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.