Targeting Tissue Factor to Tumor Vessels. Experimental Results and First-in-Man Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 469-469
Author(s):  
Wolfgang E Berdel ◽  
Torsten Kessler ◽  
Christian Schwöppe ◽  
Ruediger Liersch ◽  
Torsten Persigehl ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tissue Factor ◽  
Fusion Proteins ◽  
Patent Application ◽  
Human Tumor ◽  
In Vivo Studies ◽  
Human Tumor Xenograft ◽  
Tumor Perfusion ◽  
Tumor Vessels

Abstract Abstract 469 Activation of blood coagulation in tumor vessels with subsequent tumor infarction is an experimental strategy in cancer therapy. We have fused different targeting peptides, including GRGDSP (RGD), GNGRAHA (NGR) and 5 cyclic derivates to the C-terminus of truncated tissue factor (tTF) to preferentially target tumor vessel endothelial cell integrins such as αvβ3 or aminopeptidase (CD13). tTF fusion proteins were expressed in E. coli, purified and refolded. Molecular integrity of the fusion proteins was evaluated by SDS-PAGE, immunoblotting and mass spectrometry. Subsequently, the tTF-fusion proteins were tested for biological activity with the following results: They retained the thrombogenic activity of tTF as measured by factor × activation in vitro. When tested with their respective target molecules either in a purified preparation or present on growing endothelial cells, there was specific binding. In vivo studies with human tumor xenograft models in nude mice showed either significant inhibition of tumor growth or regression of established tumors of different histologies (e.g. lung, breast, melanoma, sarcoma) by systemic application of the tTF-fusion proteins in contrast to controls including non-targeted tTF. Histology of the tumors treated with tTF fusion proteins revealed thrombotic occlusion of vasculature and blood pooling. Contrast-enhanced magnetic resonance imaging (MRI) of the tumors in vivo before and shortly after application of tTF-RGD and tTF-NGR showed a significant reduction of tumor perfusion. Degree of reduction correlated with in vivo tumor response. Toxicity studies showed acceptable therapeutic range and at therapeutic dosage there was no thrombo-embolic event in histology of normal organs, such as lung, heart, liver, and kidney. After upscaling production to amounts sufficient for clinical use, we have treated the first cancer patients with tTF-NGR. MRI studies even at the lowest dose (1 mg/kg i.v.) given showed reduction of tumor perfusion with no side effects. Targeted infarction of tumor vasculature with tTF fusion proteins may be promising as cancer therapy and should be further studied. Disclosures: Berdel: private: patent application on targeting tissue factor. Mesters:private: patent application on targeting tissue factor.

Infarction of tumor vessels by NGR-peptide–directed targeting of tissue factor: experimental results and first-in-man experience

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 5019-5027 ◽  
Author(s):  
Ralf Bieker ◽  
Torsten Kessler ◽  
Christian Schwöppe ◽  
Teresa Padró ◽  
Thorsten Persigehl ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Tissue Factor ◽  
Solid Tumors ◽  
Xenograft Model ◽  
Coagulation Factor ◽  
In Vivo Studies ◽  
Tumor Perfusion ◽  
Good Tolerability ◽  
Tumor Vessels ◽  
Ngr Peptide

Abstract We induced thrombosis of blood vessels in solid tumors in mice by a fusion protein consisting of the extracellular domain of tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA, targeting aminopeptidase N (CD13) and the integrin αvβ3 (CD51/CD61) on tumor vascular endothelium. The designed fusion protein tTF-NGR retained its thrombogenic activity as demonstrated by coagulation assays. In vivo studies in mice bearing established human adenocarcinoma (A549), melanoma (M21), and fibrosarcoma (HT1080) revealed that systemic administration of tTF-NGR induced partial or complete thrombotic occlusion of tumor vessels as shown by histologic analysis. tTF-NGR, but not untargeted tTF, induced significant tumor growth retardation or regression in all 3 types of solid tumors. Thrombosis induction in tumor vessels by tTF-NGR was also shown by contrast enhanced magnetic resonance imaging (MRI). In the human fibrosarcoma xenograft model, MRI revealed a significant reduction of tumor perfusion by administration of tTF-NGR. Clinical first-in-man application of low dosages of this targeted coagulation factor revealed good tolerability and decreased tumor perfusion as measured by MRI. Targeted thrombosis in the tumor vasculature induced by tTF-NGR may be a promising strategy for the treatment of cancer.

Inhibition of Tumor Growth by RGD Peptide Directed Delivery of Truncated Tissue Factor to the Tumor Vasculature.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1934-1934
Author(s):  
Torsten Kessler ◽  
Ralf Bieker ◽  
Teresa Padro ◽  
Federico Herrera ◽  
Sandra Ruiz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fusion Protein ◽  
Tumor Growth ◽  
Tissue Factor ◽  
Tumor Vasculature ◽  
Binding Activity ◽  
In Vivo Studies ◽  
Binding Assays ◽  
Tumor Vessels

Abstract Selective activation of blood coagulation in tumor vessels with subsequent tumor infarction is a promising anticancer strategy. To this end, a fusion protein consisting of the extracellular domain of tissue factor (truncated tissue factor, tTF) was fused to the peptide GRGDSP selectively targeting avb3 and avb5 integrins on tumor endothelial cells. The fusion protein tTF-RGD retained its thrombogenic and integrin binding activity as demonstrated by coagulation assays and binding assays with purified avb3 and endothelial cells. In vivo studies in mice bearing established human adenocarcinomas (CCL185), human melanoma (M21) and human fibrosarcoma (HT1080) revealed that i.v. administration of tTF-RGD induced partial or complete thrombotic occlusion of tumor vessels as indicated by histological analysis. Furthermore, treatment studies showed that tTF-RGD but not untargeted tTF induced significant tumor growth retardation or regression in all three types of solid tumors in mice without apparent side effects such as thrombosis in liver, kidney, heart or lung. Thus, selective thrombosis in the tumor vasculature induced by tTF-RGD may be a promising strategy for the treatment of cancer.

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

scholarly journals Force estimation from 4D OCT data in a human tumor xenograft mouse model

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Maximilian Neidhardt ◽  
Nils Gessert ◽  
Tobias Gosau ◽  
Julia Kemmling ◽  
Susanne Feldhaus ◽  
...  
Keyword(s):  
Deep Learning ◽  
Mouse Model ◽  
Haptic Feedback ◽  
Human Tumor ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft ◽  
Force Estimation ◽  
Xenograft Mouse Model ◽  
Dead Tissue

AbstractMinimally invasive robotic surgery offer benefits such as reduced physical trauma, faster recovery and lesser pain for the patient. For these procedures, visual and haptic feedback to the surgeon is crucial when operating surgical tools without line-of-sight with a robot. External force sensors are biased by friction at the tool shaft and thereby cannot estimate forces between tool tip and tissue. As an alternative, vision-based force estimation was proposed. Here, interaction forces are directly learned from deformation observed by an external imaging system. Recently, an approach based on optical coherence tomography and deep learning has shown promising results. However, most experiments are performed on ex-vivo tissue. In this work, we demonstrate that models trained on dead tissue do not perform well in in vivo data. We performed multiple experiments on a human tumor xenograft mouse model, both on in vivo, perfused tissue and dead tissue. We compared two deep learning models in different training scenarios. Training on perfused, in vivo data improved model performance by 24% for in vivo force estimation.

Enhanced xenobiotic transporter expression in normal teleost hepatocytes: response to environmental and chemotherapeutic toxins

2001 ◽  
Vol 204 (2) ◽  
pp. 217-227
Author(s):  
J.A. Albertus ◽  
R.O. Laine
Keyword(s):  
Mammalian Cells ◽  
Cellular Localization ◽  
Fundulus Heteroclitus ◽  
Environmental Pollutants ◽  
Human Tumor ◽  
Aquatic Organisms ◽  
In Vivo Studies ◽  
Multixenobiotic Resistance

Many aquatic organisms are resistant to environmental pollutants, probably because their inherent multi-drug-resistant protein extrusion pump (pgp) can be co-opted to handle man-made pollutants. This mechanism of multixenobiotic resistance is similar to the mechanism of multidrug resistance exhibited in chemotherapy-resistant human tumor cells. In the present study, a variety of techniques were used to characterize this toxin defense system in killifish (Fundulus heteroclitus) hepatocytes. The cellular localization and activity of the putative drug efflux system were evaluated. In addition, in vitro and in vivo studies were used to examine the range of expression of this putative drug transporter in the presence of environmental and chemotherapeutic toxins. The broad range of pgp expression generally observed in transformed mammalian cells was found in normal cells of our teleost model. Our findings suggest that the expression of the pgp gene in the killifish could be an excellent indicator of toxin levels or stressors in the environment.

Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

1984 ◽  
Vol 2 (4) ◽  
pp. 282-286 ◽  
Author(s):  
S E Salmon ◽  
L Young ◽  
B Soehnlen ◽  
R Liu
Keyword(s):  
Antitumor Activity ◽  
Clonogenic Assay ◽  
Human Tumor ◽  
Therapeutic Index ◽  
In Vivo Studies ◽  
Early Results ◽  
Colony Forming Units ◽  
Human Solid Tumors

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.

scholarly journals Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736

2020 ◽  
Vol 4 (7) ◽  
pp. 1478-1491 ◽  
Author(s):  
Andrew S. Moore ◽  
Amir Faisal ◽  
Grace W. Y. Mak ◽  
Farideh Miraki-Moud ◽  
Vassilios Bavetsias ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Human Tumor ◽  
Drug Candidate ◽  
Tyrosine Kinase Domain ◽  
Human Tumor Xenograft ◽  
Dual Inhibitor ◽  
Aurora Kinases ◽  
Acute Myeloid

Abstract Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.

scholarly journals Direct in vivo measurement of targeted binding in a human tumor xenograft

1997 ◽  
Vol 94 (5) ◽  
pp. 1785-1790 ◽  
Author(s):  
D. A. Berk ◽  
F. Yuan ◽  
M. Leunig ◽  
R. K. Jain
Keyword(s):  
Human Tumor ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft ◽  
In Vivo Measurement
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