University Hospitals, Leuven, Belgium. Sandra.Liekens@rega.kuleuven.ac.be
authors.forename: S
authors.initials: S
authors.lastname: Liekens
authors.forename: E
authors.initials: E
authors.lastname: Verbeken
authors.forename: M
authors.initials: M
authors.lastname: Vandeputte
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000517:prevention & control* / Q000821:virology; D002472:Cell Transformation, Viral; D003510:Cyclohexanes; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006391:Hemangioma / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007279:Injections, Subcutaneous; D007369:Interferon Inducers / Q000627:therapeutic use; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011070:Poly I-C / Q000627:therapeutic use; D011120:Polyomavirus / Q000472:pathogenicity*; D027601:Polyomavirus Infections / Q000188:drug therapy*; D051381:Rats; D012717:Sesquiterpenes / Q000627:therapeutic use*; D012737:Sex Factors; D014412:Tumor Virus Infections / Q000188:drug therapy*; D019562:Viral Load
chemical_list: D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D007369:Interferon Inducers; D012717:Sesquiterpenes; D011070:Poly I-C; D000077609:O-(Chloroacetylcarbamoyl)fumagillol