Bradykinin antagonists as new drugs for prostate cancer.
Bradykinin (BK) is an autocrine growth factor for lung and prostate cancers. BK also facilitates tumor extension by increasing tissue permeability and stimulating angiogenesis. Peptide BK antagonists are in development as potential new drugs for lung cancer. Newer nonpeptide BK antagonists have even higher potency against lung cancer, in vitro and in vivo. These compounds have now been applied to the study of prostate cancers, and have been found to be effective. Prostate cancer cell line PC3 is derived from a late-stage, hormone-independent, metastatic tumor; its growth is difficult to inhibit. Our established BK antagonists, while less effective against this line of prostate cancer in xenografts in nude mice than against lung cancer, are active and have led the way to development of new peptide and nonpeptide agents for prostate cancer. In addition to inhibiting cancer cell growth directly, they inhibit angiogenesis mediated by vascular endothelial growth factor, and inhibit increased tissue permeability mediated by membrane metalloproteases in these tumors. This class of compounds offers hope for development of new drugs for refractory prostate cancer.
Stewart
John M
JM
Department of Biochemistry, University of Colorado School of Medicine, Denver, CO 80262, USA. john.stewart@uchsc.edu
Chan
Daniel C
DC
Simkeviciene
Vitalija
V
Bunn
Paul A
PA
Helfrich
Barbara
B
York
Eunice J
EJ
Taraseviciene-Stewart
Laimute
L
Bironaite
Daiva
D
Gera
Lajos
L
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D065168:Bradykinin Receptor Antagonists; D002462:Cell Membrane / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D018002:Receptors, Bradykinin / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D065168:Bradykinin Receptor Antagonists; D011480:Protease Inhibitors; D018002:Receptors, Bradykinin; D008666:Metalloendopeptidases