Liekens S, Verbeken E, Vandeputte M, De Clercq E, Neyts J
Rega Institute for Medical Research, University Hospitals, Leuven, Belgium.
Cancer Res. 1999 May 15;59(10):2376-83.
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.
血管瘤是婴儿期最常见的肿瘤。然而，这些肿瘤的发病机制仍 largely 未知，目前对青少年血管瘤的治疗仍不尽人意。在此，我们提出一种新的动物模型，用于研究增殖性血管瘤并评估血管生成抑制化合物对其生长的影响。4 日龄大鼠腹腔内（i.p.）感染鼠多瘤病毒后，会以 100%的频率发生多发性皮肤、肌肉内（i.m.）和脑血管瘤。感染后 4 天（p.i.），对大脑进行组织学检查发现形成了不成熟病变。随后血管瘤在数量和大小上呈指数增长，并伴有严重出血和贫血。脑、皮肤和肌肉内病变由充满血液的囊肿组成，组织学上类似于人类海绵状血管瘤，增殖细胞核抗原、尿激酶型纤溶酶原激活剂和血管内皮生长因子染色呈阳性。成熟的脑血管瘤也表达血管性血友病因子。未经治疗的动物在感染后 19.2±1.1 天内死于脑部病变。在用血管生成抑制剂 TNP - 470 进行皮下治疗的动物中，发生的血管瘤明显更少且更小。因此，从感染后 3 天开始，每周两次给予 TNP - 470（50mg/kg），可显著延迟肿瘤相关死亡率[平均死亡天数，28.2±3.3（P < 0.001）]。即使在脑血管瘤已经肉眼可见时（即感染后 9 天）开始治疗，也观察到与血管瘤相关的死亡率显著延迟。此外，当从感染后 3 天开始，每周两次腹腔内给予 5mg/kg 的 IFN 诱导剂聚肌苷酸 - 聚胞苷酸时，可使肿瘤相关死亡率延迟 9 天（P < 0.005）。这里描述的模型可能有助于研究（a）血管瘤进展的血管生成机制；以及（b）抗血管生成化合物对血管肿瘤生长的影响。
