Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J
Department of Surgery, Children's Hospital, Boston, Massachusetts.
Nature. 1990 Dec 6;348(6301):555-7. doi: 10.1038/348555a0.
Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.
新血管生成对肿瘤生长至关重要，并且是多种血管生成性疾病（如糖尿病性视网膜病变、血管瘤、关节炎和牛皮癣）的主要特征。认识到控制不受抑制的毛细血管生长所具有的潜在治疗益处，促使人们寻找安全有效的血管生成抑制剂。我们在此报告了一类新型抑制剂的合成，这些抑制剂是烟曲霉素（烟曲霉自然分泌的一种抗生素）的类似物。我们最初是从受污染的毛细血管内皮细胞培养物中分离出这种真菌的。纯化后的烟曲霉素在体外可抑制内皮细胞增殖，在体内可抑制肿瘤诱导的血管生成；它还能抑制小鼠肿瘤生长，但由于会导致严重体重减轻，长期给药受到限制。烟曲霉素类似物的合成产生了强效血管生成抑制剂（“血管抑制素”），其能抑制多种肿瘤生长且副作用相对较少。
