Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis

Apparailly, Florence; Bouquet, Céline; Millet, Virginie; Noël, Danièle; Jacquet, Chantal; Opolon, Paule; Perricaudet, Michel; Sany, J; Yeh, Patrice; Jørgensen, Christian

doi:10.1038/sj.gt.3301628

Cited by 30 publications

(26 citation statements)

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“…We have previously shown that ATF and ATF-HSA inhibit plasminogen activation and uPA activity: 30.9% plasminogen activation with AdATF-HSA vs 20.8% with AdATF at MOI 100. 15 As shown in Figure 1b, K1-3-HSA, ES-HSA and Can-HSA conjugates appeared to be cytotoxic factors on HUVEC endothelial cells, as most of cells are destroyed 96 h after virus infection at MOI 600 comparing to AdCO1 control infection. Results following AdATF-HSA infection did not differ significantly from those obtained with AdCO1 infection.…”

Section: Resultsmentioning

confidence: 79%

“…10 The ATF-HSA chimeric protein contains the native secretion signal and the first 135 residues of murine urokinase (uPA) linked to 586 residues of mature HSA. 15 Can-HSA describes the C-terminal NC1 domain of the human a2 chain of type IV collagen (Can, 24 kDa) fused with HSA.…”

Section: Resultsmentioning

confidence: 99%

“…8 Moreover, we already showed that HSA stabilization enhanced K1-3 and ATF bioavailability without altering their biological effect. 10,15 Furthermore, adenovirus-derived vectors are particularly interesting for the evaluation of new therapeutic genes for systemic cancer therapy because they can efficiently transduce the host liver and then use it as an endogenous factory for the production of high circulating levels of the therapeutic proteins.…”

Section: Discussionmentioning

confidence: 99%

“…15 The fused gene K1-3-HSA contains the native signal peptide followed by the first 333 residues of mature human plasminogen (K1-3), which is genetically linked to the 586 aa of mature HSA. 10 The fused gene ES-HSA contains the murine-uPA signal peptide followed by the last 183 C-terminal residues of murine collagen XVIII, genetically linked to the 586 aa of HSA.…”

Section: Construction and Propagation Of Recombinant Adenovirusesmentioning

confidence: 99%

“…In a previous study, we showed that genetic coupling of mATF or K1-3 of angiostatin to human serum albumin (HSA): (i) preserved their antiangiogenic properties and (ii) dramatically improved their serum half-lives. 15,10 Protein production, long-term storage of bioreactive proteins and cumbersome daily administration are serious hurdles in this context. In contrast, the antitumor effects that follow antiangiogenic gene delivery from a variety of viral and non-viral vectors in vivo highlight the potential of antiangiogenic gene therapy as an additional strategy for treatment against cancer and metastatic dissemination.…”

Section: Introductionmentioning

confidence: 99%

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A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

et al. 2006

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Different antiangiogenic and antimetastatic recombinant adenoviruses were tested in a transgenic mouse model of metastatic ocular cancer (TRP1/SV40 Tag transgenic mice), which is a highly aggressive tumor, developed from the pigmented epithelium of the retina. These vectors, encoding amino-terminal fragments of urokinase plasminogen activator (ATF), angiostatin Kringles (K1-3), endostatin (ES) and canstatin (Can) coupled to human serum albumin (HSA) were injected to assess their metastatic and antiangiogenic activities in our model. Compared to AdCO1 control group, AdATF-HSA did not significantly reduce metastatic growth. In contrast, mice treated with AdK1-3-HSA, AdES-HSA and AdCan-HSA displayed significantly smaller metastases (1.1971.19, 0.8771.5, 0.4370.56 vs controls 4.0475.12 mm 3 ). Moreover, a stronger inhibition of metastatic growth was obtained with AdCan-HSA than with AdK1-3-HSA (P ¼ 0.04). Median survival was improved by 4 weeks. A close correlation was observed between the effects of these viruses on metastatic growth and their capacity to inhibit tumor angiogenesis. Our study indicates that systemic antiangiogenic factors production by recombinant adenoviruses, particularly Can, might represent an effective way of delaying metastatic growth via inhibition of angiogenesis.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Construction and Propagation Of Recombinant Adenovirusesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

et al. 2006

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Gene therapy for arthritis: What next?

Evans

Ghivizzani

Robbins

2006

Arthritis & Rheumatism

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Therapeutic efficacy of once‐daily oral administration of a Kunitz‐type protease inhibitor, bikunin, in a mouse model and in human cancer

Kobayashi

Yagyu²,

Inagaki³

et al. 2004

Cancer

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BACKGROUND Bikunin, a Kunitz‐type protease inhibitor, specifically inhibits tumor invasion and metastasis. METHODS The authors initially evaluated the therapeutic efficacy of once‐daily oral administration of different doses of bikunin against human ovarian carcinoma HRA cells growing in the peritonea of nude mice. For the in vivo studies, female 7‐week‐old nude mice were randomized to 1 of 4 groups: bikunin‐treated groups (n = 9 in each group) received 3, 10, or 30 μg/g body weight per day bikunin for 7 days via gastrointestinal gavage, and a control group (n = 9) received the vehicle solution (phosphate‐buffered saline) via gastrointestinal gavage. On Day 9, the abdominal cavity was examined by two observers who were blinded to treatment. RESULTS After oral administration, intact bikunin was detectable in mouse serum specimens at 3 and 6 hours. This was followed by a decline at 12 hours. The mice given bikunin at the highest dose level had a 40% decrease in tumor load. The highest uptake in the tumor was obtained with [125I]bikunin 12 hours postadministration. No effect on either food intake or body weight was observed in the treated versus sham groups. The current study was the first to report the potent activity of once‐daily oral administration of bikunin against ovarian carcinoma. Next, the authors performed a Phase I trial to determine the maximum‐tolerated dose (MTD) and safety of a once‐daily oral administration schedule. The indication was locally advanced uterine cervical carcinoma after definitive treatment. An escalating dose (3, 10, and 30 mg/kg per day) of bikunin was administered orally to nine patients for 7 days. There were no dose‐limiting toxicities and the MTD of the bikunin schedule was not defined. The authors also obtained preliminary data on its effect on urokinase‐type plasminogen activator expression at the highest dose level. CONCLUSIONS Once‐daily oral administration of bikunin was found to be safe in humans and exhibited signs of biologic activity. Cancer 2004;100:869–77. © 2004 American Cancer Society.

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Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis

Abstract: Plasmin is essential for metalloproteases activation

Cited by 30 publications

References 25 publications

A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer

Gene therapy for arthritis: What next?

Therapeutic efficacy of once‐daily oral administration of a Kunitz‐type protease inhibitor, bikunin, in a mouse model and in human cancer

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