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New Use of Glutamate Antagonists for the Treatment of Cancer

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New Use of Glutamate Antagonists for the Treatment of Cancer Europäisches Patentamt (19) European Patent Office Office européen des brevets (11) EP 1 002 535 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int. Cl.7: A61K 31/435, A61K 31/55, 24.05.2000 Bulletin 2000/21 A61K 31/495 (21) Application number: 98250380.7 (22) Date of filing: 28.10.1998 (84) Designated Contracting States: (71) Applicant: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Ikonomidou, Hrissanthi MC NL PT SE 13505 Berlin (DE) Designated Extension States: AL LT LV MK RO SI (72) Inventor: Ikonomidou, Hrissanthi 13505 Berlin (DE) (54) New use of glutamate antagonists for the treatment of cancer (57) New therapies can be devised based upon a are likely to be useful in treating cancer and can be for- demonstration of the role of glutamate in the pathogen- mulated as pharmaceutical compositions. They can be esis of cancer. Inhibitors of the interaction of glutamate identified by appropriate screens. with the AMPA, kainate, or NMDA receptor complexes EP 1 002 535 A1 Printed by Xerox (UK) Business Services 2.16.7 (HRS)/3.6 12EP 1 002 535 A1 Description system, seizures and hypoglycemia. In addition, gluta- mate is thought to be involved in the pathogenesis of [0001] Glutamate is a major neurotransmitter but chronic neurodegenerative disorders, such as amyo- possesses also a wide metabolic function in the body. It trophic lateral sclerosis, Huntington's, Alzheimer's and is released from approximately 40% of synaptic termi- 5Parkinson's disease. Functional glutamate receptors nals and mediates many physiological functions by acti- have been also identified in lung, muscle, pancreas and vation of different receptor types (Watkins and Evans bone (Mason DJ, Suva LJ, Genever PG, Patton AJ, (1981) Excitatory amino acid transmitters, Annu. Rev. Steuckle S, Hillam RA, Skerry TM (1997) Mechanically Pharmacol., 21: 165-189; Gasic and Hollmann (1992) regulated expression of a neural glutamate transporter Molecular neurobiology of glutamate receptors, Annu. 10 in bone: a role for excitatory amino acids as osteotropic Rev. Physiol., 54: 507-536). Two main categories of agents? Bone 20: 199-205; Patton AJ, Genever PG. glutamate receptors have been identified, ionotropic Birch MA, Suva LJ, Skerry TM (1998) Expression of an and metabotropic (Bettler and Mulle, (1995) Neuro- N-methyl-D-aspartate-type receptor by human and rat transmitter Receptors II, AMPA and Kainate Receptors, osteoblasts and osteoclasts suggests a novel glutamate Neuropharmacology, 34: 123-139; Pin and Duvoisin 15 signaling pathway in bone, Bone 22; 645-649). How- (1995) Neurotransmitter receptors I, The Metabotropic ever, no link has been established so far between gluta- Glutamate Receptors: Structure and Functions, Neu- mate receptor stimulation and tumor growth. ropharmacology, 34: 1-26; Mori and Mishina (1995) [0003] Many forms of cancer have been described Neurotransmitter Receptors VIII, Structure and Func- affecting every form of tissue known in man. Of the tion of the NMDA Receptor Channel, Neuropharmacol- 20 described forms of human cancer, none is curable in ogy, 34: 1219-1237). Ionotropic glutamate receptors 100% of the affected patients. Treatment modes include can be subdivided into N-methyl-D-aspartate (NMDA), surgical removal, chemotherapy with cytostatic agents α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate alone or in combination with hormone receptor modula- (AMPA), and kainate receptors. Metabotropic glutamate tors and/or steroids and/or interferons, and radiation receptors can be subdivided into three classes, mGluRI, 25 (Hill R (1992): Cellular basis for radiotherapy, in The mGluRII and mGluRIII (Pin and Duvoisin (1995) Neuro- Basic Science of Oncology, McGraw-Hill, pp. 259-275). transmitter receptors I, The Metabotropic Glutamate [0004] The present inventor has provided evidence Receptors: Structure and Functions, Neuropharmacol- that glutamate antagonists supress tumor growth. This ogy, 34: 1-26). Five receptor subunits form the func- invention represents a major advance in the treatment tional NMDA receptor which is modulated by glycine 30 of cancer. and polyamines and blocked by Mg2+ Activation of [0005] According to the present invention, gluta- NMDA receptors leads to influx of Na+ and K+- ions into mate antagonists which block glutamate function at the cell as well as Ca2+-ions, either through the receptor NMDA, AMPA or kainate receptor complexes, when channel itself or through voltage dependent Ca2+-chan- used in combination with cytostatic agents or physical nels (Bettler and Mulle, (1995) Neurotransmitter Recep- 35 measures, such as irradiation, will result in anticancer tors II, AMPA and Kainate Receptors, Neuro- activity superior to that achieved with cytostatic agents pharmacology, 34: 123-139; Mori and Mishina (1995) or physical measures alone. Neurotransmitter Receptors VIII, Structure and Func- tion of the NMDA Receptor Channel, Neuropharmacol- I. The term inhibitor of the interaction of glutamate ogy, 34: 1219-1237). Four different subunits, named 40 with the AMPA receptor complex applies to: GluR1-GluR4, form the AMPA receptor channel. AMPA receptors are highly permeable to Na+- and K+-ions. [0006] AMPA receptor assemblies lacking the GluR2 subunit are also permeable to Ca2+-ions (Hollmann M, Heine- 1. all agents that bind to the AMPA receptor and mann S (1994): Cloned glutamate receptors, Annu. 45 prevent or reduce the binding of glutamate to the Rev. Neurosci., 17: 31-108). AMPA binding site in a competitive- or non-compet- [0002] Kainate receptors are built from five subu- itive manner. These are antagonists of the binding nits, GluR5-7 as well as KA1 and KA2. Kainate receptor of glutamate to the AMPA receptor; associated ion channels are permeable to Na+- and K+- ions as well as Ca2+. Ca2+-permeability of kainate 50 2. all agents that do not bind to the AMPA receptor receptor associated ion channels is dependent on the binding site but bind or interact with AMPA receptor presence of the GluR6 subunit within the receptor com- modulatory sites and thus prevent glutamate from plex (Hollmann M, Heinemann S (1994): Cloned gluta- triggering the signal that would occur when gluta- mate receptors, Annu. Rev. Neurosci., 17: 31-108). mate binds to the AMPA binding site; There is considerable experimental and clinical evi- 55 dence indicating that glutamate is involved in the patho- 3. all agents that interact directly with the AMPA-ion genesis of neuronal degeneration in the context of channel, i.e. AMPA receptor channel blockers. hypoxia/ischemia and trauma of the central nervous These agents reduce permeability of the ion chan- 2 34EP 1 002 535 A1 nels associated with the AMPA receptor to ions associated with the KA receptor to ions (preferably (preferably Na+, K+ and/or Ca2+); Na+, K+ and/or Ca2+). 4. all agents that decrease the release of glutamate 4. all agents that decrease the release of glutamate from nerve endings or other tissues and thus pre- 5from nerve endings or other tissues and thus pre- vent glutamate from binding to the AMPA binding vent glutamate from binding to the KA binding sites sites and from triggering the signal that would occur and from triggering the signal that would occur as a as a result of binding of glutamate to AMPA binding result of binding of glutamate to KA binding site; site; 10 5. all agents that decrease synthesis of glutamate 5. all agents that decrease synthesis of glutamate and thus prevent glutamate from binding to its bind- and thus prevent glutamate from binding to its bind- ing sites; ing sites; 6. all agents that increase the metabolism of gluta- 6. all agents that increase the metabolism of gluta- 15 mate and therefore prevent glutamate from trigger- mate and therefore prevent glutamate from trigger- ing the signal that would occur as a result of binding ing the signal that would occur as a result of binding of glutamate to its binding sites; of glutamate to its binding sites; 7. all agents that increase the uptake of glutamate 7. all agents that increase the uptake of glutamate 20 and thus decrease the binding of glutamate to KA and thus decrease the binding of glutamate to binding site; AMPA binding site; 8. all agents that interfere with glutamate trans- 8. all agents that interfere with glutamate trans- porter systems and decrease the concentration of porter systems and decrease the concentration of 25 glutamate in synaptic cleft and thus prevent gluta- glutamate in synaptic cleft and thus prevent gluta- mate from triggering the signal that would occur as mate from triggering the signal that would occur as a result of binding of glutamate to its binding sites; a result of binding of glutamate to its binding sites; 9. all agents that interact with glutamate and pre- 9. all agents that interact with glutamate and pre- 30 vent its binding to the KA receptor. Such com- vent its binding to the AMPA receptor. Such com- pounds include e.g. glutamate partial agonists or pounds include i.e. glutamate partial agonists or molecules binding to glutamate; molecules binding to glutamate; 10. antibodies to KA receptor subunits, or to the KA 10. antibodies to AMPA receptor subunits, or to the 35 receptor, or to glutamate decreasing the binding of AMPA receptor, or to glutamate decreasing the glutamate to KA binding site. binding of glutamate to AMPA binding site. III. The term inhibitor of the interaction of glutamate II. The term inhibitor of the interaction of glutamate with the NMDA/glycine/polyamine receptor complex with the KA receptor complex applies to: 40 applies to: [0007] [0008] 1. all agents that bind to the KA receptor and pre- 1. all agents that bind to the NMDA receptor or vent or reduce the binding of glutamate to the KA 45 NMDA ion channel associated glycine or polyamine binding site in a competitive- or non-competitive binding site and prevent or reduce the binding of manner.
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