Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis.
The potent antiangiogenic pigment epithelium-derived factor (PEDF) has shown promise against osteosarcoma, a tumour that originates in the bone and metastasises to the lungs. Neurotrophic, antiangiogenic, antiproliferative, and antimetastatic properties of PEDF have been attributed to a number of functional epitopes on the PEDF glycoprotein. StVOrth-2 (residues 78-102) and StVOrth-3 (residues 90-114) are two PEDF-derived peptides based on these functional epitopes. StVOrth-2 has previously been shown to inhibit osteosarcoma cell proliferation, while StVOrth-3 increased osteosarcoma cell adhesion to collagen I in vitro. In this paper, we have evaluated systemically and continuously delivered StVOrth-2 and StVOrth-3 using a clinically relevant murine model of osteosarcoma with spontaneous metastasis. Treatment with StVOrth-2 or StVOrth-3 with microosmotic pumps was initiated after primary osteosarcoma was established in the tibia. While treatment with StVOrth-2 and StVOrth-3 did not appear to affect local tumour invasion, tumour necrosis or apoptosis, StVOrth-2 predominantly restricted the growth of primary tumours, while StVOrth-3 restricted the burden of pulmonary metastatic disease. No peptide caused gross toxicity in mouse tissues as assessed by measuring weight of animals, serum biochemistry, and gross tissue observation. The differential effects exhibited by StVOrth-2 and StVOrth-3 in this orthotopic model of osteosarcoma may be related to the functional epitopes on the PEDF glycoprotein that they represent.
Department of Orthopaedics and Department of Surgery, St. Vincent's Hospital, University of Melbourne, Fitzroy VIC 3065, Australia. matthew.broadhead@gmail.com
Matthew L
ML
Broadhead
Peter F M
PF
Choong
Crispin R
CR
Dass
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000187:drug effects / Q000276:immunology; D005136:Eye Proteins / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000737:chemistry*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis; D015843:Serpins / Q000008:administration & dosage / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays; D000099174:Pigment Epithelium-Derived Factor
D000939:Epitopes; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010455:Peptides; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor