© 2005 Oxford University Press
ARTICLE |
Specific Occlusion of Murine and Human Tumor Vasculature by VCAM-1–Targeted Recombinant Fusion Proteins
Affiliations of authors: Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany (AD, AG, MU, BR, CG); Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan, Ann Arbor (JEN); Department of Pathology, University Hospital Cologne, Cologne, Germany (JWUF)
Correspondence to: Claudia Gottstein, MD, University Hospital Cologne, Department of Internal Medicine I, Experimental Oncology and Vascular Biology, LFI E4 R707, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany (e-mail: claudia.gottstein{at}uni-koeln.de).
Background: The tumor vasculature is increasingly recognized as a target for cancer therapy. We developed and evaluated recombinant fusion proteins targeting the coagulation-inducing protein soluble tissue factor (sTF) to the luminal tumor endothelial antigen vascular cell adhesion molecule 1 (VCAM-1, CD106). Methods: We generated fusion proteins consisting of sTF fused to antibody fragments directed against mouse or human VCAM-1 and characterized them in vitro by flow cytometry, surface plasmon resonance, and two-stage coagulation assays. Their therapeutic effects were tested in three human xenograft tumor models: L540rec Hodgkin lymphoma, Colo677 small-cell lung carcinoma, and Colo677/HDMEC small-cell lung carcinoma with human vasculature. Toxicity was analyzed by histologic examination of organs and determination of laboratory blood parameters. Results: The fusion proteins bound VCAM-1 with nanomolar affinities and had the same coagulation activity as an sTF standard. Xenograft tumor–bearing mice treated with fusion protein (FP) alone or in combination with lipopolysaccharide (FP/L) or doxorubicin (FP/D) exhibited tumor-selective necrosis (L540rec tumors: 74% tumor necrosis [95% confidence interval {CI} = 55% to 93%] with FP/L versus 13% tumor necrosi1s [95% CI = 4% to 22%] with vehicle; Colo677 tumors: 26% [95% CI = 16% to 36%] with FP versus 8% [95% CI = 2% to 14%] with vehicle); tumor growth delay (Colo677/HDMEC: mean tumor weights after 3 days = 42 mg in FP-treated mice versus 71 mg in vehicle-treated mice, difference = 29 mg, 95% CI = 8 to 100, Mann–Whitney P = .008); and some tumor regressions (one of seven FP-treated Colo677 tumor–bearing mice and two of seven FP/D-treated mice). The fusion protein was well tolerated. Conclusions: Recombinant tissue factor–based fusion proteins directed against an intraluminal tumor endothelial cell marker induce tumor-selective intravascular coagulation, tumor tissue necrosis, and tumor growth delay.
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Editorial about this Article
- Targeting Coagulation to the Tumor Microvasculature: Perspectives and Therapeutic Implications From Preclinical Studies
- Masashi Narazaki and Giovanna Tosato
J Natl Cancer Inst 2005 97: 705-707.[Extract] [Full Text] [PDF]
Related Memo to the Media
- Press Release: Protein Targets Tumor Vasculature, Delays Tumor Growth in Animal Study
- Sarah L. Zielinski
J Natl Cancer Inst 2005 97: 701.[Extract] [Full Text]
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