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

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Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins. / Dienst, A; Grunow, A; Unruh, M; Rabausch, B; Nor, Jacques; Fries, JW; Gottstein, C.

In: Journal of the National Cancer Institute, Vol. 97, No. 10, 18.05.2005, p. 733-747.

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Dienst, A, Grunow, A, Unruh, M, Rabausch, B, Nor, J, Fries, JW & Gottstein, C 2005, 'Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins', Journal of the National Cancer Institute, vol. 97, no. 10, pp. 733-747. https://doi.org/10.1093/jnci/dji130

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Dienst, A ; Grunow, A ; Unruh, M ; Rabausch, B ; Nor, Jacques ; Fries, JW ; Gottstein, C. / Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins. In: Journal of the National Cancer Institute. 2005 ; Vol. 97, No. 10. pp. 733-747.

Bibtex

@article{466748b3f70d4920b3c77f3e5887e6a7,
title = "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.",
author = "A Dienst and A Grunow and M Unruh and B Rabausch and Jacques Nor and JW Fries and C Gottstein",
year = "2005",
month = may,
day = "18",
doi = "10.1093/jnci/dji130",
language = "English",
volume = "97",
pages = "733--747",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "10",

}

RIS

TY - JOUR

T1 - Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins

AU - Dienst, A

AU - Grunow, A

AU - Unruh, M

AU - Rabausch, B

AU - Nor, Jacques

AU - Fries, JW

AU - Gottstein, C

PY - 2005/5/18

Y1 - 2005/5/18

N2 - 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.

AB - 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.

U2 - 10.1093/jnci/dji130

DO - 10.1093/jnci/dji130

M3 - Article

C2 - 15900043

VL - 97

SP - 733

EP - 747

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 10

ER -