The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model
Michael H Weber1, Joanne Lee, F William Orr
1Department of Pathology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada. michael.weber@nrc.ca
Abstract:
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.
Insights
Neovastat (AE-941) significantly reduced bone destruction and osteolytic lesions caused by breast cancer cell metastasis in mice. This natural angiogenesis inhibitor shows promise in preventing bone metastases in cancer patients.
Area of Science:
- Oncology
- Cancer Metastasis
- Bone Biology
Background:
- Bone metastases are characterized by bone destruction driven by factors from metastatic cells.
- These factors include osteoclast activators and collagen-degrading proteases.
- The human breast cancer cell line MDA-MB-231 is known to metastasize to bone.
Purpose of the Study:
- To investigate if Neovastat (AE-941), an angiogenesis inhibitor, can regulate factors relevant to bone metastasis formation.
- To assess Neovastat's effect on MDA-MB-231 cell-induced bone destruction in vitro and in vivo.
Main Methods:
- In vitro: Assessed Neovastat's effect on extracellular matrix degradation induced by MDA-MB-231 cells and SaOS-2 osteoblast-like cells.
- In vitro: Measured Neovastat's inhibition of matrix metalloproteinase (MMP)-9 activity.
- In vivo: Evaluated Neovastat's impact on MDA-MB-231 cell-induced bone metastases in nude mice via intracardiac inoculation.
Main Results:
- Neovastat prevented osteoid-like matrix degradation in vitro.
- Neovastat inhibited MMP-9 activity in MDA-MB-231 cells.
- In vivo, Neovastat treatment significantly reduced medullary bone loss (19% decrease vs. 83% in controls) and decreased osteolytic lesions by 33%.
Conclusions:
- Neovastat effectively inhibits key processes involved in bone metastasis.
- The compound shows potential in preventing the spread, growth, and osteolysis associated with bone metastases.
- Neovastat may be a valuable therapeutic agent for managing bone metastases in cancer patients.
