Suppression of solid tumor growth by a monoclonal antibody against tumor vasculature in rats: involvement of intravascular thrombosis and fibrinogenesis.
We have reported that immunization of rat tumor-derived endothelial cells (TEC) isolated from KMT-17 solid tumors results in the generation of several monoclonal antibodies (MAbs). TES-23, one of these MAbs, recognizes a naturally occurring 80-kDa antigen expressed on endothelial cells of tumor blood vessels. To determine whether such MAbs can suppress solid tumor growth in vivo by impairment of endothelial cells in tumors following direct binding, we tested the biodistribution of (125)I-labeled TES-23 in rats bearing KMT-17 solid tumors. We also examined the effect of treatment using unconjugated TES-23 on tumor growth and histo-pathological changes in tumor tissues. Biodistribution studies showed localization of TES-23 into tumor tissues 60 min after intravenous injection. TES-23 suppressed significantly the growth of KMT-17 solid tumors following administration for 5 days. Histo-pathological examination showed that TES-23 caused degeneration, apoptosis and/or necrosis and denudation of endothelial cells in viable tumor areas following local aggregation and adhesion of lymphocytes, with subsequent intravascular thrombus formation by platelets and fibrin. Our results indicate that TES-23, which recognizes TEC, can target endothelial cells of solid tumor vasculature directly, resulting in growth suppression in vivo by reduction of blood flow due to intravascular thrombosis. Our results also suggest that targeting tumor vasculature is a potentially attractive approach for the treatment of solid tumors.
Ohizumi
I
I
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan. ooizumiiwo@gt.chugai-pharm.co.jp
Taniguchi
K
K
Saito
H
H
Kawata
H
H
Tsunoda
S
S
Makimoto
H
H
Wakai
Y
Y
Tsutsumi
Y
Y
Nakagawa
S
S
Utoguchi
N
N
Kaiho
S
S
Ohsugi
Y
Y
Mayumi
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001772:Blood Cell Count; D002448:Cell Adhesion; D002449:Cell Aggregation; D002455:Cell Division; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology; D005260:Female; D005354:Fibrosarcoma / Q000097:blood / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008214:Lymphocytes / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D012513:Sarcoma, Experimental / Q000097:blood / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D006454:Hemoglobins; D007457:Iodine Radioisotopes; D002945:Cisplatin