Nozaki Shinichi, Sissons Sean, Chien Du-Shieng, Sledge George W
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Clin Exp Metastasis. 2003;20(5):407-12. doi: 10.1023/a:1025473709656.
Matrix metalloproteinases (MMPs) have been implicated in the invasion, metastasis, and angiogenesis associated with human cancer by mediating the degradation of extracellular matrix components. In this paper, we report data that show that BAY 12-9566, a novel inhibitor of MMPs, inhibits angiogenesis, tumor regrowth, and the growth of lung metastases. BAY 12-9566, at 15-100 microM, inhibited tubule formation by human endothelial cells in an in vitro model, but did not prevent the proliferation of endothelial and human breast cancer cells. In the MDA-MB-435 human mammary carcinoma xenograft model, in which the primary tumor is transplanted into the murine mammary fat pad, BAY 12-9566, administered daily at a dose of 100 mg/kg/day p.o. after resection of the primary tumor, inhibited local tumor regrowth by 58% without causing any toxic effect. In addition, BAY 12-9566 treatment inhibited the number and volume of lung metastases by 57 and 88%, respectively. These effects were highly correlated with the serum concentration of BAY 12-9566 at the end of treatment. The serum of the treated animals, harvested 24 h after the last treatment, and the tumor regrown at the site of tumor transplant in the treated animals, contained less protein with MMP-9 activity (as measured in a gelatin zymography assay) than the corresponding controls. However, no difference in the activity of MMP-2 was observed. Although all clinical trials in cancer involving BAY 12-9566 have been halted, this MMP inhibitor has never been used in clinical trials in breast cancer. These results suggest that the novel MMP inhibitor BAY 12-9566 maybe a useful and safe oral treatment for breast cancer, adjunctive to surgery.
基质金属蛋白酶（MMPs）通过介导细胞外基质成分的降解，与人癌症的侵袭、转移和血管生成有关。在本文中，我们报告的数据表明，新型MMP抑制剂BAY 12 - 9566可抑制血管生成、肿瘤再生长以及肺转移灶的生长。在体外模型中，15 - 100微摩尔的BAY 12 - 9566可抑制人内皮细胞形成小管，但不影响内皮细胞和人乳腺癌细胞的增殖。在将原发性肿瘤移植到小鼠乳腺脂肪垫的MDA - MB - 435人乳腺癌异种移植模型中，在切除原发性肿瘤后，每天口服给予100毫克/千克/天的BAY 12 - 9566，可抑制局部肿瘤再生长58%，且未产生任何毒性作用。此外，BAY 12 - 9566治疗分别使肺转移灶的数量和体积减少了57%和88%。这些效应与治疗结束时BAY 12 - 9566的血清浓度高度相关。在最后一次治疗后24小时采集的治疗动物血清，以及治疗动物肿瘤移植部位再生长的肿瘤，与相应对照组相比，具有MMP - 9活性的蛋白质含量较少（通过明胶酶谱分析测定）。然而，未观察到MMP - 2活性的差异。尽管涉及BAY 12 - 9566的所有癌症临床试验均已停止，但这种MMP抑制剂从未用于乳腺癌的临床试验。这些结果表明，新型MMP抑制剂BAY 12 - 9566可能是一种对乳腺癌有用且安全的口服治疗药物，可作为手术的辅助治疗。
