Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-22
2002-06-11
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210010, C514S247000, C514S252010, C514S341000, C514S365000, C514S372000, C514S374000, C514S378000, C514S399000, C514S400000, C514S403000, C514S407000, C514S602000, C514S603000, C514S604000, C514S605000, C514S709000, C424S138100, C424S155100, C424S174100
Reexamination Certificate
active
06403630
ABSTRACT:
TECHNICAL FIELD
This invention is directed to treatment of HER-2
eu overexpressing cancers.
BACKGROUND OF THE INVENTION
The HER-2
eu (erbB-2) gene product is a 185-kDA transmembrane receptor tyrosine kinase that belongs to the family of receptors for epidermal growth factor. It is described in some detail in Reese, D. M., et al., Stem Cells, 15, 1-8 (1997) which is incorporated herein by reference.
Recently, enormous attention has been given to the importance of HER-2
eu in breast cancer. HER-2
eu is overexpressed in 20-30% of human breast cancers and the increased expression has been associated with poor prognosis. The discovery of this has led to the development of HERCEPTIN®, an antibody to HER-2
eu, which in tests has been found to lengthen remission time in metastatic breast cancer. HER-2
eu is a cell-surface receptor that transmits growth signals to the cell nucleus. HERCEPTIN® appears to block these signals thereby apparently inhibiting proliferation of cells mediated by HER-2
eu in HER-2
eu positive breast cancer.
Overexpression of HER-2
eu has also been found in a portion of ovarian cancers, gastric cancers, endometrial cancers, salivary cancers, pancreatic cancers, prostate cancers, colorectal cancers, and non-small-cell lung cancers. The other cancers associated with overexpression of HER-2-neu are potentially treatable with HERCEPTIN®.
SUMMARY OF THE INVENTION
The invention herein is directed to treating cancers associated with overexpression of HER-2
eu with agent different from HERCEPTIN® or as a supplement to HERCEPTIN® to block the pathological results of HER-2
eu overexpression and thereby inhibit the development of cancers associated with overexpression of HER-2
eu.
It is shown herein that HER-2
eu expression causes increase of c-Jun and it is posited that the c-Jun induces cyclooxygenase-2 (COX-2) gene expression via the cyclic AMP response element and that this results in overexpression of COX-2 which mediates tumor formation. It is concluded from this that cancers associated with overexpression of HER-2
eu expression are beneficially treated with selective inhibitors of cyclooxygenase-2.
In a broad embodiment, the invention is directed at a method of treating cancer associated with overexpression of HER-2
eu in a patient affected with this condition, comprising administering to said patient a therapeutically effective amount of a selective inhibitor of cyclooxygenase-2. The cyclooxygenase-2 inhibitor can be administered as the only therapy or in a combination regimen with a therapeutically effective amount of HERCEPTIN®, a HER-2
eu antibody available from Genentech, and/or conventional therapy for the kind of cancer being treated.
In a narrower embodiment, the invention is directed at a method of treating breast cancer associated with overexpression of HER-2
eu in a patient affected with this condition comprising administering to said patient a therapeutically effective amount of a selective inhibitor of cyclooxygenase-2. The cyclooxygenase-2 inhibitor can be administered for or as part of adjuvant therapy for HER-2
eu positive breast cancer or for treatment of or as part treatment of HER-2
eu positive breast cancer that has metastasized. The cyclooxygenase-2 inhibitor is preferably administered in a combination regimen with HERCEPTIN® and preferably also is administered in combination regimen with standard chemotherapy or endocrine therapy or radiation treatment.
The term “cancer associated with overexpression of HER-2
eu” is used herein to mean that cancerous tissue contains more HER-2
eu than non-cancerous tissue from the same portion of the body.
The term “HER-2
eu positive breast cancer” is used herein to mean breast cancer associated with overexpression of HER-2
eu.
DETAILED DESCRIPTION
The cancers associated with overexpression of HER-2
eu include all those cancers where overexpression of HER-2
eu is found in cancerous tissue and comprise breast cancers, ovarian cancers, gastric cancers, endometrial cancers, salivary cancers, pancreatic cancers, prostate cancers, colorectal cancers and non-small-cell lung cancers, where overexpression of HER-2
eu is found in the cancerous tissue.
Assays for HER-2
eu overexpression have been developed or are under development. These include the Vysis PathVysion HER2 DNA Probe Kit developed by Vysis Inc., Downer's Grove, Ill., which is based on fluorescent in situ hybridization and a diagnostic kit being developed by DAKO A/S of Glostrup, Denmark which is directed to detecting antibodies to the HER-2
eu protein based on immunohistochemistry.
We turn now to the selective inhibitors of cyclooxygenase-2. The selective inhibitors of cyclooxygenase-2 are synthetic compounds.
The selective inhibitors of cyclooxygenase-2 are preferably those where the ratio of the IC
50
concentration for cyclooxygenase-1 to the IC
50
concentration for cyclooxygenase-2 is 5 or more, very preferably 100 or more.
Selective inhibitors of cyclooxygenase-2 include the following compounds:
(1) 4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(2) 4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(3) 4-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(4) 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(5) 4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(6) 4-[5-(4-Trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(7) 4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(8) 4-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(9) 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(10) 4-[5-(4-Trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(12) 4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(12) 4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(13) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxylate
(14) 4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxamide
(15) 4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(16) 4-[5-(4-[Methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(17) 4-[5-(2,4-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(18) 4-[5-(2,6-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(19) 4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(20) 4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide
(21) 4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(22) 4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(23) 4-[5-(4-Biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(24) 4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(25) 4-[5-(5-Chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(26) 4-[5-(4-Morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(27) 4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(28) 4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(29) 4-[5-(4-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(30) 4-[5-(4-[Trifluoromethyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(31) 4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(32) 4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
(33) 4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl
Dannenberg Andrew J.
Subbaramaiah Kotha
Cornell Research Foundation Inc.
Krass Frederick
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