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The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing
A C Berger1, A L Feldman, M F Gnant
1Surgery Branch, National Cancer Institute, Bethesda, Maryland, 20892, USA.
Background:
Endostatin is a potent angiogenesis inhibitor, which is currently being used in Phase I trials as an antitumor agent. The purpose of this study was to determine whether endostatin has an effect on wound healing in a murine model.
Materials And Methods:
The function of endostatin was confirmed using a human microvascular endothelial cell (HMVEC) proliferation assay in which cells are treated for 4 days with growth media plus or minus endostatin. Full-thickness incisions were made on the dorsum of athymic nude mice and closed primarily with skin staples. PVA sponges were implanted in some wounds to determine vascular ingrowth. Subsequently, mice were treated with recombinant human endostatin at 20 mg/kg/day or 50 mg/kg/dose BID versus control for a total of 14 days. On Days 2, 4, 8, 12, and 16, three mice per group had serum samples drawn and were sacrificed. Perpendicular breaking strength (N) was determined using an Instron 5540 tensometer. Wound strength was determined by dividing breaking strength by wound area (N/cm(2)). Vascular density in sponges was determined using CD31 immunohistochemistry. Serum endostatin concentrations were determined using a commercially available ELISA kit.
Results:
Endostatin caused a significant reduction of endothelial cell proliferation after 4 days compared to media alone (72%, P = 0.031). At all time points tested, there was no statistical difference in the wound-breaking strength between endostatin and control-treated mice at either the low or high dose. Serum endostatin levels were consistently 10-fold higher in endostatin-treated mice than in controls. No differences in vascular density were seen in endostatin versus control-treated mice as determined by CD31 immunohistochemistry of PVA sponges.
Conclusion:
Therapy with human endostatin does not induce a significant decrease in breaking strength of cutaneous wounds in mice.
Insights
This study investigated endostatin
Area of Science:
- Biomedical research
- Angiogenesis inhibition
- Wound healing
Background:
- Endostatin is a known angiogenesis inhibitor.
- It is currently in Phase I trials for cancer treatment.
- Its effect on wound healing was previously unknown.
Purpose of the Study:
- To evaluate the impact of endostatin on wound healing.
- To assess endostatin's effect in a murine model.
Main Methods:
- Endothelial cell proliferation assays confirmed endostatin's inhibitory function.
- Full-thickness skin wounds were created in mice and treated with endostatin or control.
- Wound breaking strength, vascular ingrowth, and serum endostatin levels were measured.
Main Results:
- Endostatin significantly reduced endothelial cell proliferation (72%, P = 0.031).
- No significant difference in wound breaking strength was observed between endostatin and control groups.
- Vascular density in sponges and wound strength showed no significant changes.
Conclusions:
- Therapeutic administration of endostatin did not impair cutaneous wound healing in mice.
- Endostatin's angiogenesis inhibition does not negatively affect wound strength.