Bradykinin antagonists as new drugs for prostate cancer John M. Stewart a,b, * , Daniel C. Chan b,c , Vitalija Simkeviciene a , Paul A. Bunn Jr. b,c , Barbara Helfrich b,c , Eunice J. York a , Laimute Taraseviciene-Stewart c , Daiva Bironaite a , Lajos Gera a a Department of Biochemistry, University of Colorado School of Medicine, Denver, CO 80262, USA b Cancer Center, University of Colorado School of Medicine, Denver, CO 80262, USA c Department of Medicine, University of Colorado School of Medicine, Denver, CO 80262, USA Abstract 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. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Angiogenesis; Bradykinin antagonists; Cancer, prostate; Membrane metalloproteases 1. Introduction Prostate cancer (PC) is a major medical threat worldwide. Surgery and radiation remain the major treatment modalities in use, as these cancers do not respond well to chemotherapy. Early PC is generally testosterone-dependent, and can be controlled by hormone ablation, but it generally escapes hormonal control and metastasizes. PC shares with lung cancer a common origin in neuroendocrine cells. These cells bear receptors for growth factor neuropeptides such as bombesin and bradykinin, and typically stimulate production of the cognate peptides. This autocrine loop effectively stimulates cancer growth. When PC escapes hormonal control, it becomes more neuro- endocrine in character. Neuropeptide antagonists have been pursued as potential drugs for lung cancers; most emphasis has been directed to promiscuous substance P antagonists, which block bombesin receptors. Unfortunately, these compounds have rather low potency and short in vivo lifetime and have not fared 1567-5769/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S1567-5769(02)00181-9 * Corresponding author. Department of Biochemistry, Univer- sity of Colorado School of Medicine, Denver, CO 80262, USA. E-mail address: john.stewart@uchsc.edu (J.M. Stewart). www.elsevier.com/locate/intimp International Immunopharmacology 2 (2002) 1781 – 1786