o-(chloroacetylcarbamoyl)fumagillol and Hemangioma

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. We have presented a novel animal model for hemangiomas. Induction of hemangioma development was achieved by intraperitoneal (i.p.) infection of 4-day-old rats with the mouse polyoma virus (PyV). This led to the development of multiple hemangiomas, which caused death of the untreated animals within 3 weeks p.i. The hemangiomas had the histological and immunohistochemical features reminiscent of human hemangiomas. Moreover, the angiogenesis inhibitor TNP-470 afforded a protective effect in this model. Tumor growth is determined by the balance between cell proliferation and apoptosis and is modulated by angiogenesis. Angiogenesis is a complex process, involving extensive interplay between cells, extracellular matrix components and soluble factors. Each of these factors represents a possible target for pharmacological intervention to inhibit blood vessel formation and subsequently tumor growth. We have focused on specific inhibitors of the angiogenesis inducers basic fibroblast growth factor and Thymidine Phosphorylase and studied their mechanism of action and anti-angiogenic activity. In addition, we have shown that the apoptosis-inducer cidofovir inhibits PyV-induced hemangioma development in rats and the growth of virus-independent, vascular tumors in mice. So far, cidofovir has only been evaluated clinically for the treatment of human papillomavirus (HPV)-associated tumors. Our findings open new perspectives for the use of cidofovir as an anti-tumor agent in the therapy of hemangiomas and other tumors that are not associated with an oncogenic virus.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Division; Cidofovir; Cyclohexanes; Cytosine; Disease Models, Animal; Fibroblast Growth Factor 2; Growth Substances; Hemangioma; Humans; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Organophosphonates; Organophosphorus Compounds; Rats; Sesquiterpenes; Thymidine Phosphorylase; Tumor Virus Infections

Vascular tumors occur in approximately 10% of infants, and range from small cherry-red lesions to large, life-threatening tumors. Although the majority of these tumors involute after several years, there are few therapeutic options and their use is limited by the risk of side-effects. The recent increase in understanding of angiogenesis has led to investigations of new antiangiogenic treatment options using models of vascular tumors in mice. These studies have demonstrated the success of a variety of antiangiogenic approaches, including systemic administration of the antiangiogenic proteins AGM-1470 and angiostatin or of the matrix metalloproteinase inhibitor batimastat, and gene gun therapy with interleukin-12. Although these trials provide further evidence of the role of angiogenesis in the enlargement of these vascular tumors, their potential utility and safety await future trials in patients.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Cyclohexanes; Disease Models, Animal; Hemangioma; Humans; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Plasminogen; Sesquiterpenes; Skin Neoplasms

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.

Topics: Animals; Animals, Newborn; Antibiotics, Antineoplastic; Body Weight; Brain Neoplasms; Cell Transformation, Viral; Cyclohexanes; Disease Models, Animal; Disease Progression; Endothelium, Vascular; Female; Hemangioma; Humans; Infant; Infant, Newborn; Injections, Subcutaneous; Interferon Inducers; Male; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Poly I-C; Polyomavirus; Polyomavirus Infections; Rats; Sesquiterpenes; Sex Factors; Tumor Virus Infections; Viral Load

Hemangioma and other angiomatous diseases of childhood are common. Although most lesions are harmless and self-limiting, some are associated with significant morbidity and may be life-threatening. Interferon-alpha, a weak angiogenesis inhibitor, recently has been found to significantly reduce the mortality rate associated with life-threatening hemangiomas. The effectiveness of AGM-1470, a potent inhibitor of angiogenesis derived from the fungal product fumagillin, was tested in a mouse model of hemangioendothelioma. Thirty syngeneic mice were implanted with cells derived from a spontaneous mouse hemangioendothelioma. Tumors formed within 2 to 3 days, and the animals were then treated systemically with AGM-1470 or with saline and vehicle alone. After 22 days, the tumor volume in the saline-treated mice was 7368 +/- 2723 mm3, versus 709 +/- 73 mm3 in the mice that received AGM-1470 (P < .001). Survival was prolonged for the AGM-1470-treated mice, and there was no evidence of drug-related toxicity. All experiments were repeated. In this study, AGM-1470 was safe and highly effective in the treatment of hemangioendothelioma. AGM-1470, and other antiangiogenic agents, may provide safe and effective treatment for hemangioma and other angiomatous diseases.

Topics: Animals; Cyclohexanes; Hemangioendothelioma; Hemangioma; Mice; Neoplasms, Experimental; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Survival Rate; Tumor Cells, Cultured