Prostate-specific membrane antigen directed selective thrombotic infarction of tumors.
Prostate-specific membrane antigen (PSMA), a glutamyl preferring carboxypeptidase, is found in prostate and other carcinomas present on both tumor cells and associated microvascular lining cells. We find that the channel structures delineated by PSMA-expressing cells in human and rat prostate tumors are in functional continuity with the vasculature and thus form part of tumor microvasculature. The PSMA-positive cell-outlined channels are CD31 negative and mutually exclusive of CD31-positive cell-lined channels elsewhere in the tumor consistent with tumor cells adapted to a pseudoendothelial phenotype in vasculogenic mimicry. To assess the functional potential of such PSMA-lined microvasculature to selectively direct infarctive tumor therapy, we coupled the soluble extracellular domain of tissue factor to a PSMA catalytic site inhibitor to create a PSMA-directed selective tumor vascular thrombogen (STVT). This protein induced selective local in vivo infarctive necrosis of the rat Mat Lu prostate tumor when administered i.v. The combined administration of this STVT with low-dose doxorubicin produced a profound tumoricidal effect, resulting in complete eradication of some tumors. This is consistent with the therapeutic potential for a PSMA-directed STVT and expands the potential for selective infarctive ablation of tumors.
D000818:Animals; D000954:Antigens, Surface; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001665:Binding Sites; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002384:Catalysis; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D007238:Infarction / Q000139:chemically induced; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D013925:Thromboplastin / Q000494:pharmacology; D013927:Thrombosis / Q000139:chemically induced; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000954:Antigens, Surface; D004151:Dipeptides; D008081:Liposomes; C038676:aspartylglutamate; D004317:Doxorubicin; D013925:Thromboplastin; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II