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Adneovirus-mediated intratumoral delivery of angiogenesis antagonist for treatment of tumors

An anti-angiogenesis and adenovirus technology, which is applied in the field of gene therapy for tumor treatment, can solve problems such as troublesome and expensive recombinant protein input

Inactive Publication Date: 2000-05-24
AVENTIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Since vasopressive therapy requires long-term maintenance of therapeutic levels in vivo, constant infusion of recombinant proteins would be costly and cumbersome

Method used

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  • Adneovirus-mediated intratumoral delivery of angiogenesis antagonist for treatment of tumors
  • Adneovirus-mediated intratumoral delivery of angiogenesis antagonist for treatment of tumors
  • Adneovirus-mediated intratumoral delivery of angiogenesis antagonist for treatment of tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] Example 1: Gene therapy using ATF inhibits tumor growth and metastasis

[0123] Example 1 demonstrates that expression of the uPA / uPAR antagonist ATF (amino-terminal fragment of urokinase) inhibits tumor growth and metastasis. A defective adenovirus (AdmATF) expressing mouse ATF from CMV promoter was constructed. A single intratumoral injection of AdmATF inhibited the growth of established tumors and delayed tumor dissemination in two different mouse models. These effects were associated with a marked inhibition of neovascularization within and in the immediate vicinity of the injection site. The magnitude of this effect is evident in the ability of mouse ATF to inhibit angiogenesis in human tumors.

[0124] method

[0125] Recombinant adenovirus. AdmATF is an E1-deficient recombinant adenovirus expressing the mouse ATF gene from a CMV promoter. Plasmid pDB151916 was used as starting material to introduce a stop codon after residue 135 of ...

Embodiment 2

[0145] Example 2: In vivo angiostatin gene therapy inhibits tumors

[0146] Example 2 demonstrates that expression of the amino-terminal fragment of human plasminogen (angiostatin K3) inhibits tumor growth in vivo by blocking endothelial cell proliferation associated with mitotic arrest. The antitumor effect following local delivery of the N-terminal fragment of human plasminogen (angiostatin K3) has been studied in 2 xenograft mouse models. Angiostatin transfer was achieved by a defective adenovirus (AdK3) expressing the secretory angiostatin K3 molecule from the CMV promoter. In in vitro studies, AdK3 selectively inhibits endothelial cell proliferation and interferes with M-phase promoter-induced G2 / M transition. AdK3-infected endothelial cells exhibit a pronounced mitotic arrest associated with downregulation of M-phase phosphoproteins. Significant tumor growth arrest following a single intratumoral injection of AdK3 into pre-established rat C6 glioma or human MDA-M...

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PUM

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Abstract

The present invention relates to gene therapy for the treatment of tumors. The invention more particularly relates to introduction of a gene encoding an anti-angiogenic factor into cells of a tumor, for example with a defective adenovirus vector, to inhibit growth or metastasis, or both, of the tumor. In a specific embodiment, delivery of a defective adenovirus that expresses the amino terminal fragment of urokinase (ATF) inhibited growth and metastasis of tumors. These effects were correlated with a remarkable inhibition of neovascularization within, and at the immediate vicinity of, the injection site. Delivery of a defective adenovirus vector that expresses kringles 1 to 3 of angiostatin inhibited tumor growth and tumorigenicity, and induced apoptosis of tumor cells. The invention further provides viral vectors for use in the methods of the invention.

Description

Field of the invention [0001] The present invention relates to gene therapy for tumor treatment. More particularly, the present invention relates to the introduction into tumor cells of a gene encoding an anti-angiogenic factor, for example using an adenoviral vector, thereby inhibiting tumor growth or metastasis, or both. Background of the invention [0002] Cell migration is a coordinated process that bridges cell activation and adhesion while the balance between pericellular proteolysis and its inhibition is disrupted (e.g., by plasminogen activator inhibitors and tissue inhibitors of metalloproteinases) (1-3). Urokinase plasminogen activator (uPA) is a key driver in this process by initiating a proteolytic cascade on the surface of migrating cells by binding to its cell surface receptor (uPAR) Those (4, 5). Binding of uPA to its receptor greatly enhances cell surface plasminogen / plasmin conversion (6). Plasmin is a broadly specific serine protease ...

Claims

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Application Information

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IPC IPC(8): C12N15/00A61K35/76A61K38/46A61K38/48A61K38/49A61K48/00A61P35/00A61P35/04C07K14/47C12N15/57
CPCA61K38/49A61K38/484C12N2799/022A61K48/00A61P35/00A61P35/04C12N15/52C12N15/11
Inventor 李红陆核F·格里塞利P·欧波隆C·索利亚T·拉格特Y·莱格兰德J·索利亚C·玛比拉特M·帕里考德特P·耶
Owner AVENTIS PHARMA INC
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