Anti-tumor activities of the angiogenesis inhibitors interferon-inducible protein-10 and the calreticulin fragment vasostatin.
Tumor growth depends upon an adequate supply of oxygen and nutrients achieved through angiogenesis and maintenance of an intact tumor vasculature. Therapy with individual agents that target new vessel formation or existing vessels has suppressed experimental tumor growth, but rarely resulted in the eradication of tumors. We therefore tested the combined anti-tumor activity of vasostatin and interferon-inducible protein-10 (IP-10), agents that differently target the tumor vasculature. Vasostatin, a selective and direct inhibitor of endothelial cell proliferation, significantly reduced Burkitt tumor growth and tumor vessel density. IP-10, an "angiotoxic" chemokine, caused vascular damage and focal necrosis in Burkitt tumors. When combined, vasostatin plus IP-10 reduced tumor growth more effectively than each agent alone, but complete tumor regression was not observed. Microscopically, these tumors displayed focal necrosis and reduction in vessel density. Combination therapy with the inhibitors of angiogenesis vasostatin and IP-10 is effective in reducing the rate of tumor growth but fails to induce tumor regression, suggesting that curative treatment may require supplemental drugs targeting directly the tumor cells.
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 12N226 MSC 1907, 10 Center Drive, Bethesda, MD, USA. yaol@mail.nih.gov
Lei
L
Yao
Sandra E
SE
Pike
Stefania
S
Pittaluga
Barry
B
Cherney
Ghanshyam
G
Gupta
Elaine S
ES
Jaffe
Giovanna
G
Tosato
D000199:Actins / Q000032:analysis; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000627:therapeutic use*; D037282:Calreticulin; D002455:Cell Division / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010446:Peptide Fragments / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012261:Ribonucleoproteins / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000199:Actins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D054357:Chemokine CXCL10; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins; C121986:vasostatin