Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-09-04
2003-04-22
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06552055
ABSTRACT:
BACKGROUND OF THE INVENTION
Adipocytes are highly specialized cells that play a critical role in energy and homeostasis. Their primary role is to store triglycerides in times of caloric excess and to mobilize this reserver during periods of nutritional deprivation. Adipocytes are derived from a multipotent stem cell of mesodermal origin that also gives rise to the muscle and cartilage lineages. Adipocyte differentiation is characterized by a coordinate increase in adipocyte-specific gene expression.
Recent years have seen important advances in our understanding of the molecular basis of adipocyte differentiation. (reviewed in Cornelius, P. et al. (1994)
Annu. Rev. Nutr.
14:99-129; Tontonoz, P. et al. (1995)
Curr. Opin. Genet. Dev.
5:571-576. A number of transcription factors are induced in fat cell differentiation (C/EBP&agr;, C/EBP&bgr; and ADD1/SREBP1) and influence this process to a certain extent (Freytag, S. O. et al. (1994)
Genes Dev.
8:1654-63; Kim, J. B. and Spiegelman, B. M. (1996)
Genes Dev.
10:1096-1107; Lin, F. T. and Lane, M. D. (1994)
PNAS USA
91:8757-61; Samuelsson, L. et al. (1991)
EMBO J.
10:3787-93; Tontonoz, P. et al. (1993)
Mol Cell Biol
13:4753-9; Umek, R. M. et al. (1991)
Science
251:288-92; Wu, C. L. et al. (1995)
Mol Cell Biol
15:253646; Yeh, W. C. et al. (1995)
Genes Dev.
9:168-81).
The peroxisome proliferator-activated receptors, or “PPAR”, are members of the type II class of steroid/thyroid superfamily of receptors and which mediate the pleiotropic effects of peroxisome proliferators. Type II class of nuclear receptors includes PPAR, the thyroid hormone receptor (T
3
R), and the vitamin D
3
receptor (VD
3
R). Type II receptors are functionally distinct from the classical steroid receptors, such as the glucocorticoid receptor, the progesterone receptor and the estrogen receptor (reviewed in Stunnenberg, H. G. (1993)
Bio Essays Vol.
15 (5): 309-15. Three properties distinguish these two classes. Firstly, type II receptors are able to bind to their responsive elements in the absence of ligand (Damm et al. (1989)
Nature
339:593-597; Sap et al.,
Nature
340:242-244; De The et al. (1990)
Nature
343:177-180), whereas ligand binding is required to dissociate to the type I receptor-hsp 90 complex and hence indirectly governs DNA binding. Secondly, type II receptors bind and transactivate through responsive elements that are composed of half-sites arranged as direct repeats, as opposed to palindromically arranged half-sites invariably separated by three nucleotides required by type I receptors. Finally, type II receptors do not bind to their respective binding site as homodimers but require an auxiliary factor, RXR (e.g., RXR&agr;, RXR&bgr;, RXR&ggr;) for high affinity binding (Yu et al. (1991)
Cell
67:1251-1266; Bugge et al. (1992)
EMBO J.
11:1409-1418; Kliewer et al. (1992)
Nature
355:446-449; Leid et al. (1992)
Cell
68:377-395; Marks et al. (1992)
EMBO J.
11:1419-1435; Zhang et al. (1992)
Nature
355:441-446). The interaction between type II receptors requires a region in the C-terminal domain (Yu et al. (1991)
Cell
67:1251-1266; Kliewer et al. (1992)
Nature
355:446-449; Leid et al. (1992)
Cell
68:377-395; Marks et al. (1992)
EMBO J.
11:1419-1435). Following binding, the transcriptional activity of a target gene (i.e., a gene associated with the specific DNA sequence) is enhanced as a function of the ligand bound to the receptor heterodimer.
SUMMARY OF THE INVENTION
The present invention is based on the finding that activation of PPAR&ggr; plays a key role in inducing growth arrest by terminal differentiation of actively proliferating PPAR&ggr;-expressing cells, particularly transformed adipose precursor cells.
Accordly, one aspect of the invention provides a method for inhibiting proliferation of a PPAR&ggr;-responsive hyperproliferative cell, comprising ectopically contacting the cell with a a PPAR&ggr; agonist in an amount effective to induce differentiation of the cell. For example, the instant method can be used for the treatment of, or prophylactically prevention of a disorder characterized by aberrant cell growth of PPAR&ggr;-responsive hyperproliferative cells, e.g., by administering a pharmaceutical preparation of a PPAR&ggr; agonist in an amount effective to inhibit growth of the PPAR&ggr;-responsive hyperproliferative cells.
For example, the subject method can be used in the treatment of sarcomas, carcinomas and/or leukemias. Exemplary disorders for which the subject method may be used as part of a treatment regimen include: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
In certain embodiments, the subject method can be used to treat such disorders as carcinomas forming from tissue of the breast, prostate, kidney, bladder or colon.
In other embodiments, the subject method can be used to treat hyperplastic or neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e.g., lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibernomas, hemangiomas and/or liposarcomas.
In still other embodiments, the subject method can be used to treat hyperplastic or neoplastic disorders of the hematopoietic system, e.g., leukemic cancers. In a preferred embodiment, the subject is a mammal, e.g., a primate, e.g., a human.
In preferred embodiments, the PPAR&ggr; agonist used in the instant method is a ligand of a PPAR&ggr; protein which activates a transcriptional activity of the PPAR&ggr; protein. For example, the PPAR&ggr; agonist can be a thiazolidinedione, or an analog thereof. Exemplary PPAR&ggr; agonists include pioglitazone, troglitazone, ciglitazone, englitazone, BRL49653, and chemical derivatives thereof. In certain preferred embodiments, the PPAR&ggr; agonist is represented in the general formula:
or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in which A
1
represents a substituted or unsubstituted aromatic heterocyclyl group; R
1
represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; R
2
and R
3
each represent hydrogen, or R
2
and R
3
together represent a bond; A
2
represents a benzyl or chromanyl moiety having, as valence permits, up to five substituents; and n represents an integer in the range of from 1 to 6.
In other embodiments, the PPAR&ggr; agonist can be a naturally-occurring ligand of the receptor, such as an arachidonate metabolite, e.g., a metabolite of PGD
2
.
In order to avoid or minimize certain unwanted side-effects to treatment with a PPARY agonists, it may be desirable in certain embodiments of the subject method that the PPAR&ggr; agonist activates PPAR&ggr;-dependent transcription at a concentration at least one order of magnitude less than required for the same level of activation of PPAR&agr;, PPAR&dgr; or RaR-dependent transcription.
The PPAR&ggr; agonist can be administered alone, or as part of a combinatorial therapy. For example, the PPAR&ggr; agonist can be conjointly administered with one or more agents such as mitotic inhibitors,
Altiok Soner
Mueller Elisabetta
Sarraf Pasha
Singer Samuel
Spiegelman Bruce M.
Dana-Farber Cancer Institute
Lahive & Cockfield LLP
Nand, Esq. Richa K.
Reamer James H.
Smith, Esq. DeAnn F.
LandOfFree
Methods and pharmaceutical compositions for inhibiting tumor... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods and pharmaceutical compositions for inhibiting tumor..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods and pharmaceutical compositions for inhibiting tumor... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3069766