Treatment of experimental brain tumors with trombospondin-1 derived peptides: an in vivo imaging study.
Antiangiogenic and antiproliferative effects of synthetic D-reverse peptides derived from the type 1 repeats of thrombospondin (TSP1) were studied in rodent C6 glioma and 9L gliosarcomas. To directly measure tumor size and vascular parameters, we employed in vivo magnetic resonance (MR) imaging and corroborated results by traditional morphometric tissue analysis. Rats bearing either C6 or 9L tumors were treated with TSP1-derived peptide (D-reverse amKRFKQDGGWSHWSPWSSac, n=13) or a control peptide (D-reverse amKRAKQAGGASHASPASSac, n=12) at 10 mg/kg, administered either intravenously or through subcutaneous miniosmotic pumps starting 10 days after tumor implantation. Eleven days later, the effect of peptide treatment was evaluated. TSP1 peptide-treated 9L tumors (50.7+/-44.2 mm3, n=7) and C6 tumors (41.3+/-34.2 mm3, n=6) were significantly smaller than tumors treated with control peptide (9L: 215.7+/-67.8 mm3, n=6; C6: 184.2+/-105.2 mm3, n=6). In contrast, the in vivo vascular volume fraction, the mean vascular area (determined by microscopy), and the microvascular density of tumors were not significantly different in any of the experimental groups. In cell culture, TSP1, and the amKRFKQDGGWSHWSPWSSac peptide showed antiproliferative effects against C6 with an IC of 45 nM for TSP1. These results indicate that TSP1-derived peptides retard brain tumor growth presumably as a result of slower de novo blood vessel formation and synergistic direct antiproliferative effects on tumor cells. We also show that in vivo MR imaging can be used to assess treatment efficacy of novel antiangiogenic drugs non-invasively, which has obvious implications for clinical trials.
Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown 02129, USA.
A
A
Bogdanov
E
E
Marecos
H C
HC
Cheng
L
L
Chandrasekaran
H C
HC
Krutzsch
D D
DD
Roberts
R
R
Weissleder
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D018316:Gliosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D019700:Thrombospondin 1 / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D010455:Peptides; D019700:Thrombospondin 1