Gene therapy of tumors with an endothelial cell-specific, cell c

Details Gene therapy of tumors with an endothelial cell-specific, cell c Gene therapy of tumors with an endothelial cell-specific, cell c

1997-04-18

1998-11-03

Campbell, Bruce R.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

4353201, 424 932, 424450, 536 241, 935 36, A61K 4800, C12N 1500, C07H 2104

Patent

active

058308806

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

A DNA sequence for the gene therapy of tumors is described. In its essential elements, the DNA sequence is composed of an activator sequence, a promoter module and a gene for the active substance.
The activator sequence is activated, in a cell-specific manner, in proliferating endothelial cells or cells which are adjacent to these endothelial cells.
This activation is regulated in a cell cycle-specific manner by the promoter module.
The active substance is an inhibitor of angiogenesis or a cytostatic or cytotoxic molecule. The DNA sequence is inserted into a viral or non-viral vector which is supplemented with a ligand which has affinity for the activated endothelial cell.


1.Tumor Growth and Angiogenesis

The deficient activity of many antitumoral active compounds can be explained, at least to some degree, by the fact that the tumor cells within a tumor node are inaccessible to the antitumoral, in particular high molecular weight, active compounds (Burrows et al., Pharm. Ther. 64, 155 (1994), Baxter et al., Microvasc. Rex. 41, 5 (1991)). Such active compounds have to diffuse through the vascular endothelium and the basal membrane, and through the tumor stroma and tumor parenchyma, in order to reach each individual tumor cell. The extent of this diffusion is essentially determined by the concentration or the concentration gradient of the active compound and its physicochemical characteristics. Moreover, convection, which is directed outwards by the higher pressure in the interior of the tumor (Burrows et al., Microvasc. Res. 41, 5 (1991)), runs counter to the diffusion.
Since tumor blood vessels are accessible even to high molecular weight active compounds, it was consequently proposed at an early stage (Denekamp, Prog. Appl. Microcirc. 4, 28 1984), Denekamp, Cancer Topics 6, 6 1986), Denekamp, Cancer Metast. Rev. 9, 267 (1990), Denekamp, Brit. J. Radiol. 66, 181 (1993)), that use be made of the angiogenesis which is induced by tumors for tumor therapy.
Thus, attempts were made to inhibit tumor growth using substances which inhibit angiogenesis (Bicknell et al., Semin. Cancer Biol. 3, 399 (1992)). Experimental investigations in animals demonstrated that systemic administration of substances which inhibit angiogenesis can also inhibit tumor proliferation. This applies, for example, to suramin (Gagliardi et al., Cancer Rex. 52, 5073 (1992)), to heparin/steroid conjugates (Thorpe et al., Cancer Res. 53, 3000 (1993)), to O-(chloroacetylcarbamoyl)fumigillol (Yamaoka et al., Cancer Res. 53, 4262 (1993)), to monoclonal antibodies against angiogenin (Olson et al., Cancer Res. 54, 4576 (1994)) and to angiostatin (O'Reilly et al., Cell 79, 315 (1994)).
However, the abovementioned methods suffered from the disadvantages of the systemic, non-tumor-specific effect of the angiogenesis inhibitors, their side effects and the risk of fresh tumor growth occurring once the therapy was discontinued.
As an alternative, the idea was conceived of inhibiting the blood supply of the tumors by damaging endothelial cells so that the tumors necrose (Denekamp, Brit. J. Radiol. 66, 181 (1993)). With this idea in mind, the administration was proposed of toxins, cytostatic agents or isotopes which were coupled to antibodies. These antibodies would be specific for the tumor-associated vascular endothelium. The intention was that the antibody conjugates would destroy the tumor-associated blood vessel in an endothelium-specific manner and thereby induce necrosis of the tumor (Burrows et al., Pharma Ther. 64, 155 (1994)).
A further suggestion was to bind thrombogenic substances, cytokines or chemokines to tumor-associated endothelial cells by way of specific antibodies and to exert an influence on tumor growth by way of the blood coagulation, inflammation or immunoregulation which was elicited thereby. Similar effects were sought by the proposal to introduce DNA into endothelial cells by way of endothelial cell-specific antibodies with the DNA transducing the endothelial cells to secrete inflammatory or immuno-regulatory su

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