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(12) Patent Application Publication (10) Pub. No.: US 2010/0190692 A1 VAN GROENINGHEN (43) Pub US 20100190692A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0190692 A1 VAN GROENINGHEN (43) Pub. Date: Jul. 29, 2010 (54) METHODS FOR REDUCING Publication Classification GNRH-POSITIVE TUMIORCELL (51) Int. Cl. PROLIFERATION A638/09 (2006.01) (76) Inventor: JOHANNES C. VAN A638/22 (2006.01) GROENINGHEN, Dortmund (DE) A 6LX 3/59 (2006.01) s A63L/704 (2006.01) Correspondence Address: Age, 30.8; } GRUND INTELLECTUAL PROPERTY GROUP NKOLAISTRASSE 15 (52) U.S. Cl. .............. 514/8: 514/15; 514/259.5; 514/34; (57) ABSTRACT (21) Appl. No.: 12/701,284 A method for recognizing and evaluating the presence and (22) Filed: Feb. 5, 2010 function of GnRH receptors on tumor cells originating in the brain and/or nervous system and/or the meninges and/or reac Related U.S. Application Data tive neuroglia cells and/or primitive neuroectodermal tumor cells and/or on Kaposi sarcoma is provided. Furthermore a (63) Continuation-in-part of application No. 10/327,621, method for reducing degenerate GnRH-positive tumor cells filed on Dec. 20, 2002, now Pat. No. 7,695,722, which and/or for decreasing cellular replication of the above GnRH is a continuation-in-part of application No. 09/446, positive tumor cells comprising administering to a cell or to a 996, filed on Dec. 30, 1999, now abandoned, filed as Subject a replication decreasing amount of a GnRH agonist application No. PCT/DE98/01902 on Jul. 3, 1998. and/or GnRH antagonist and/or an erythropoietin agonist, and/or a thrombopoietin agonist, and/or a endothelin antago (30) Foreign Application Priority Data nist and/or a gonadotropin inhibiting hormone agonist is also provided. Furthermore, a diagnostic kit for detecting GnRH Jul. 4, 1997 (DE) ............................... 197 28 737.9 receptors on tumor cells according to the present methods is Jul. 4, 1997 (DE) ................................. 19728.737.9 disclosed. dy's 8 days 12 sys Controls Patent Application Publication US 2010/0190692 A1 SÁeG ap?uy||0Infil-3 Patent Application Publication Jul. 29, 2010 Sheet 2 of 20 US 2010/0190692 A1 SÁed Patent Application Publication Jul. 29, 2010 Sheet 3 of 20 US 2010/0190692 A1 sÁed -9'0 Patent Application Publication Jul. 29, 2010 Sheet 4 of 20 US 2010/0190692 A1 885 top m FIG. 4 885bp - 885 bp - FIG. 5 Patent Application Publication Jul. 29, 2010 Sheet S of 20 US 2010/0190692 A1 F.G. 6 NS= .Ss·SS? LHRH-A (log dose My FIG. 7 Patent Application Publication Jul. 29, 2010 Sheet 6 of 20 US 2010/0190692 A1 11 §5 §4 ANT (log dose M) FIG. 8A FIG. 8B Patent Application Publication Jul. 29, 2010 Sheet 7 Of 20 US 2010/0190692 A1 'N * „oixaneidsløb º|××××××××*****.**.No.º S? N log dose he FIG. 9 Patent Application Publication Jul. 29, 2010 Sheet 8 of 20 US 2010/0190692 A1 4 days 8. days 2 sity's F.G. 10 Patent Application Publication Jul. 29, 2010 Sheet 9 of 20 US 2010/0190692 A1 F.G. 11 Patent Application Publication Jul. 29, 2010 Sheet 10 of 20 US 2010/0190692 A1 --- Ragonist (log tissels FIG. 12 Patent Application Publication Jul. 29, 2010 Sheet 11 of 20 US 2010/0190692 A1 3:3&£: & - 3:3:3::::: : &".SSS 3. 2. 3.33 s FIG. 13 Patent Application Publication Jul. 29, 2010 Sheet 12 of 20 US 2010/0190692 A1 FIG. 14A FG, 14B Patent Application Publication Jul. 29, 2010 Sheet 13 of 20 US 2010/0190692 A1 FIG. 15 Patent Application Publication Jul. 29, 2010 Sheet 14 of 20 US 2010/0190692 A1 Effect of LHRH antagonist (Cetrorelix) on U87 proliferation . 8000 60000 is AOCOO 8. r 8 8 S 8 3 8 & s 8SS 8 8: O : C 8 6 al Cetrorelix (log dose MD FG 16 Patent Application Publication Jul. 29, 2010 Sheet 15 of 20 US 2010/0190692 A1 98 K me 62K noma 49 K mana FIG 17A 38K - 28 K. -- 7 K. -a- - MG3 MG2 MG 1 GB 4 GB 3 GB1 98 K m 62K 49 K FIG 17B 38 K 28 K. 7 K. H. MN5 MN3 MN2 MN Patent Application Publication Jul. 29, 2010 Sheet 16 of 20 US 2010/0190692 A1 98 K - 62K - 49 K - GBl GB3 GB4 MG MG2 MG3 FIG 18A 98 K - 49 K - MN1 MN2 MN3 MN5 FIG 18B Patent Application Publication Jul. 29, 2010 Sheet 17 of 20 US 2010/0190692 A1 45 kDa 36 kDa 29 kDa 24 kDa 20,1 MG3 MG2 MG GB4 GB3 GB1 FIG 19A Patent Application Publication Jul. 29, 2010 Sheet 18 of 20 US 2010/0190692 A1 400000 is 300000 S CA 5S 200000 C D-Lys, 5uM 100000" Gossypol, 51M D-Lys +Gossypol, 5uM Conjugate, 5uM FIG20A 500000 400000 S 300000 s: - ck S O 200000 | OOOOO C D-Lys Goss Goss Goss Goss 2uM 3M 5uM 7.5uM FIG 20B Patent Application Publication Jul. 29, 2010 Sheet 19 of 20 US 2010/0190692 A1 9?eId/SII3O C 0 5uM luM 2.5uM 5uM Gossypol FG 20O Patent Application Publication Jul. 29, 2010 Sheet 20 of 20 US 2010/0190692 A1 10000 - ==c 100 g/day T 7500 - S = 200 g/day gs 5000 - gE. s o End of treatment 2500 - 0 --------|-- 4 7 9 11 14 16 18 21 25 28 (days) FIG 21 US 2010/0190692 A1 Jul. 29, 2010 METHODS FOR REDUCING on the tumor tissue itself; cf. Emons and Schally, 1994, GNRH-POSITIVE TUMIORCELL Human Reproduction Update 9, 1364-1379. PROLIFERATION 0006. This observed indirect effect due to steroid hormone dependence has been known for decades concerning prostate CROSS-REFERENCE TO RELATED and the mammary carcinoma; cf. Gonzalez-Barcena et al., APPLICATION 1994, The Prostate 24, 84-92; Jonat et al., 1995, European Journal of Cancer 31A, 137-142. 0001. This application is a continuation in part of co 0007. The direct anti-proliferative effect of GnRH ago pending U.S. application Ser. No. 10/327.621, filed on Dec. nists and GnRH antagonists on e.g. prostate carcinomas, 20, 2002, and a continuation in part of U.S. application Ser. mammary carcinomas, and ovarian carcinomas has been con No. 09/446,996, filed on Dec. 30, 1999, now abandoned, the firmed by clinical studies. Several of the GnRH agonists contents of both are incorporated by reference; the latter employed in these treatments that have a direct anti-prolif application was a national phase entry under 35 U.S.C. S371 erative effect are known by the following trademarks of these of International Patent Application PCT/DE98/01902, filed medicaments, which are approved in Germany, for example: Jul. 3, 1998, published as International Patent Publication ZOLADEXR (goserelin acetate implant), ZOLADEX 10.81R WO99/01764 on Jan. 14, 1999. (goserelin acetate implant), ZOLADEX GYNR (goserelin acetate implant), PROFACTR-DEPOT, PROFACTR PRO FIELD OF THE INVENTION INJECTIONE/NASAL, SYNARELAR, ENANTONE 0002 The present invention relates to tumor diagnosis and MONATS-DEPOTR, UNO-ENANTONER, ENANTONE therapy. In particular, it is directed to the therapy of tumors GYN MONATS-DEPOTR, TRENANTONER), SUPRE bearing GnRH receptors using GnRH agonists, GnRH CURR, CARCINIL(R), or DECAPEPTYL(R) 0.5 mg/0.1 mg, antagonists, and/or a combination thereof. DECAPEPTYL(R) DEPOT, DECAPEPTYLR GYN as well as DECAPEPTYLOR DIAGNOSTIK. BACKGROUND OF THE INVENTION 0008 Research using cell cultures has revealed that GnRH receptors are present on human primary liver cell carcinomas 0003 Post-operative treatment of prostate and mammary and pancreatic adenocarcinomas. In addition, the beginning carcinomas using gonadotropin releasing hormone (or of a biochemical metabolic reaction with respect to cleavage “GnRH”, also referred to as luteinizing hormone releasing of GnRH between tyrosine 5 and glycine 6 in ratglioma and hormone, or “LHRH” in the literature) agonists is a standard rat neuroblastoma has been described; cf. Tao et al., 1991, treatment; cf. Gonzalez-Barcena et al., 1994, The Prostate 24, Neuropeptides 20, 125-131. Ligand binding of GnRH to the 84-92; Emons and Schally, 1994, Human Reproduction GnRH receptor and its signal transduction, however, takes Update 9, No. 7, 1364-1379. The GnRH receptor is a well place in a different way, namely at the eighth amino acid of known target in tumor therapy. GnRH, arginine, and this exclusively occurs in the case of an 0004. The amino acid sequence of human GnRH has been intact conformation of the GnRH molecule and its amino acid characterized as pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro side chains (Naor, Z. Schacham, Sh. Harris, D., Seger, R., Gly-NH. A second form, or isoform of GnRH, referred to as and Reiss, N., 1995, Signal Transduction of the Gonadotropin “GnRH-II”, is widely conserved among vertebrates, includ Releasing Hormone (GnRH) Receptor: Cross-Talk of Cal ing humans, and has been shown to exhibit a high binding cium, Protein Kinase C(PKC), and Arachidonic Acid. Cel affinity for the GnRH receptor both in primate and human lular and Molecular Neurobiology, Vol. 15, 527-545). In a (Davidson, J. S., McArdle, C. A., Davies, P. et al. (1996) normal rat adenohypophysis, where GnRH receptors reside, ASn' of the gonadotropin-releasing hormone receptor is a GnRH leads to an increased cAMP production, however, it is critical determinant of potency for agonists containing C-ter still unclear whether this is a director an indirect effect (i.e. a minal glycamide. J. Biol. Chem., 271, 15510-15514; Sher paracrine interaction). For the functioning of the GnRH wood, N. M., Lovejoy, D. A. and Coe, I. R. (1993) Origin of receptor in rat, including secretion of LH as well as an mammalian gonadotropin-releasing hormones.
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