Products containing a lithium salt and a tumor necrosis factor

Details Products containing a lithium salt and a tumor necrosis factor Products containing a lithium salt and a tumor necrosis factor

1990-11-02

1994-07-26

Russel, Jeffrey E.

Drug, bio-affecting and body treating compositions

Lymphokine

530351, A61K 4506, A61K 3702

Patent

active

053325710

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to products containing a lithium salt and a tumor necrosis factor, and to the use of lithium salts for enhancing the action of tumor necrosis factors.
It has already been disclosed that tumor necrosis factor a (TNF-.alpha.) or tumor necrosis factor .beta. (TNF-.beta., also called lymphotoxin), as well as muteins of these two substances, can inhibit the growth of cancer cells, cf. Eur. J. Biochem. 152, 515, 1985; EP 187 991, WO 86/04 606, EP 100 641.
It has now been found that the action of tumor necrosis factors can be increased by administration of lithium salts.
The invention relates to products containing a lithium salt and a tumor necrosis factor as combination product for simultaneous or sequential use for the treatment of malignant tumors in humans and their associated phenomena.
The invention furthermore relates to the use of lithium salts for enhancing the action of exogenously administered or endogenously induced tumor necrosis factors.
The term malignant tumors means tumors of the hemopoietic organs, especially leukemias and lymphomas, as well as malignant tumors of various organs. The malignant tumors include, in particular, tumors of the lungs, of the gastrointestinal tract, of the urogenital tract, of the breast and of the skin and of appendages thereof.
The associated phenomena in cases of malignant tumors include, in particular, malignant effusions into body cavities as a consequence of these tumors.
The term tumor necrosis factor means TNF-.alpha., TNF-.beta. (lymphotoxin) and the active muteins thereof.
The tumor necrosis factor is, as a rule, used in a daily amount of from 1 to 500 .mu.g/m.sup.2 of body surface area, especially in a daily amount of from 40 to 400 .mu.g/m.sup.2. In this connection, administration is intravenous, subcutaneous, intraperitoneal or intra- or peritumoral.
Suitable lithium salts are, in particular, the carbonate, D,L-hydrogenaspartate, sulfate, orotate, acetate and the chloride. The lithium salts are administered orally, intravenously, intraperitoneally or intra- or peritumorally in an amount such that the level of Li.sup.+ ions in the blood is between 0.4 and 1.8 mmol, but in particular between 0.7 and 1.4 mmol.
The tumor necrosis factor and the lithium salt can be used in known pharmaceutical administration forms, cf. Rote Liste 1988, Nos. 70223 to 70227, EP-A 209 030.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the enhancement of the TNF-related cytotoxicity by LiCl with various malignant cell lines.
FIG. 2 shows the dose-dependent action of the LiCl on the cytotoxicity of L929 cells caused by TNF.
FIG. 3 shows the effects of treatments with TNF and TNF+LiCl on the growth of s.c. L929 tumors in nu
u mice.
FIG. 4 shows the survival of mice which received s.c. injections of L929 cells and treatment with TNF and/or LiCl.
FIG. 5 shows the effects of the treatment with TNF and/or LiCl on the growth of s.c. Hela D98/AH2 tumors in nu
u mice.
The superiority of the novel combination therapy was shown in vitro and in vivo as follows:


In Vitro Experiments

24 hours before the treatment, the cells were streaked in a concentration of from 5 to 10.sup.3 cells/flask in a cell-specific medium on microtiter plates. Then several TNF dilutions were added. To test LiCl, this was added to the cells 2 hours before the treatment with TNF in various concentrations. After an incubation time of 72 hours at 37.degree. C., the adherent cells were fixed and stained for 15 minutes with a solution which contained 0.5% (w/v) crystal violet, 4% (v/v) formaldehyde, 30% (v/v) ethanol and 0.17% (w/v) NaCl. The flasks were thoroughly rinsed with tap water, and the adherent cells were then detached in 33% (v/v) acetic acid (0.1 ml/test tube). The liberated dye was measured by spectrophotometry using an Immunoreader NJ-2000 (Nippon Intermed, Tokyo, Japan).
The influence of LiCl on the cytolytic/cytostatic activity of TNF was investigated on two cell lines of mice (L929 and WHI 164, clone 13) and five cell lines of humans (MCF7-AZ, ME180, Bt20 and HeLa D98(A

REFERENCES:
International Preliminary Examination Report.
European Journal of Biochemistry, vol. 152, 1985.
Beyaert et al, Proc. Natl. Acad. Sci. USA 36: 9494-9498 (Dec. 1989).
Kleinerman et al, J. of Leukocyte Biology 46: 484-492 (Nov. 1989).
Stein et al, Cancer 48:2696-2701 (Dec. 15, 1981).

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