Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins.

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, 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 necrosis [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.

• Authors: Ariane Dienst, Andrea Grunow, Maike Unruh, Berit Rabausch, Jacques E Nör, Jochen W U Fries, Claudia Gottstein
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 97 Issue 10 Pg. 733-47 (May 18 2005) ISSN: 1460-2105 [Electronic] United States
• PMID: 15900043 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Recombinant Fusion Proteins
• Vascular Cell Adhesion Molecule-1

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology, therapeutic use)
• Animals
• Blood Coagulation Tests
• Carcinoma, Small Cell (blood supply, drug therapy)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Hodgkin Disease (drug therapy, pathology)
• Humans
• Immunohistochemistry
• Lung Neoplasms (blood supply, drug therapy)
• Mice
• Microcirculation (drug effects)
• Necrosis
• Neoplasms, Experimental (blood supply, drug therapy)
• Recombinant Fusion Proteins (chemistry, pharmacology, therapeutic use)
• Research Design
• Surface Plasmon Resonance
• Transplantation, Heterologous
• Vascular Cell Adhesion Molecule-1 (drug effects)