title: A urokinase-derived peptide (A6) increases survival of mice bearing orthotopically grown prostate cancer and reduces lymph node metastasis.
abstract: The high rate of prostate cancer mortality invariably reflects the inability to control the spread of the disease. The urokinase-type plasminogen activator and its receptor (u-PAR) contribute to prostate cancer metastases by promoting extracellular matrix degradation and growth factor activation. The current study was undertaken to determine the efficacy of a urokinase-derived peptide (A6) in reducing the lymph node metastases of prostate cancer using a model in which prostatic tumors established in nude mice from orthotopically implanted PC-3 LN4 prostate cancer cells disseminate to the lymph nodes. As a first step in evaluating the in vivo effectiveness of A6, we determined its effect on in vitro invasiveness. In vitro, A6 reduced the invasiveness of PC-3 LN4 cells through a Matrigel-coated filter without affecting growth rate. A first in vivo survival experiment showed that all A6-treated mice were alive after 57 days, and half of them tumor-free, whereas all control mice receiving vehicle had died. In a second experiment with a larger tumor inoculum and a longer delay until treatment, whereas 71% of control mice and 83% of mice treated with a scrambled peptide developed lymph node metastases, only 22 to 25% of A6-treated mice had positive lymph nodes. Further, lymph node volume, reflective of tumor burden at the secondary site, was diminished 70% in A6-treated mice. In conclusion, we provide definitive evidence that a peptide spanning the connecting region of urokinase suppresses metastases and, as a single modality, prolongs the life span of prostate tumor-bearing mice.
authors.affiliation: Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA. dboyd@mdanderson.org
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Boyd
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.forename: Terence R
authors.initials: TR
authors.lastname: Jones
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
mesh_terms: D000818:Animals; D004792:Enzyme Precursors / Q000235:genetics; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D004792:Enzyme Precursors; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator