NF-kappaB activation inhibitors, and their pharmaceutical uses

Abstract

Compounds inhibiting the activation of the nuclear factor κB (NF-κB) are used for the preparation of medications adapted for the treatment of malignant hemopathies and solid tumors, and for the prevention of the appearance or the treatment, of phenomena of resistance to cytotoxic molecules used in the scope of treatment of the above pathologies, appearing in patients treated with these molecules when the latter are adapted to activate NF-κB.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a division of co-pending application Ser. No. 09 / 856,796, filed on May 25, 2001, the entire contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention has for its object the use of biological inhibitors of NF-κB, in the field of treating cancers, and more particularly malignant hemopathies or solid tumors. [0004] 2. Description of Related Art [0005] Numerous tumoral cells have developed sophisticated mechanisms permitting them to resist the effect of certain agents used in anti-cancer chemotherapy. One of the counter-measures at present developed by clinicians is the increase of the dosage of these medications, with the result of aggravating the side effects observed in the patients. Thus, for example, most of the leukemias and certain lymphomas are treated by the administration of anthracyclines (daunomycin, dauxorubicin) whose tox...

AI Technical Summary

Benefits of technology

[0011] The present invention results from the discovery by the inventors of new effects of the human growth hormone (HGH), also called somatotropin, namely, on the one hand that HGH, and other compounds connected specifically to the transmembrane receptors of class I cytokines, are inhibitors of the activation of NF-κB by a cytotoxic molecule, and, on the other hand, that HGH, and other above-mentioned compounds, permit potentiating the effects of cytotoxic molecules and hence reducing the concentrations of these latter in the field of therapeutic treatments.

[0013] Then, the inventors discovered that the human monocytes died after bridging (or engagement) of the surface molecule AP01 / CD95 / Fas, and have shown that HGH decreases the death mediated through the molecule Fas, by increasing the synthesis of an antiapoptogenic proto-oncogene Bcl-2.

[0014] Finally, the inventors have studied the effects of HGH on the α-TNF response, because Fas and the p55 receptor of the α-TNF belong to the same family of nerve growth receptors. The human promyeloid leukemic line U937 has been used to carry out this work, because of the insensitivity of human monocytes to the death mediated by α-TNF. Obtaining results opposite those observed with Fas, namely that HGH accelerates the death of these cells mediated by α-TNF, has permitted the inventors to conclude as to the inhibitory effect of HGH on the activation of NF-κB by α-TNF, or by other cytotoxic molecules activating NF-κb, such as daunomycin. OBJECTS OF THE INVENTION

[0015] Thus, the present invention has for its object to provide a new method for the treatment of cancers, and more particularly malignant hemopathies and solid tumors, offering the advantage of improving both the response of the sick person to certain anti-cancer treatments and also, potentially, the general condition of the sick person.

[0016] The invention also has for its object to provide new products for the treatment of said pathologies, having both the advantage of increasing the tumoral cell response to chemotherapy, and to improve the general condition of the patients. The new products of the invention permit decreasing the activation of the NF-κB factor by means of the compound that is used to inhibit the activation of NF-κB, such as the human growth hormone, which is adapted to give rise to the inhibition of the transcription of the MDR genes and hence a reinforcement of the cytotoxic effects of the anti-tumor agents used, with the expected result of decreasing the dosage of these anti-tumor medications.

Problems solved by technology

One of the counter-measures at present developed by clinicians is the increase of the dosage of these medications, with the result of aggravating the side effects observed in the patients.

Thus, this does not permit their direct use in therapeutic applications.

This technology is also in the state of development because of the complexity and the vectorization necessary for its good operation.

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