Sasaki A, Alcalde R E, Nishiyama A, Lim D D, Mese H, Akedo H, Matsumura T
Department of Oral and Maxillo-Facial Surgery II, Okayama University Dental School, Japan.
Cancer Res. 1998 Feb 1;58(3):462-7.
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 Histological examination of the femurs of the untreated group revealed that most of the cancellous bone had been replaced by the metastatic cancer.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.
血管生成抑制剂TNP - 470，即6 - O -（N - 氯乙酰基 - 氨基甲酰基）- 烟曲霉素，是烟曲霉素的半合成类似物，对多种肿瘤的体内肿瘤生长和转移具有强大的抑制活性。然而，该药物是否抑制骨转移尚不清楚。我们在裸鼠骨转移模型中研究了TNP - 470的作用，该模型通过心内注射人乳腺癌细胞系MDA - MB - 231（MDA - 231）产生溶骨性骨转移。将MDA - 231细胞接种到左心室后，每周三次皮下注射TNP - 470（30 mg/kg）或PBS，持续4周。在此期间后，TNP - 470不仅减少了溶骨性骨转移的数量和面积（分别约为60%和70%），还降低了其放射性透亮度。对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取代。在转移性MDA - 231癌细胞侵袭骨髓周围的小梁骨表面，有大量活跃的破骨细胞。相比之下，在TNP - 470治疗小鼠的骨骼中，骨破坏明显受到抑制，破骨细胞也少得多。在1,25 - 二羟基维生素D3作用下的小鼠骨髓培养中，成熟的功能性破骨细胞在体外形成，TNP - 470显著抑制抗酒石酸酸性磷酸酶阳性多核破骨细胞样细胞的形成。此外，TNP - 470抑制了白细胞介素 - 1β（一种破骨细胞刺激剂）处理的颅骨的体内骨吸收。这些数据表明，TNP - 470不仅通过抑制血管生成发挥抗肿瘤作用，还通过抑制破骨细胞性骨吸收来抑制骨转移。我们的结果表明，TNP - 470应该是一种潜在有益的药物，可用于治疗溶骨性转移。
