The angiogenesis inhibitor vasostatin does not impair wound healing at tumor-inhibiting doses.
Inhibition of tumor angiogenesis represents a promising new approach for the treatment of human cancers. It has remained unclear, however, whether inhibition of tumor angiogenesis may also result in impaired wound healing, a process thought to be angiogenesis dependent. To determine the effects of the angiogenesis inhibitor vasostatin, a 180 amino acid calreticulin fragment, on wound healing at tumor inhibiting doses, full-thickness wounds were generated on the back of nude mice that were also injected intradermally with CA46 Burkitt lymphoma cells. Mice were treated with daily injections of vasostatin or vehicle control at a site between the wounds and the transplanted tumor cells over 14 d. Vasostatin potently inhibited tumor growth and significantly reduced tumor angiogenesis, as measured by computer-assisted image analysis of CD31-stained tumor sections. Moreover, vasostatin treatment resulted in an increased fraction of mature tumor-associated blood vessels. In contrast, no impairment of wound healing was observed in vasostatin-treated mice, despite a significantly reduced vascularity of the wound granulation tissue. Our results reveal a different sensitivity of malignant tumor growth and physiologic wound healing to inhibition of angiogenesis, and they suggest that therapeutic inhibition of tumor angiogenesis may be achieved without impairment of tissue repair.
Lange-Asschenfeldt
B
B
Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Velasco
P
P
Streit
M
M
Hawighorst
T
T
Pike
S E
SE
Tosato
G
G
Detmar
M
M
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000473:pathology / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D037282:Calreticulin; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006097:Granulation Tissue / Q000098:blood supply; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology; D012261:Ribonucleoproteins / Q000008:administration & dosage* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D010446:Peptide Fragments; D012261:Ribonucleoproteins; C121986:vasostatin