A urokinase-derived peptide (A6) increases survival of mice bearing orthotopically grown prostate cancer and reduces lymph node metastasis.
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.
Boyd
Douglas D
DD
Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA. dboyd@mdanderson.org
Kim
Sun-Jin
SJ
Wang
Heng
H
Jones
Terence R
TR
Gallick
Gary E
GE
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*
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