Comparison of three different targeted tissue factor fusion proteins for inducing tumor vessel thrombosis.
Tissue Factor (TF) is a cell membrane receptor protein that is the initiator of the extrinsic pathway of the blood coagulation cascade and normally released from damaged tissues. By substituting the attachment site with a tumor delivery agent, this potent thrombogenic protein in its truncated form (tTF) can be targeted to the tumor where it can initiate clotting, thereby occluding the tumor's blood supply and causing rapid tumor destruction. To test the therapeutic potential of this vascular targeting approach, three fusion proteins, chTNT-3/tTF, chTV-1/tTF, and RGD/tTF, which target DNA exposed in degenerative areas of tumors, fibronectin on the tumor vascular basement membrane, and alpha nu beta 3 on the luminal side of tumor vessels, respectively, were developed and tested for their antitumor effects. Antigen binding and clotting assays demonstrated that each of the fusion proteins retained their antigen binding and thrombogenic activities. In vivo studies in mice bearing established MAD109 lung and Colon 26 carcinomas revealed that all three reagents induced histological evidence of microregional thrombosis and massive cell necrosis. Of interest, the chTV-1/tTF and RGD/tTF fusion proteins induced thrombosis in small and medium sized tumor vessels, whereas the chTNT-3/tTF induced clotting in relatively larger vessels. Treatment studies showed that chTNT-3/tTF and chTV-1/tTF but not RGD/tTF had a significant inhibition of tumor growth. These studies demonstrate that multiple targets exist which can be used to localize tTF to occlude tumor vessels in two diversely different murine tumor models. To attain a significant antitumor effect, however, these thrombogenic agents had to occlude medium and large vessels within the tumor. Additional studies are warranted to identify maximal conditions for inducing therapeutic vascular coagulation as a new and potent method of cancer therapy.
Hu
Peisheng
P
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
Yan
Jianghua
J
Sharifi
Jahangir
J
Bai
Thomas
T
Khawli
Leslie A
LA
Epstein
Alan L
AL
D000818:Animals; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000627:therapeutic use*; D013925:Thromboplastin / Q000032:analysis / Q000627:therapeutic use*; D013927:Thrombosis / Q000139:chemically induced*; D014407:Tumor Cells, Cultured
D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; C047981:arginyl-glycyl-aspartic acid; D013925:Thromboplastin