Suppression of tumor recurrence and metastasis by a combination of the PHSCN sequence and the antiangiogenic compound tetrathiomolybdate in prostate carcinoma.
Plasma fibronectin-mediated invasion of human DU145 prostate cancer cell line was efficaciously inhibited in a rat tumor model by treatment with Ac-PHSCN-NH(2) peptide. Invasion of DU145 cells was stimulated by the PHSRN sequence of plasma fibronectin. However, PHSCN acts as a competitive inhibitor of PHSRN-mediated invasion. In the current study, we determined whether PHSCN could inhibit the recurrence and metastasis of DU145 tumors after excision of the primary tumor in an athymic nude mouse model. We demonstrated that mice treated thrice weekly with intravenous Ac-PHSCN-NH(2) peptide survived tumor-free for more than 30 weeks post-primary tumor excision, whereas their untreated counterparts succumbed to recurrence and/or metastatic disease in significantly less time. Because of the universal requirement for angiogenesis in solid tumor growth, we tested the efficacy of copper deficiency induced by tetrathiomolybdate (TM) to retard tumor growth in the Dunning prostate cancer model. Significant reduction in size of the primary tumor was observed in mice rendered copper deficient. We sought to reduce tumor growth at the primary and metastatic sites by combining the anti-invasion Ac-PHSCN-NH(2) peptide with TM. Improved survival, fewer metastatic lesions, and excellent tolerability were observed with the combination therapy.
van Golen
Kenneth L
KL
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0948, USA. kgolen@umich.edu
Bao
LiWei
L
Brewer
George J
GJ
Pienta
Kenneth J
KJ
Kamradt
Jeffrey M
JM
Livant
Donna L
DL
Merajver
Sofia D
SD
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003300:Copper / Q000172:deficiency; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008982:Molybdenum / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control* / Q000628:therapy; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide