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- Title
Specific Occlusion of Murine and Human Tumor Vasculature by VCAM-1-Targeted Recombinant Fusion Proteins.
- Authors
Diens, Ariane; Grunow, Andrea; Unruh, Maike; Rabausch, Berit; Nör, Jacques E.; Fries, Jochen W. U.; Gottstein, Claudia
- Abstract
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, CD 106). 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: LS4Orec Hodgkin lymphoma, Co1o677 small-cell lung carcinoma, and Co1o677/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 (FPIL) or doxorubicin (F PlO) exhibited tumor-selective necrosis (LS4Orec tumors: 74% tumor necrosis 195% confidence interval {CI} 55% to 93%] with FP/L versus 13% tumor necrosis 195% CI = 4% to 22%I with vehicle; Colo677 tumors: 26% 195% Cl = 16% to 36%I with FP versus 8% 195% CI = 2% to 14%I with vehicle); tumor growth delay (Co1o677IHDMEC: 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 FF10-treated mice). The fusion protein was well tolerated. Conclusions: Recombinant tissue factor-based fusion proteins directed against an intraluminal tumor endothelia 1 cell marker induce tumor-selective intravascular coagulation, tumor tissue necrosis, and tumor growth delay.
- Subjects
TUMORS; BLOOD vessels; RECOMBINANT proteins; CELL adhesion molecules; BLOOD coagulation; CANCER treatment
- Publication
JNCI: Journal of the National Cancer Institute, 2005, Vol 97, Issue 10, p733
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/dji130