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

Bieker, Ralf; Keßler, Torsten; Schwöppe, Christian; Padró, Teresa; Persigehl, Thorsten; Bremer, Christoph; Dreischalück, Johannes; Kolkmeyer, Astrid; Heindel, Walter; Mesters, Rolf M.; Berdel, Wolfgang E.

doi:10.1182/blood-2008-04-150318

Cited by 123 publications

(181 citation statements)

References 31 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…no. 550037, PE-linked) to verify presence of these molecules on HUVECs (details not shown) (30). For binding analysis, cells were blocked using human immunoglobulin (Ig), washed and incubated with His-tag-tTF-NGR for 20 min at RT at different concentrations as specified.…”

Section: Cell Culture Human Umbilical Vein Endothelial Cells (Huvecs)mentioning

confidence: 99%

“…The HT1080 fibrosarcoma cell line (30) was cultured in Dulbecco's medium supplemented with 10% fetal calf serum (FCS, Gibco-BRL, Eggenstein, Germany).…”

Section: Cell Culture Human Umbilical Vein Endothelial Cells (Huvecs)mentioning

confidence: 99%

“…I.v. infusion of tTF-NGR in cancer patients at dose levels without side effects was shown to reduce tumor blood flow in situ (30). In this study, we have analysed antitumor activity and toxicity profile of s.c. injection of tTF-NGR in human tumor xenograft models, s.c. injection of tTF-NGR represents an active but toxic way of application and compares unfavourably to the i.v.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, NGR undergoes a rapid nonenzymatic asparagine deamidation to isoaspartate-glycinearginine (isoDGR) generating a further ligand for · v ß 3 (28,29). We have constructed fusion proteins consisting of NGRpeptide sequences coupled to the C-terminal end of tTF (30,31). Several of these fusion proteins including tTF-NGR, retain their thrombogenic activity in vitro, bind to their respective targets on endothelial cells, and upon intravenous (i.v.)…”

Section: Introductionmentioning

confidence: 99%

“…Several of these fusion proteins including tTF-NGR, retain their thrombogenic activity in vitro, bind to their respective targets on endothelial cells, and upon intravenous (i.v.) infusion induce thrombosis in blood vessels in several solid tumors in mice with subsequent tumor growth retardation and regression (30,31). I.v.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile

Dreischalück

Schwöppe²,

Spieker³

et al. 2010

Int J Oncol

View full text Add to dashboard Cite

Abstract. tTF-NGR consists of the extracellular domain of the (truncated) tissue factor (tTF), a central molecule for coagulation in vivo, and the peptide GNGRAHA (NGR), a ligand of the surface protein aminopeptidase N (CD13). After deamidation of the NGR-peptide moiety, the fusion protein is also a ligand for integrin · v ß 3 (CD51/CD61). Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR showed binding to specific binding sites on endothelial cells in vitro as shown by flow cytometry. Subcutaneous injection of tTF-NGR into athymic mice bearing human HT1080 fibrosarcoma tumors induced tumor growth retardation and delay. Contrast enhanced ultrasound detected a decrease in tumor blood flow in vivo after application of tTF-NGR. Histological analysis of the tumors revealed vascular disruption due to blood pooling and thrombotic occlusion of tumor vessels. Furthermore, a lack of resistance was shown by re-exposure of tumor-bearing mice to tTF-NGR after regrowth following a first cycle of treatment. However, after subcutaneous (s.c.) push injection with therapeutic doses (1-5 mg/kg bw) side effects have been observed, such as skin bleeding and reduced performance. Since lethality started within the therapeutic dose range (LD 10 approximately 2 mg/kg bw) no safe therapeutic window could be found. Limiting toxicity was represented by thrombo-embolic events in major organ systems as demonstrated by histology. Thus, subcutaneous injection of tTF-NGR represents an active, but toxic application procedure and compares unfavourably to intravenous infusion.

show abstract

Section: Cell Culture Human Umbilical Vein Endothelial Cells (Huvecs)mentioning

confidence: 99%

“…The HT1080 fibrosarcoma cell line (30) was cultured in Dulbecco's medium supplemented with 10% fetal calf serum (FCS, Gibco-BRL, Eggenstein, Germany).…”

Section: Cell Culture Human Umbilical Vein Endothelial Cells (Huvecs)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile

Dreischalück

Schwöppe²,

Spieker³

et al. 2010

Int J Oncol

View full text Add to dashboard Cite

show abstract

Glycine N‐Methylation in NGR‐Tagged Nanocarriers Prevents Isoaspartate Formation and Integrin Binding without Impairing CD13 Recognition and Tumor Homing

Corti

Gasparri

Ghitti

et al. 2017

Adv Funct Materials

View full text Add to dashboard Cite

NGR (asparagine-glycine-arginine) is a tumor vasculature-homing peptide motif widely used for the functionalization of drugs, nanomaterials, and imaging compounds for cancer treatment and diagnosis. Unfortunately, this motif has a strong propensity to undergo rapid deamidation. This reaction, which converts NGR into isoDGR, is associated with receptor switching from CD13 to integrins, with potentially important manufacturing and pharmacological and toxicological implications. It is found that glycine N-methylation of NGR-tagged nanocarriers completely prevents asparagine deamidation without impairing CD13 recognition. Studies in animal models have shown that the methylated NGR motif can be exploited for delivering radiolabeled compounds and nanocarriers, such as tumor necrosis factor-α-bearing nanogold and liposomal doxorubicin, to tumors with improved selectivity. These findings suggest that this NGR derivative is a stable and efficient tumor-homing ligand that can be used for delivering functional nanomaterials to tumor vasculature.

show abstract

Thrombin and Thrombin‐Incorporated Biomaterials for Disease Treatments

Zhang,

Duan,

et al. 2023

Adv Healthcare Materials

View full text Add to dashboard Cite

Thrombin, a coagulation‐inducing protease, has long been used in the hemostatic field. During the past decades, many other therapeutic uses of thrombin have been developed. For instance, burn treatment, pseudoaneurysm therapy, wound management, and tumor vascular infarction (or tumor vasculature blockade therapy) have all utilized the unique and powerful function of thrombin. Based on their therapeutic effects, many thrombin‐associated products have been certificated by the Food and Drug Administration, including bovine thrombin, human thrombin, recombinant thrombin, fibrin glue, etc. Besides, several thrombin‐based drugs are currently undergoing clinical trials. In this article, we summarize the therapeutic uses of thrombin (from the initial hemostasis to the latest cancer therapy), the commercially available drugs associated with thrombin, and the pros and cons of thrombin‐based therapeutics (e.g., adverse immune responses related to bovine thrombin, thromboinflammation, and vasculogenic “rebounds”). Further, we discuss the current challenges and possible future research directions of thrombin‐incorporated biomaterials and therapies. It is hoped that this review may provide a valuable reference for researchers in this field and help them to design safer and more effective thrombin‐based drugs for fighting against various intractable diseases.This article is protected by copyright. All rights reserved

show abstract

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

Cited by 123 publications

References 31 publications

Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile

Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile

Glycine N‐Methylation in NGR‐Tagged Nanocarriers Prevents Isoaspartate Formation and Integrin Binding without Impairing CD13 Recognition and Tumor Homing

Thrombin and Thrombin‐Incorporated Biomaterials for Disease Treatments

Contact Info

Product

Resources

About