The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model.
Bone metastases are generally associated with bone destruction which occurs in response to factors secreted by metastatic cells. Some of these factors secreted by the metastatic cells activate osteoclats while others are proteases that degrade bone collagen. To determine if Neovastat (AE-941), a naturally occurring multi-functional inhibitor of angiogenesis, is able to regulate properties that are thought to have relevance to their propensity to form bone metastases in vivo, we used the human breast cancer MDA-MB-231 cell line which can metastasize to bone. We showed that Neovastat prevented the degradation of osteoid-like radiolabeled extracellular matrices which was induced by incubation of human SaOS-2 osteoblast-like cells with MDA-MB-231 cells. Moreover, Neovastat was demonstrated to inhibit the gelatinolytic activity of matrix metalloproteinase (MMP)-9 expressed by MDA-MB-231 cells. The potential of Neovastat to retard the spread, growth, and osteolysis of MDA-MB-231 cells was then estimated in vivo. Histomorphometric analysis of the vertebral bodies indicated that MDA-MB-231 cells inoculated in nude mice (intracardiac) successfully generate osteolytic metastases with an 83% reduction of the volume of medullary bone (p< or =0.01). However, when tumor-bearing animals were treated orally with Neovastat, there was only a 19% decrease in medullary bone thus indicating that Neovastat can prevent bone metastasis in this model. Consistent with histological results, radiographic analysis indicated that Neovastat decreased the number of osteolytic lesions by 33% (p< or =0.3). Moreover, a decrease in the tumor volume in bone was observed in Neovastat-treated animals. These results indicate that Neovastat may be useful in preventing bone metastasis in cancer patients.
Weber
Michael H
MH
Department of Pathology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada. michael.weber@nrc.ca
Lee
Joanne
J
Orr
F William
FW
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000556:secondary*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D011859:Radiography; D014020:Tissue Extracts / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D014020:Tissue Extracts; C111481:shark cartilage extract; D020780:Matrix Metalloproteinase 9