Soluble tissue factor induces coagulation on tumor endothelial cells in vivo if coadministered with low-dose lipopolysaccharides.
OBJECTIVE
This study was performed to evaluate the mechanisms leading to tumor vessel occlusion by tissue factor-based drugs, which are used in vascular targeting approaches for the treatment of malignant tumors.


RESULTS
The effects of nontargeted soluble tissue factor were evaluated in vitro and in vivo. Tumor-bearing mice were treated with (1) the extracellular portion of tissue factor (soluble tissue factor), (2) low nontoxic doses of lipopolysaccharides, or (3) a combination thereof. The combination treatment showed the best effects and resulted in selective thrombosis of tumor vessels. On the basis of our data from subsequent in vitro analyses, including surface plasmon resonance measurements and endothelial cell based coagulation assays, we propose a model on how soluble tissue factor, although lacking its membrane anchor, can promote selective tumor vessel occlusion.


CONCLUSIONS
To our knowledge, this is the first report to describe the molecular mechanisms of coagulation induction by untargeted soluble tissue factor in vivo. Combination treatments including soluble tissue factor might represent an alternative vascular targeting approach for the treatment of malignant tumors.
Philipp
Jana
J
Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.
Dienst
Ariane
A
Unruh
Maike
M
Wagener
Anke
A
Grunow
Andrea
A
Engert
Andreas
A
Fries
Jochen W U
JW
Gottstein
Claudia
C
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004621:Embolization, Therapeutic / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects; D015951:Factor Xa / Q000096:biosynthesis; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012995:Solubility; D020349:Surface Plasmon Resonance; D018243:Teratocarcinoma / Q000098:blood supply / Q000628:therapy*; D013925:Thromboplastin / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D013925:Thromboplastin; D015951:Factor Xa