Use of glutamate antagonists for the treatment of cancer

Details Use of glutamate antagonists for the treatment of cancer Use of glutamate antagonists for the treatment of cancer

2001-04-25

2004-09-28

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S080000, C514S247000

Reexamination Certificate

active

06797692

ABSTRACT:

TECHNICAL FIELD
Pharmaceutical compositions and their uses
BACKGROUND ART
Glutamate is a major neurotransmitter but possesses also a wide metabolic function in the body. It is released from approximately 40% of synaptic terminals and mediates many physiological functions by activation of different receptor types (Watkins and Evans (1981) Excitatory amino acid transmitters. Annu. Rev. Pharmacol., 21: 165-189; Gasic and Hollmann (1992) Molecular neurobiology of glutamate receptors, Annu. Rev. Physiol., 54: 507-536). Two main categories of glutamate receptors have been identified, ionotropic and metabotropic (Bettler and Mulle, (1995) Neurotransmitter Receptors II, AMPA and Kainate Receptors, Neuropharmacology, 34: 123-139; Pin and Duvoisin (1995) Neurotransmitter receptors I, The Metabotropic Glutamate Receptors: Structure and Functions, Neuropharmacology, 34: 1-26; Mori and Mishina (1995) Neurotransmitter Receptors VIII, Structure and Function of the NMDA Receptor Channel, Neuropharmacology, 34: 1219-1237). Ionotropic glutamate receptors can be subdivided into N-methyl-D-aspartate (NMDA), &agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), and kainate receptors. Metabotropic glutamate receptors can be subdivided into three classes, mGluRI, mGluRII and mGluRIII (Pin and Duvoisin (1995) Neurotransmitter receptors I, The Metabotropic Glutamate Receptors: Structure and Functions, Neuropharmacology, 34: 1-26). Five receptor subunits form the functional NMDA receptor which is modulated by glycine and polyamines and blocked by M
2+
. Activation of NMDA receptors leads to influx of Na
+
- and K
+
-ions into the cell as well as Ca
2+
-ions, either through the receptor channel itself or through voltage dependent Ca
2+
-channels (Bettler and Mulle, (1995) Neurotransmitter Receptors II, AMPA and Kainate Receptors, Neuropharmacology, 34: 123-139; Mori and Mishina (1995) Neurotransmitter Receptors VIII, Structure and Function of the NMDA Receptor Channel, Neuropharmacology, 34: 1219-1237). Four different subunits, named GluR1-GluR4, form the AMPA receptor channel. AMPA receptors are highly permeable to Na
+
- and K
+
-ions. AMPA receptor assemblies lacking the GluR2 subunit are also permeable to Ca
2+
-ions (Hollmann M, Heinemann S (1994): Cloned glutamate receptors, Annu. Rev. Neurosci., 17: 31-108).
Kainate receptors are built from five subunits, GluR5-7 as well as KA1 and KA2. Kainate receptor associated ion channels are permeable to Na
+
and K
+
-ions as well as Ca
2+
. Ca
2+
-permeability of kainate receptor associated ion channels is dependent on the presence of the GluR6 subunit within the receptor complex (Hollmann M, Heinemann S (1994): Cloned glutamate receptors, Annu. Rev. Neurosci., 17: 31-108). There is considerable experimental and clinical evidence indicating that glutamate is involved in the pathogenesis of neuronal degeneration in the context of hypoxia/ischemia and trauma of the central nervous system, seizures and hypoglycemia. In addition, glutamate is thought to be involved in the pathogenesis of chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis, Huntington's, Alzheimer's and Parkinson's disease. Functional glutamate receptors have been also identified in lung, muscle, pancreas and bone (Mason D J, Suva L J, Genever P G, Patton A J, Steuckle S, Hillam R A, Skerry T M (1997) Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone 20: 199-205; Patton A J, Genever P G, Birch M A, Suva L J, Skerry T M (1998) Expression of an N-methyl-D-aspartate-type receptor by human and rat osteoblasts and osteoclasts suggests a novel glutamate signaling pathway in bone, Bone 22; 645-649). However, no link has been established so far between glutamate receptor stimulation and tumor growth.
Many forms of cancer have been described affecting every form of tissue known in man. Of the described forms of human cancer, none is curable in 100% of the affected patients. Treatment modes include surgical removal, chemotherapy with cytostatic agents alone or in combination with hormone receptor modulators and/or steroids and/or interferons, and radiation (Hill R (1992): Cellular basis for radiotherapy, in The Basic Science of Oncology, McGraw-Hill, pp. 259-275).
I. The Term Inhibitor of the Interaction of Glutamate with the AMPA Receptor Complex Applies to:
1. all agents that bind to the AMPA receptor and prevent or reduce the binding of glutamate to the AMPA binding site in a competitive- or non-competitive manner. These are antagonists of the binding of glutamate to the AMPA receptor;
2. all agents that do not bind to the AMPA receptor binding site but bind or interact with AMPA receptor modulatory sites and thus prevent glutamate from triggering the signal that would occur when glutamate binds to the AMPA binding site;
3. all agents that interact directly with the AMPA-ion channel, i.e. AMPA receptor channel blockers. These agents reduce permeability of the ion channels associated with the AMPA receptor to ions (preferably Na
+
, K
+
and/or Ca
2+
);
4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus prevent glutamate from binding to the AMPA binding sites and from triggering the signal that would occur as a result of binding of glutamate to AMPA binding site;
5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to its binding sites;
6. all agents that increase the metabolism of glutamate and therefore prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;
7. all agents that increase the uptake of glutamate and thus decrease the binding of glutamate to AMPA binding site;
8. all agents that interfere with glutamate transporter systems and decrease the concentration of glutamate in synaptic cleft and thus prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;
9. all agents that interact with glutamate and prevent its binding to the AMPA receptor. Such compounds include i.e. glutamate partial agonists or molecules binding to glutamate;
10. antibodies to AMPA receptor subunits, or to the AMPA receptor, or to glutamate decreasing the binding of glutamate to AMPA binding site.
II. The Term Inhibitor of the Interaction of Glutamate with the AMPA Receptor Complex Applies to:
1. all agents that bind to the KA receptor and prevent or reduce the binding of glutamate to the KA binding site in a competitive- or non-competitive manner. These are antagonists of the binding of glutamate to the KA receptor;
2. all agents that do not bind to the KA receptor binding site but bind or interact with KA receptor modulatory sites and thus prevent glutamate from triggering the signal that would occur when glutamate binds to the KA binding site;
3. all agents that interact directly with the KA-ion channel, i.e. KA receptor channel blockers. These agents reduce permeability of the ion channels associated with the KA receptor to ions (preferably Na
+
, K
+
and/or Ca
2+
).
4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus prevent glutamate from binding to the KA binding sites and from triggering the signal that would occur as a result of binding of glutamate to KA binding site;
5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to its binding sites;
6. all agents that increase the metabolism of glutamate and therefore prevent glutamate from triggering the signal that would occur as a result of binding of glutamate to its binding sites;
7. all agents that increase the uptake of glutamate and thus decrease the binding of glutamate to KA binding site;
8. all agents that interfere with glutamate transporter systems and decrease the concentration of glutamate in synaptic cleft and thus prevent glutamate fro

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