Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
USE OF CYCLOOXYGENASE-2 INHIBITOR, A MATRIX METALLAPROTEINASE INHIBITOR, AN ANTINEOPLASTIC AGENT AND OPTIONALLY RADIATION AS A COMBINATION TREATMENT OF NEOPLASIA
Document Type and Number:
WIPO Patent Application WO/2000/037107
Kind Code:
A2
Abstract:
The present invention provides methods to treat or prevent neoplasia disorders in a mammal using a combination of a cyclooxygenase-2 inhibitor, a matrix metalloproteinase inhibitor and an antineoplastic agent.

Inventors:
MCKEARN JOHN P (US)
GORDON GARY (US)
CUNNINGHAM JAMES J (US)
GATELY STEPHEN T (US)
KOKI ALANE T (US)
MASFERRER JAIME L (US)
Application Number:
PCT/US1999/030776
Publication Date:
June 29, 2000
Filing Date:
December 22, 1999
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
SEARLE & CO (US)
MCKEARN JOHN P (US)
GORDON GARY (US)
CUNNINGHAM JAMES J (US)
GATELY STEPHEN T (US)
KOKI ALANE T (US)
MASFERRER JAIME L (US)
International Classes:
A61K31/00; A61K31/07; A61K31/122; A61K33/243; A61K31/135; A61K45/00; A61K31/136; A61K31/138; A61K31/16; A61K31/165; A61K31/166; A61K31/18; A61K31/191; A61K31/192; A61K31/197; A61K31/198; A61K31/203; A61K31/255; A61K31/28; A61K31/282; A61K31/337; A61K31/341; A61K31/351; A61K31/353; A61K31/36; A61K31/381; A61K31/402; A61K31/415; A61K31/4162; A61K31/4164; A61K31/4168; A61K31/4178; A61K31/4184; A61K31/4188; A61K31/4196; A61K31/42; A61K31/421; A61K31/422; A61K31/425; A61K31/427; A61K31/429; A61K31/435; A61K31/4353; A61K31/437; A61K31/4375; A61K31/44; A61K31/4402; A61K31/4418; A61K31/4427; A61K31/4433; A61K31/4439; A61K31/444; A61K31/445; A61K31/4453; A61K31/45; A61K31/451; A61K31/4535; A61K31/4545; A61K31/4709; A61K31/4741; A61K31/4745; A61K31/475; A61K31/496; A61K31/501; A61K31/505; A61K31/506; A61K31/51; A61K31/519; A61K31/525; A61K31/541; A61K31/55; A61K31/5513; A61K31/566; A61K31/567; A61K31/569; A61K31/57; A61K31/575; A61K31/66; A61K31/664; A61K31/675; A61K31/704; A61K31/7048; A61K31/7068; A61K33/04; A61K33/10; A61K38/00; A61K39/395; A61K41/00; A61K45/06; A61P1/00; A61P11/00; A61P13/10; A61P15/00; A61P15/14; A61P17/00; A61P35/00; A61P41/00; A61P43/00; C07D211/54; C07D211/66; C07D211/96; C07D213/74; C07D261/18; C07D309/08; C07D401/06; C07D401/12; C07D403/12; C07D405/12; C07D413/12; C07D417/12; C07D471/04; C07K5/023; C07K5/062; C07K16/18; (IPC1-7): A61K45/06; A61P35/00; A61K41/00
Domestic Patent References:
WO1998016227A11998-04-23
WO1997048685A11997-12-24
WO1999021583A11999-05-06
WO1998022101A21998-05-28
Foreign References:
US5629343A1997-05-13
US5672583A1997-09-30
EP0927555A11999-07-07
EP0985666A12000-03-15
Attorney, Agent or Firm:
Keane, Timothy J. (Corporate Patent Dept. P.O. Box 511, Chicago IL, US)
Weisert, Annekäte (Thomas-Wimmer-Ring 15, Munich, DE)
Download PDF:
View/Download PDF      PDF Help
Claims:
What is claimed is:
1. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administering to said mammal a therapeuticallyeffective amount of a combination of a cyclooxygenase2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent, wherein said antineoplastic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP461, docetaxel, doxorubicin, etoposide, fluorouracil (5FU), fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone, exemestane and eflornithine (DFMO).
2. The method of Claim 1 wherein the combination is administered in a sequential manner.
3. The method of Claim 1 wherein the combination is administered in a substantially simultaneous manner.
4. The method of Claim 1 wherein the antineoplastic agent is capecitabine.
5. The method of Claim 1 wherein the antineoplastic agent is carboplatin.
6. The method of Claim 1 wherein the antineoplastic agent is cisplatin.
7. The method of Claim 1 wherein the antineoplastic agent is Cell Pathways CP461.
8. The method of Claim 1 wherein the antineoplastic agent is docetaxel.
9. The method of Claim 1 wherein the antineoplastic agent is doxorubicin.
10. The method of Claim 1 wherein the antineoplastic agent is etoposide.
11. The method of Claim 1 wherein the antineoplastic agent is fluoxymestrine.
12. The method of Claim 1 wherein the antineoplastic agent is gemcitabine.
13. The method of Claim 1 wherein the antineoplastic agent is goserelin.
14. The method of Claim 1 wherein the antineoplastic agent is irinotecan.
15. The method of Claim 1 wherein the antineoplastic agent is ketoconazole.
16. The method of Claim 1 wherein the antineoplastic agent is letrozol.
17. The method of Claim 1 wherein the antineoplastic agent is leucovorin.
18. The method of Claim 1 wherein the antineoplastic agent is levamisole.
19. The method of Claim 1 wherein the antineoplastic agent is megestrol.
20. The method of Claim 1 wherein the antineoplastic agent is mitoxantrone.
21. The method of Claim 1 wherein the antineoplastic agent is paclitaxel.
22. The method of Claim 1 wherein the antineoplastic agent is raloxifene.
23. The method of Claim 1 wherein the antineoplastic agent is retinoic acid.
24. The method of Claim 1 wherein the antineoplastic agent is tamoxifen.
25. The method of Claim 1 wherein the antineoplastic agent is thiotepa.
26. The method of Claim 1 wherein the antineoplastic agent is topotecan.
27. The method of Claim 1 wherein the antineoplastic agent is toremifene.
28. The method of Claim 1 wherein the antineoplastic agent is vinorelbine.
29. The method of Claim 1 wherein the antineoplastic agent is vinblastine.
30. The method of Claim 1 wherein the antineoplastic agent is vincristine.
31. The method of Claim 1 wherein the antineoplastic agent is selenium (selenomethionine).
32. The method of Claim 1 wherein the antineoplastic agent is sulindac sulfone.
33. The method of Claim 1 wherein the antineoplastic agent is eflornithine (DFMO).
34. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: rofecoxib, 4 (4 (methylsulfonyl) phenyl]3 phenyl2 (5H)furanone, 4 (5methyl3phenylisoxazol4 yl) benzenesulfonamide, 7) N [ [4 (5methyl3phenylisoxazol 4yl]phenyl] sulfonyl] propanamide, 4 [5 (4chorophenyl)3 (trifluoromethyl)lH pyrazole1yl] benzenesulfonamide, 6[[5(4chlorobenzoyl)1,4dimethyl1H pyrrol2yl] methyl]3 (2H)pyridazinone, N (4nitro2phenoxyphenyl) methanesulfonamide, 3 (3,4difluorophenoxy)5,5dimethyl4 [4 (methylsulfonyl) phenyl]2 (5H)furanone, N [6 [ (2,4difluorophenyl)thio]2,3dihydro1 oxo1Hinden5yl]methanesulfonamide, 3 (4chlorophenyl)4 [4 (methylsulfonyl) phenyl]2 (3H)oxazolone, 4 [3 (4fluorophenyl)2,3dihydro2oxo4 oxazolyl] benzenesulfonamide, 3 [4 (methylsulfonyl) phenyl]2phenyl2<BR> <BR> cyclopenten1one, 4 (2methyl4phenyl5 oxazolyl) benzenesulfonamide, 3 (4fluorophenyl)4 [4 (methylsulfonyl) phenyl]2 (3H)oxazolone, 5 (4fluorophenyl)l [4 (methylsulfonyl)phenyl]3(trifluoromethyl) 1Hpyrazole, 4 [5phenyl)3 (trifluoromethyl)lHpyrazoll yl) benzenesulfonamide, 4 [lphenyl3 (trifluoromethyl)lHpyrazol5 yl] benzenesulfonamide, 4 [5 (4fluorophenyl)3 (trifluoromethyl)lH pyrazol1yl]benzenesulfonamide, N [2 (cyclohexyloxy)4 nitrophenyl] methanesulfonamide, N [6 (2,4difluorophenoxy)2,3dihydro1oxo 1Hinden5yl]methanesulfonamide, 3 (4chlorophenoxy)4 [(methylsulfonyl)amino]benzenesulfonamide, 3 (4fluorophenoxy)4 [ (methylsulfonyl) amino] benzenesulfonamide, 3 [ (lmethyllHimidazol2yl) thio]4 [(methylsulfonyl) amino] benzenesulfonamide, 5,5dimethyl4 [4 (methylsulfonyl) phenyl]3 phenoxy2 (5H)furanone, N [6 [ (4ethyl2thiazolyl) thio]1,3dihydro 1oxo5isobenzofuranyl] methanesulfonamide, 3 [ (2,4dichlorophenyl)thio]4 [ (methylsulfonyl) amino] benzenesulfonamide, 1fluoro4 [2 [4 (methylsulfonyl) phenyl] cyclopentenl yl]benzene, 4 [5 (4chlorophenyl)3 (difluoromethyl)lH pyrazol1yl] benzenesulfonamide, 3 [l [4 (methylsulfonyl) phenyl]4 (trifluoromethyl)1Himidazol2yl]pyridine, 4 [2 (3pyridinyll)4 (trifluoromethyl)lH<BR> <BR> imidazollyl] benzenesulfonamide, 4 [5 (hydroxymethyl)3phenylisoxazol4 yl] benzenesulfonamide, 4 [3 (4chlorophenyl)2,3dihydro2oxo4 oxazolyl] benzenesulfonamide, 4 [5 (difluoromethyl)3phenylisoxazol4 yl] benzenesulfonamide, [1, 1': 2', 1"terphenyl]4sulfonamide, 4(methylsulfonyl)1,1',2],1"terphenyl, 4 (2phenyl3pyridinyl) benzenesulfonamide, N (2, 3dihydro1, 1dioxido6phenoxy1,2 benzisothiazol5yl) methanesulfonamide, and N [3 (formylamino)4oxo6phenoxy4H1<BR> <BR> benzopyran7yl] methanesulfonamide,.
35. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is 5chloro3 (4 (methylsulfonyl) phenyl)2 (methyl5pyridinyl) pyridine.
36. The method of Claim 1 wherein the cycloo7xygenase2 inhibitor is 2 (3,5difluorophenyl)3 4 (methylsulfonyl) phenyl)2cyclopentenlone.
37. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is 4 [5 (4methylphenyl)3 (trifluoromethyl)lH<BR> <BR> pyrazollyl]benzenesulfonamide.
38. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is rofecoxib, 4 (4 (methylsulfonyl) phenyl]3 phenyl2 (5H)furanone.
39. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is 4 (5methyl3phenylisoxazol4 yl) benzenesulfonamide.
40. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is N [ [4 (5methyl3 <BR> <BR> phenylisoxazol4yl] phenyl] sulfonyl] propanamide.
41. The method of Claim 1 wherein the cyclooxygenase2 inhibitor is 4 [5 (4chorophenyl)3 (trifluoromethyl)lH<BR> <BR> pyrazolelyl] benzenesulfonamide.
42. The method of Claim 1 wherein the neoplasia is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.
43. The method of Claim 1 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatinsecreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.
44. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino)[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]), Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl)oxy]2 [ (phenylthio) methyl] butanoic acid, Agouron Pharmaceuticals AG3340, Nhydroxy2,2 dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide, 12) CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline, 13) Chiroscience D2163,2 [1S ( [ (2R, S) acetylmercapto5phthalimido] pentanoyl L leucyl)amino 3methylbutyl] imidazole, Nhydroxy4[[4(phenylthio)phenyl]sulfonyl] 1 (2propynyl)4piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinearboxamide, 1cyclopropylNhydroxy4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 4 [ [4 (cyclohexylthio) phenyl] sulfonyl]N hydroxyl (2propynyl)4piperidinecarboxamide monohydrochloride, 4 [ [4 (4 chlorophenoxy) phenyl] sulfonyl] tetrahydroN hydroxy2Hpyran4carboxamide, Nhydroxy4 [ [4 (4 methoxyphenoxy) phenyl) sulfonyl]l (2 propynyl)4piperidinecarboxamide, 1cyclopropyl4[[4[(4 fluorophenyl) thio] phenyl] sulfonyl]Nhydroxy 4piperidinecarboxamide, 1cyclopropylNhydroxy4[[4 (phenylthio) phenyl] sulfonyl]4 piperidinecarboxamide, tetrahydroNhydroxy4 [ [4 (4 pyridinylthio)phenyl] sulfonyl]2Hpyran4 carboxamide, and tetrahydroNhydroxy4 [ [4 [4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]2H pyran4carboxamide.
45. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
46. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
47. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride.
48. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
49. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide.
50. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
51. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
52. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
53. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]).
54. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl) oxy]2 [ (phenylthio) methyl] butanoic acid.
55. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Agouron Pharmaceuticals AG3340, Nhydroxy 2,2dimethyl4 [ [4 (4 pyridinyloxy)phenyl] sulfonyl] 3 thiomorpholinecarboxamide.
56. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline.
57. The method of Claim 1 wherein the matrix metalloproteinase inhibitor is Chiroscience D2163,2 [1S ( [ (2R, S) acetylmercapto5phthalimido] pentanoyl Lleucyl) amino 3methylbutyl] imidazole.
58. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administering to said mammal a therapeuticallyeffective amount of a combination of radiation, a cyclooxygenase2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent, wherein said antineoplastic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP461, docetaxel, doxorubicin, etoposide, fluorouracil (5FU), fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone, exemestane and eflornithine (DFMO).
59. The method of Claim 58 wherein the combination is administered in a sequential manner.
60. The method of Claim 58 wherein the combination is administered in a substantially simultaneous manner.
61. The method of Claim 58 wherein the antineoplastic agent is capecitabine.
62. The method of Claim 58 wherein the antineoplastic agent is carboplatin.
63. The method of Claim 58 wherein the antineoplastic agent is cisplatin.
64. The method of Claim 58 wherein the antineoplastic agent is Cell Pathways CP461.
65. The method of Claim 58 wherein the antineoplastic agent is docetaxel.
66. The method of Claim 58 wherein the antineoplastic agent is doxorubicin.
67. The method of Claim 58 wherein the antineoplastic agent is etoposide.
68. The method of Claim 58 wherein the antineoplastic agent is fluoxymestrine.
69. The method of Claim 58 wherein the antineoplastic agent is gemcitabine.
70. The method of Claim 58 wherein the antineoplastic agent is goserelin.
71. The method of Claim 58 wherein the antineoplastic agent is irinotecan.
72. The method of Claim 58 wherein the antineoplastic agent is ketoconazole.
73. The method of Claim 58 wherein the antineoplastic agent is letrozol.
74. The method of Claim 58 wherein the antineoplastic agent is leucovorin.
75. The method of Claim 58 wherein the antineoplastic agent is levamisole.
76. The method of Claim 58 wherein the antineoplastic agent is megestrol.
77. The method of Claim 58 wherein the antineoplastic agent is mitoxantrone.
78. The method of Claim 58 wherein the antineoplastic agent is paclitaxel.
79. The method of Claim 58 wherein the antineoplastic agent is raloxifene.
80. The method of Claim 58 wherein the antineoplastic agent is retinoic acid.
81. The method of Claim 58 wherein the antineoplastic agent is tamoxifen.
82. The method of Claim 58 wherein the antineoplastic agent is thiotepa.
83. The method of Claim 58 wherein the antineoplastic agent is topotecan.
84. The method of Claim 58 wherein the antineoplastic agent is toremifene.
85. The method of Claim 58 wherein the antineoplastic agent is vinorelbine.
86. The method of Claim 58 wherein the antineoplastic agent is vinblastine.
87. The method of Claim 58 wherein the antineoplastic agent is vincristine.
88. The method of Claim 58 wherein the antineoplastic agent is selenium (selenomethionine).
89. The method of Claim 58 wherein the antineoplastic agent is sulindac sulfone.
90. The method of Claim 58 wherein the antineoplastic agent is eflornithine (DFMO).
91. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: 1) JTE522,4 (4cyclohexyl2methyloxazol5yl) 2fluorobenzenesulfonamide, 2) 5chloro3 (4 (methylsulfonyl) phenyl)2 (methyl5pyridinyl) pyridine, 3) 2 (3,5difluorophenyl)34 (methylsulfonyl)phenyl)2cyclopenten1one, 4) 4 [5 (4methylphenyl)3 (trifluoromethyl)lH<BR> <BR> pyrazol1yl]benzenesulfonamide, rofecoxib, 4 (4 (methylsulfonyl) phenyl]3 phenyl2 (5H)furanone, 4 (5methyl3phenylisoxazol4 yl) benzenesulfonamide, 7) N[[4(5methyl3phenylisoxazol 4yl] phenyl] sulfonyl] propanamide, 4 [5 (4chorophenyl)3 (trifluoromethyl)lH pyrazolelyl] benzenesulfonamide, 6[[5(4chlorobenzoyl)1,4dimethyl1H pyrrol2yl] methyl]3 (2H)pyridazinone, N (4nitro2phenoxyphenyl) methanesulfonamide, 3 (3,4difluorophenoxy)5,5dimethyl4 [4 (methylsulfonyl) phenyl]2 (5H)furanone, N [6 [ (2,4difluorophenyl)thio]2,3dihydro1<BR> <BR> oxolHinden5yl] methanesulfonamide, 3 (4chlorophenyl)4 [4 (methylsulfonyl) phenyl]2 (3H)oxazolone, 4 [3 (4fluorophenyl)2,3dihydro2oxo4 oxazolyl] benzenesulfonamide, 3 [4 (methylsulfonyl) phenyl]2phenyl2<BR> <BR> cyclopenten1one, 4 (2methyl4phenyl5 oxazolyl) benzenesulfonamide, 3 (4fluorophenyl)4 [4 (methylsulfonyl) phenyl]2 (3H)oxazolone, 5(4fluorophenyl)1[4 (methylsulfonyl) phenyl]3 (trifluoromethyl) IHpyrazole, 4 [5phenyl)3 (trifluoromethyl)lHpyrazoll yl) benzenesulfonamide, 4 [lphenyl3 (trifluoromethyl)lHpyrazol5 yl] benzenesulfonamide, 4 [5 (4fluorophenyl)3 (trifluoromethyl)lH pyrazol1yl]benzenesulfonamide, N [2 (cyclohexyloxy)4 nitrophenyl] methanesulfonamide, N [6 (2,4difluorophenoxy)2,3dihydro1oxo lHinden5yl] methanesulfonamide, 3 (4chlorophenoxy)4 [(methylsulfonyl) amino] benzenesulfonamide, 3 (4fluorophenoxy)4 [(methylsulfonyl)amino]benzenesulfonamide, 3 [ (lmethyllHimidazol2yl) thio]4 [ (methylsulfonyl) amino] benzenesulfonamide, 5,5dimethyl4 [4 (methylsulfonyl) phenyl]3 phenoxy2 (5H)furanone, N [6 [ (4ethyl2thiazolyl) thio]1,3dihydro loxo5isobenzofuranyl] methanesulfonamide, 3 [ (2,4dichlorophenyl)thio]4 [ (methylsulfonyl) amino] benzenesulfonamide, 1fluoro4 [2 [4 (methylsulfonyl) phenyl] cyclopentenl yl] benzene, 4 [5 (4chlorophenyl)3 (difluoromethyl)lH pyrazol1yl]benzenesulfonamide, 3 [1 [4 (methylsulfonyl) phenyl]4 (trifluoromethyl)1Himidazol2yl]pyridine, 4 [2 (3pyridinyll)4 (trifluoromethyl)lH imidazollyl] benzenesulfonamide, 4 [5 (hydroxymethyl)3phenylisoxazol4 yl] benzenesulfonamide, 4 [3 (4chlorophenyl)2,3dihydro2oxo4 oxazolyl] benzenesulfonamide, 4 [5 (difluoromethyl)3phenylisoxazol4 yl] benzenesulfonamide, [1,1':2',1"terphenyl]4sulfonamide, 4 (methylsulfonyl)1, 1', 2], 1"terphenyl, 4 (2phenyl3pyridinyl) benzenesulfonamide, N (2, 3dihydro1, 1dioxido6phenoxy1,2 benzisothiazol5yl) methanesulfonamide, and N [3 (formylamino)4oxo6phenoxy4H1<BR> <BR> benzopyran7yl] methanesulfonamide,.
92. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is 5chloro3 (4 (methylsulfonyl) phenyl)2 (methyl5pyridinyl) pyridine.
93. The method of Claim 58 wherein the cycloo7xygenase2 inhibitor is 2 (3,5difluorophenyl)3 4 (methylsulfonyl) phenyl)2cyclopentenlone.
94. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is 4 [5 (4methylphenyl)3 (trifluoromethyl)lH<BR> <BR> pyrazol1yl]benzenesulfonamide.
95. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is rofecoxib, 4 (4 (methylsulfonyl) phenyl]3 phenyl2 (5H)furanone.
96. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is 4 (5methyl3phenylisoxazol4 yl) benzenesulfonamide.
97. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is N [ [4 (5methyl3 <BR> <BR> phenylisoxazol4yl] phenyl] sulfonyl] propanamide.
98. The method of Claim 58 wherein the cyclooxygenase2 inhibitor is 4 [5 (4chorophenyl)3 (trifluoromethyl)lH pyrazolelyl] benzenesulfonamide.
99. The method of Claim 58 wherein the neoplasia is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.
100. The method of Claim 58 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatinsecreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.
101. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(phenylmethyl4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino)[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]), Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl)oxy]2 [(phenylthio) methyl] butanoic acid, Agouron Pharmaceuticals AG3340, Nhydroxy2,2 dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide, 12) CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline, 13) Chiroscience D2163,2 [1S ( [ (2R, S) acetylmercapto5phthalimido] pentanoylL leucyl)amino 3methylbutyl] imidazole, Nhydroxy4[[4(phenylthio)phenyl]sulfonyl] 1 (2propynyl)4piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinearboxamide, 1cyclopropylNhydroxy4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 4[[4(cyclohexylthio)phenyl]sulfonyl]N hydroxyl (2propynyl)4piperidinecarboxamide monohydrochloride, 4 [ [4 (4 chlorophenoxy) phenyl] sulfonyl] tetrahydroN hydroxy2Hpyran4carboxamide, Nhydroxy4 [ [4 (4 methoxyphenoxy) phenyl) sulfonyl]l(2 propynyl)4piperidinecarboxamide, 1cyclopropyl4[[4[(4 fluorophenyl) thio] phenyl] sulfonyl]Nhydroxy 4piperidinecarboxamide, 1cyclopropylNhydroxy4[[4 (phenylthio) phenyl] sulfonyl]4 piperidinecarboxamide, tetrahydroNhydroxy4 [ [4 (4 pyridinylthio) phenyl] sulfonyl]2Hpyran4 carboxamide, and tetrahydroNhydroxy4 [ [4 [4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]2H pyran4carboxamide.
102. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
103. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
104. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride.
105. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
106. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide.
107. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
108. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
109. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
110. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]).
111. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl) oxy]2 [ (phenylthio) methyl] butanoic acid.
112. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Agouron Pharmaceuticals AG3340, Nhydroxy 2,2dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide.
113. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline.
114. The method of Claim 58 wherein the matrix metalloproteinase inhibitor is Chiroscience D2163,2 [lS ([(2R, S)acetylmercapto5phthalimido] pentanoyl Lleucyl) amino 3methylbutyl] imidazole.
115. A combination comprising a cyclooxygenase2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent, wherein said antineoplastic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP461, docetaxel, doxorubicin, etoposide, fluorouracil (5FU), fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone, exemestane and eflornithine (DFMO).
116. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: 1) JTE522,4 (4cyclohexyl2methyloxazol5yl) 2fluorobenzenesulfonamide, 2) 5chloro3 (4 (methylsulfonyl) phenyl)2 (methyl5pyridinyl) pyridine, 3) 2 (3,5difluorophenyl)34 (methylsulfonyl) phenyl)2cyclopenten1one, 4 [5 (4methylphenyl)3 (trifluoromethyl)lH<BR> <BR> pyrazollyl]benzenesulfonamide, rofecoxib, 4 (4 (methylsulfonyl) phenyl]3 phenyl2 (5H)furanone, 4 (5methyl3phenylisoxazol4 yl) benzenesulfonamide, 7) N [ [4 (5methyl3phenylisoxazol 4yl] phenyl] sulfonyl] propanamide, 4 [5 (4chorophenyl)3 (trifluoromethyl)lH pyrazolelyl] benzenesulfonamide, 6[[5(4chlorobenzoyl)1,4dimethyl1H pyrrol2yl] methyl]3 (2H)pyridazinone, N (4nitro2phenoxyphenyl) methanesulfonamide, 3 (3,4difluorophenoxy)5,5dimethyl4 [4 (methylsulfonyl) phenyl]2 (5H)furanone, N [6 [ (2,4difluorophenyl)thio]2,3dihydro1<BR> <BR> oxolHinden5yl] methanesulfonamide, 3 (4chlorophenyl)4 [4 (methylsulfonyl) phenyl]2 (3H)oxazolone, 4 [3 (4fluorophenyl)2,3dihydro2oxo4 oxazolyl] benzenesulfonamide, 3 [4 (methylsulfonyl) phenyl]2phenyl2<BR> <BR> cyclopenten1one, 4 (2methyl4phenyl5 oxazolyl) benzenesulfonamide, 3 (4fluorophenyl)4 [4 (methylsulfonyl) phenyl]2 (3H)oxazolone, 5 (4fluorophenyl)1 [4 (methylsulfonyl)phenyl]3 (trifluoromethyl) 1Hpyrazole, 4 [5phenyl)3 (trifluoromethyl)lHpyrazoll yl) benzenesulfonamide, 4[1phenyl3(trifluoromethyl)1Hpyrazol5 yl] benzenesulfonamide, 4 [5 (4fluorophenyl)3 (trifluoromethyl)lH pyrazol1yl]benzenesulfonamide, N [2 (cyclohexyloxy)4 nitrophenyl] methanesulfonamide, N [6 (2,4difluorophenoxy)2,3dihydro1oxo<BR> <BR> lHinden5yl] methanesulfonamide, 3 (4chlorophenoxy)4 [ (methylsulfonyl) amino] benzenesulfonamide, 3 (4fluorophenoxy)4 [(methylsulfonyl) amino] benzenesulfonamide, 3 [ (lmethyllHimidazol2yl) thio]4 [(methylsulfonyl)amino]benzenesulfonamide, 5,5dimethyl4 [4 (methylsulfonyl) phenyl]3 phenoxy2 (5H)furanone, N [6 [ (4ethyl2thiazolyl) thio]1,3dihydro loxo5isobenzofuranyl] methanesulfonamide, 3 [ (2,4dichlorophenyl)thio]4 [(methylsulfonyl)aminp]benzenesulfonamide, 1fluoro4 [2 [4 (methylsulfonyl) phenyl] cyclopentenl yl] benzene, 4 [5 (4chlorophenyl)3 (difluoromethyl)lH pyrazol1yl] benzenesulfonamide, 3 [l [4 (methylsulfonyl) phenyl]4 (trifluoromethyl)1Himidazol2yl]pyridine, 4 [2 (3pyridinyll)4 (trifluoromethyl)lH imidazollyl] benzenesulfonamide, 4 [5 (hydroxymethyl)3phenylisoxazol4 yl]benzenesulfonamide, 38) 4 [3 (4chlorophenyl)2,3dihydro2oxo4 oxazolyl] benzenesulfonamide, 4 [5 (difluoromethyl)3phenylisoxazol4 yl] benzenesulfonamide, [1,1':2',1"terphenyl]4sulfonamide, 4(methyylsulfonyl)1,1',2],1"terphenyl, 4 (2phenyl3pyridinyl) benzenesulfonamide, N(2, 3dihydro1, 1dioxido6phenoxy1,(2, 3dihydro1, 1dioxido6phenoxy1, 2 benzisothiazol5yl) methanesulfonamide, and N [3 (formylamino)4oxo6phenoxy4H1<BR> <BR> benzopyran7yl] methanesulfonamide,.
117. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is 5chloro3 (4 (methylsulfonyl) phenyl)2 (methyl5pyridinyl) pyridine.
118. The combination of Claim 115 wherein the cycloo7xygenase2 inhibitor is 2 (3,5difluorophenyl)3 4 (methylsulfonyl) phenyl)2cyclopentenlone.
119. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is 4 [5 (4methylphenyl)3 (trifluoromethyl)lH pyrazollyl]benzenesulfonamide.
120. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is rofecoxib, 4 (4 (methylsulfonyl) phenyl]3 phenyl2 (5H)furanone.
121. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is 4 (5methyl3phenylisoxazol4 yl) benzenesulfonamide.
122. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is N [ [4 (5methyl3 phenylisoxazol4yl] phenyl] sulfonyl] propanamide.
123. The combination of Claim 115 wherein the cyclooxygenase2 inhibitor is 4 [5 (4chorophenyl)3 (trifluoromethyl)lH<BR> <BR> pyrazolelyl] benzenesulfonamide.
124. The combination of Claim 115 wherein the neoplasia is selected from the group consisting of lung cancer, breast cancer, gastrointestinal cancer, bladder cancer, head and neck cancer and cervical cancer.
125. The combination of Claim 115 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatinsecreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.
126. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino)[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]), Bayer Ag Bay129566,4 [ (4'chloro [1, 1' iphenyl]4yl)oxy]2 [ (phenylthio) methyl] butanoic acid, Agouron Pharmaceuticals AG3340, Nhydroxy2,2 dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide, 12) CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline, 13) Chiroscience D2163,2 [1S ( [ (2R, S) <BR> <BR> acetylmercapto5phthalimido] pentanoylL<BR> <BR> leucyl) amino3methylbutyl] imidazole, Nhydroxy4[[4(phenylthio)phenyl]sulfonyl] 1 (2propynyl)4piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinearboxamide, 1cyclopropylNhydroxy4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 4 [ [4 (cyclohexylthio) phenyl] sulfonyl]N hydroxyl (2propynyl)4piperidinecarboxamide monohydrochloride, 4 [ [4 (4 chlorophenoxy) phenyl] sulfonyl] tetrahydroN hydroxy2Hpyran4carboxamide, Nhydroxy4 [ [4 (4 methoxyphenoxy) phenyl) sulfonyl]l (2 propynyl)4piperidinecarboxamide, 1cyclopropyl4[[4[(4 fluorophenyl) thio] phenyl] sulfonyl]Nhydroxy 4piperidinecarboxamide, 1cyclopropylNhydroxy4[[4 (phenylthio) phenyl] sulfonyl]4 piperidinecarboxamide, tetrahydroNhydroxy4 [ [4 (4 pyridinylthio) phenyl] sulfonyl]2Hpyran4 carboxamide, and tetrahydroNhydroxy4 [ [4 [4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]2H pyran4carboxamide.
127. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
128. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
129. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride.
130. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
131. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy2,3dimethoxy6[[4[4 (trifluoromethyl)phenoxy]l piperidinyl] sulfonyl] benzamide.
132. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
133. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride.
134. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride.
135. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]).
136. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl)oxy]2 [(phenylthio) methyl] butanoic acid.
137. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Agouron Pharmaceuticals AG3340, Nhydroxy 2,2dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide.
138. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline.
139. The combination of Claim 115 wherein the matrix metalloproteinase inhibitor is Chiroscience D 2163,2 [1S ( [ (2R, S) acetylmercapto5 <BR> phthalimido] pentanoylLleucyl) amino3<BR> methylbutyl] imidazole.
140. The method of Claim 1 wherein the antineoplastic agent is anastrozole.
141. The method of Claim 1 wherein the antineoplastic agent is calcium carbonate.
142. The method of claim 1 wherein the antineoplastic agent is exemestane.
143. The method of Claim 58 wherein the combination is administered in a sequential manner.
144. The method of Claim 58 wherein the combination is administered in a substantially simultaneous manner.
145. The method of claim 1 wherein the antineoplastic agent is exemestane.
146. A method for treating or preventing a neoplasia disorder in a mammal in need of such treatment or prevention, which method comprises administering to said mammal a therapeuticallyeffective amount of a combination of a cyclooxygenase2 inhibitor and a matrix metalloproteinase inhibitor, wherein said matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]), Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl) oxy]2 [ (phenylthio) methyl] butanoic acid, Agouron Pharmaceuticals AG3340, Nhydroxy2,2 dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide, 12) CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline, 13) Chiroscience D2163,2 [1S ( [ (2R, S) acetylmercapto5phthalimido] pentanoyl L leucyl)amino 3methylbutyl] imidazole, Nhydroxy4[[4(phenylthio)phenyl]sulfonyl] 1 (2propynyl)4piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinearboxamide, 1cyclopropylNhydroxy4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 4[[4(chclohexylthio)phenyl]sulfonyl]N hydroxyl (2propynyl)4piperidinecarboxamide monohydrochloride, 4 [ [4 (4 chlorophenoxy) phenyl] sulfonyl] tetrahydroN hydroxy2Hpyran4carboxamide, Nhydroxy4 [ [4 (4 methoxyphenoxy) phenyl) sulfonyl]l(2 propynyl)4piperidinecarboxamide, 1cyclopropyl4[[4[(4 fluorophenyl) thio] phenyl] sulfonyl]Nhydroxy 4piperidinecarboxamide, 1cyclopropylNhydroxy4[[4 (phenylthio) phenyl] sulfonyl]4 piperidinecarboxamide, tetrahydroNhydroxy4 [ [4 (4 pyridinylthio) phenyl] sulfonyl]2Hpyran4 carboxamide, and tetrahydroNhydroxy4 [ [4 [4 (trifluoromethyl)phenoxy] phenyl] sulfonyl]2H pyran4carboxamide.
147. The method of Claim 146 comprising administering to said mammal a therapeuticallyeffective amount of a combination of an cyclooxygenase2 inhibitor, a matrix metalloproteinase inhibitor, and an antineoplastic agent, wherein the antineoplastic agent is selected from the group consisting of anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP461, docetaxel, doxorubicin, etoposide, fluorouracil (5FU), fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone and eflornithine (DFMO).
148. The method of Claim 146 comprising administering to said mammal a therapeuticallyeffective amount of a combination of radiation, a cyclooxygenase2 inhibitor and a matrix metalloproteinase inhibitor.
149. A combination comprising a cyclooxygenase2 inhibitor and a matrix metalloproteinase inhibitor, wherein said matrix metalloproteinase inhibitor is selected from compounds, and their pharmaceutically acceptable salts thereof, of the group consisting of: Nhydroxy1(4methylphenyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 2) 1cyclopropylNhydroxy4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(phenylmethyl)4[[4[4 (trifluoromethoxy)phenoxy]l <BR> <BR> piperidinyl] sulfonyl]4piperidinecarboxamide monohydrochloride, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy2,3dimethoxy6 [ [4 [4 (trifluoromethyl) phenoxy]l piperidinyl] sulfonyl] benzamide, Nhydroxy1(4pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(3pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide dihydrochloride, Nhydroxy1(2pyridinylmethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, British Biotech BB2516 (Marimastat), N4 [2,2 dimethyll[(methylamino) carbonyl] propyl] N1,2dihydroxy3 (2methylpropyl), [2S [N4 (R*), 2R*, 3S*]]), 10) Bayer Ag Bay129566,4 [ (4'chloro [l, l' iphenyl]4yl)oxy]2 [ (phenylthio) methyl] butanoic acid, Agouron Pharmaceuticals AG3340, Nhydroxy2,2 dimethyl4 [ [4 (4 pyridinyloxy) phenyl] sulfonyl] 3 thiomorpholinecarboxamide, 12) CollaGenex Pharmaceuticals CMT3 (Metastat), 6demethyl6deoxy4 dedimethylaminotetracycline, 13) Chiroscience D2163,2 [1S ( [ (2R, S) acetylmercapto5phthalimido] pentanoylL leucyl)amino 3methylbutyl] imidazole, Nhydroxy4 [ [4 (phenylthio) phenyl] sulfonyl]<BR> <BR> 1 (2propynyl)4piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethoxy) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, Nhydroxy1(2methoxyethyl)4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinearboxamide, 1cyclopropylNhydroxy4[[4[4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]4 piperidinecarboxamide monohydrochloride, 4[[4(cyclohexylthio)phenyl]sulfonyl]N hydroxyl (2propynyl)4piperidinecarboxamide monohydrochloride, 4 [ [4 (4 chlorophenoxy) phenyl] sulfonyl] tetrahydroN hydroxy2Hpyran4carboxamide, Nhydroxy4 [ [4 (4 methoxyphenoxy) phenyl) sulfonyl]l(2 propynyl)4piperidinecarboxamide, 1cyclopropyl4[[4[(4 fluorophenyl) thio] phenyl] sulfonyl]Nhydroxy 4piperidinecarboxamide, 1cyclopropylNhydroxy4[[4 (phenylthio) phenyl] sulfonyl]4 piperidinecarboxamide, tetrahydroNhydroxy4 [ [4 (4 pyridinylthio) phenyl] sulfonyl]2Hpyran4 carboxamide, and tetrahydroNhydroxy4 [ [4 [4 (trifluoromethyl) phenoxy] phenyl] sulfonyl]2H pyran4carboxamide.
Description:
INTERNATIONALSEARCHREPORT InteonalApplicationNo PCT/US99/30776 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Category°Citationofdocument,withindication.whereappropriate ,oftherelevantpassagesRelevanttoclaimNo. YUS5629343A(HAGMANNWILLIAMETAL)1-145 13May1997(1997-05-13) column1,line16-20 column3,line33-36 column11,line62-68 claims7-13 YUS5672583A(CHAPMANKEVINETAL)1-145 30September1997(1997-09-30) column1,line28-37 column3,line40-53 claims10-17 P,YEP0927555A(SANKYOCO)1-145 7July1999(1999-07-07) claim42 page24,line28-34 P,YWO9921583A(WARNERLAMBERTCO;SUNYI1-145 (US))6May1999(1999-05-06) claims1-8 XWO9822101A(RAZAMIRAM;MASFERRERJAIME146-149 L(US);SEARLE&CO(US)) 28May1998(1998-05-28) page43,line5-9 page3,line32-34 EEP0985666A(PFIZER)146-149 15March2000(2000-03-15) page20,line25-36 Int...tionalapplicationNo. INTERNATIONALSEARCHREPORTPCT/US99/30776 Box)Observationswherecertainclaimswerefoundunsearchable(Cont inuationofitem1offirstsheet) ThisInternationalSearchReporthasnotbeenestablishedinrespecto fcertainclaimsunderArticle17(2)(a)forthefollowingreasons: 1.Claims Nos.: becausetheyrelatetosubjectmatternotrequiredtobesearchedbythi sAuthority,namely: 2.Claims Nos. : becausetheyrelatetopartsoftheIntemational Applicationthatdonotcomplywiththeprescribedrequirementstosuc h anextentthatnomeaningfulInternationalSearchcanbecarriedout,s pecifically: seeFURTHERINFORMATIONsheetPCT/ISA/210 3.ClClaims Nos.: becausetheyaredependentclaimsandarenotdraftedinaccordancewit hthesecondandthirdsentencesofRule 6.4(a). Box11Observationswhereunityofinventionislacking(Continuation ofitem2offirstsheet) ThisInternationalSearchingAuthorityfoundmultipleinventionsin thisinternationalapplication,asfollows: seeadditionalsheet 1 As allrequiredadditionalsearchfeesweretimelypaidbytheapplicant, thisInternationalSearchReportcoversall searchable claims. 2.As all searchable claims couldbesearchedwithouteffortjustifyinganadditionalfee,thisAu thoritydidnotinvitepayment ofanyadditional fee. 3.Asonlysomeoftherequiredadditionalsearchfeesweretimelypaidb ytheapplicant,thisIntemational SearchReport covers onlythoseclaimsforwhichfeeswerepaid,specificallyclaimsNos.: 4.Norequiredadditionalsearchfeesweretimelypaidbytheapplicant .Consequentty,thisInternationalSearchReportis restrictedtotheinventionfirstmentionedintheclaims;itiscovere dbyclaimsNos.: RemarkonProtestThe additionalsearchfeeswereaccompaniedbytheapplicant'sprotest. u 3Noprotestaccompaniedthepaymentofadditionalsearchfees. au FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 Continuation of Box 1.2 Present claims 1-149 relate to an extremely large number of possible products and/or methods. Support within the meaning of Article 6 PCT and/or disclosure within the meaning of Article 5 PCT is to be found, however, for only a very small proportion of the products and/or methods claimed. In the present case, the claims so lack support, and the application so lacks disclosure, that a meaningful search over the whole of the claimed scope is impossible. Consequently, the search has been carried out for those parts of the claims which appear to be supported and disclosed, namely those parts relating to the general concept, i. e. the triple combination treatment in general.

It is further pointed out that the second invention, i. e. the invention as claimed in claims 146-149 also lacks unity. The only feature being common for the compounds disclosed in claim 146 is that they are all MMP inhibitors.

Both wo The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure.

FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 This International Searching Authority found multiple (groups of) inventions in this international application, as follows: 1. Claims: 1-145 Use of a COX-2 inhibitor, a MMP inhibitor, an antineoplastic agent selected from a defined group and optionally radiation for the treatment or prevention of a neoplasia disorder and combinations (products) comprising said three active components 2. Claims: 146-149 Use of a COX-2 inhibitor and a MMP inhibitor selected from a defined group for the treatment or prevention of a neoplasia disorder and combinations (products) comprising said active components. INTERNATIONALSEARCHREPORT Inte onal ApplicationNo informationonpatenttamDymemters PCT/US 99/30776 PatentdocumentPublication Patent family Publication citedinsearchreportdate member(s)date WO9816227A23-04-1998AU 4904897 A 11-05-1998 BR 9712314 A 31-08-1999 CN 1244122 A 09-02-2000 CZ 9901171 A 14-07-1999 EP 0932402 A 04-08-1999 NO 991793 A 15-04-1999NO 991793 A 15-04-1999 WO9748685A24-12-1997US 5990112 A 23-11-1999 AU 3102397 A 07-01-1998 US 5817751 A 06-10-1998US 5817751 A 06-10-1998 US5629343A13-05-1997AU 5292193 A 26-04-1994 WO 9407481 A 14-04-1994 US5672583A30-09-1997AU 679474 B 03-07-1997 AU 5612994 A 22-06-1994 EP 0671911 A 20-09-1995 JP 8503475 T 16-04-1996 WO 9412169 A 09-06-1994 EP0927555A07-07-1999AU 9822598 A 15-07-1999 CN 1230407 A 06-10-1999 CZ 9804258 A 14-07-1999 HU 9803018 A 28-10-1999 JP 11246403 A 14-09-1999 NO 986089 A 25-06-1999 PL 330496 A 05-07-1999 JP 11279078 A 12-10-1999 JP 2000095685 A 04-04-2000 WO9921583A06-05-1999AU 1110799 A 17-05-1999 WO9822101A28-05-1998AU 7298298 A 10-06-1998 CZ 9901768 A 13-10-1999 EP 0941080 A 15-09-1999 NO 992309 A 12-05-1999 PL 333370 A 06-12-1999 EP 0985666 A 15-03-2000 JP 2000086630 A 28-03-2000




 
Previous Patent: ORAL VACCINE AGAINST DIARRHEA

Next Patent: OIL-IN-WATER EMULSION EXHIBITING A PROTECTIVE ACTION AGAINST DAMAGES TO HUMAN ORGANS RESULTING FROM ...