Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption.
Angiogenesis inhibitor TNP-470 inhibits human breast cancer osteolytic bone metastasis in nude mice through the reduction of bone resorption.
复制标题
血管生成抑制剂TNP-470通过减少骨吸收抑制人乳腺癌裸鼠溶骨性骨转移。
作者：
Akira Sasaki;R. Alcalde;A. Nishiyama;Darwin D. Lim;H. Mese;Hitoshi Akedo;Tomohiro Matsumura
血管生成抑制剂TNP-470是烟曲霉素的半合成类似物6-O-（N-氯乙酰基-氨甲酰基）-烟曲霉醇（6-O-（N-chloroacetyl-carbamoyl）-fumagilol），对多种肿瘤的生长和转移有较强的抑制作用。然而，这种药物是否抑制骨转移仍是未知的。我们研究了TNP-470在裸鼠骨转移模型中的作用，在该模型中，心内注射人乳腺癌细胞系MDA-MB-231（MDA-231）产生溶骨性骨转移。在将MDA-231细胞接种到左心室中之后，将TNP-470（30 mg/kg，每周三次）或PBS皮下注射到左心室中。给药4周。此后，TNP-470不仅减少了溶骨性骨转移瘤的数量和面积（分别约为60%和70%），还减少了其射线可透性。未治疗组股骨的组织学检查显示，大部分松质骨已被转移性癌症取代。大量活跃的破骨细胞沿着骨小梁表面存在，周围是侵袭骨髓的转移性MDA-231癌细胞。相反，在TNP-470处理的小鼠的骨中，骨破坏被显著抑制，破骨细胞少得多。在小鼠骨髓培养下的1，25-二羟维生素D3，其中成熟的功能性破骨细胞在体外形成，TNP-470显着抑制形成的抗酒石酸酸性磷酸酶阳性多核破骨细胞样细胞。此外，TNP-470抑制了用破骨细胞刺激剂白细胞介素-1 β处理的颅盖骨的体内骨吸收。这些数据表明，TNP-470抑制骨转移不仅通过其抑制血管生成的抗肿瘤作用，而且通过抑制骨细胞骨吸收。我们的研究结果表明，TNP-470应该是一个潜在的有益的药物，用于治疗溶骨性转移。
Angiogenesis inhibitor TNP-470, 6-O-(N-chloroacetyl-carbamoyl)-fumagillol, semisynthetic analogue of fumagillin, has strong inhibitory activities against in vivo tumor growth and metastasis in a wide variety of tumors. However, it is still unknown whether this agent inhibits bone metastasis. We examined the effects of TNP-470 in a bone metastasis model in nude mice in which intracardiac injection of the human breast cancer cell line MDA-MB-231 (MDA-231) produced osteolytic bone metastasis. After inoculation of MDA-231 cells into the left heart ventricle, TNP-470 (30 mg/kg, three times a week) or PBS was s.c. administrated for 4 weeks. After this period, the TNP-470 had reduced not only the number and area of osteolytic bone metastases (approximately 60 and 70%, respectively) but also their radiolucency. Histological examination of the femurs of the untreated group revealed that most of the cancellous bone had been replaced by the metastatic cancer. Numerous active osteoclasts were present along the trabecular bone surface surrounded by the metastatic MDA-231 cancer cells aggressively invading the bone marrow. In contrast, in the bone from TNP-470-treated mice, bone destruction was markedly inhibited, and there were much fewer osteoclasts. In a murine bone marrow culture under 1,25-dihydroxyvitamin D3 in which mature functional osteoclasts formed in vitro, TNP-470 significantly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells. And also, TNP-470 suppressed the in vivo bone resorption in calvaria treated with interleukin-1beta, an osteoclast stimulator. These data suggested that TNP-470 inhibited bone metastasis through not only antitumor action by its angiogenesis inhibition but also by the inhibition of osteoclastic bone resorption. Our results indicate that TNP-470 should be a potentially beneficial drug to be used in the treatment of osteolytic metastasis.