Methods of generating hyper INOS expressing cells and uses thereof

Patent metadata

Field	Value
Publication number	US-9421197-B2
Application number	US-201414444509-A
Country	US
Kind code	B2
Filing date	Jul 28, 2014
Priority date	Feb 12, 2010
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

A method of generating a hyper iNOS expressing cell includes administering to a myeloid derived cell an amount of a PPARγ agonist and an IL-6/STAT3 signaling pathway antagonist effective to substantially inhibit STAT3 activation in the cell and administering an inflammatory insult to the cell to stimulate hyper iNOS expression from the cell.

First claim

Having described the invention, the following is claimed:

1. A method of treating skin cancer or a skin tumor in a subject comprising:
administering an amount of a PPARy agonist and an IL-6/STAT3 signaling
pathway antagonist to the subject effective to substantially inhibit STAT3 activation in the macrophages of the subject; and
administering an amount of an inflammatory or damaging insult to the skin cancer or skin tumor of the subject effective to induce hyper iNOS expression of the macrophages that are in or about the periphery of the skin cancer or skin tumor.

2. The method of claim 1 , the insult being administered directly to or about the periphery of the skin cancer or skin tumor.

3. The method of claim 1 , the insult comprising at least one of trauma, physical stress, chemical stress, biological stress, or radiation.

4. The method of claim 1 , the PPARy agonist comprising a thiazolidinedione or a derivative thereof.

5. The method of claim 1 , the PPARy agonist comprising at least one compound or a pharmaceutically salt thereof selected from the group consisting of: (+)-5[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)m ethoxy]phenyl]methyl]-2,4thiazolidinedione; 5-[4-[2-(5-ethylpyridin-2-yl)ethoxyl]benzyl]thiazolidine-2,4-dione; 5-[4-[(l methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione; (ciglitazone); 4-(2-naphthylmethyl)-1,2,3,5-oxathiadiazole-2-oxide; 5-[4-[2-[(N-(benzoxazol-2-yl)-Nmethylamino]ethoxy]benzyl]-5-methlthiazolidine-2,4-dione; 5-[4-[2-[2,4dioxo-5-phenylthiazolidine-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione; 5-[4-[2-[(N-methyl-N(phenoxycarbonyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione; 5-[4-[2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione; 5-[4-[2-(4-chorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione; 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione; 5-[[4-(3-hydroxy-1-methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione; 5-[4-[2-(5-methy 1-2-phenyloxazol-4-yl)ethoxyl]benzyl]thiazolidine-2,4-dione; 5-[(2-benzyl-2,3-dihydrobenzopyran)-5-ylmethyl]thiazolidine-2,4-dione; 5-[[2-(2-42-naphthylmethyl)benzoxazol]-5-ylmethyl]thiazolidine-2,4-dione; 5-[4-[2-(3-phenylureido)ethoxyl]benzyl]thiazolidine-2,4-dione; 5-[4-[2-(N-benzoxazol-2-yl)-Nmetholamino]ethoxy]benzyl]thiazolidine-2,4-dione; 5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione; 5-[2-(5-methyl-2-phenyloxazol-4-ylmethyl)benzofuran-5-ylmethyl]oxazolidine-2,4-dione; 5-[4-[2-(N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione; and 5-[4-[2-(N-(benzoxazol-2-yl)-Nmethylamino]ethoxy]benzyl]oxazolidine-2,4-dione.

6. The method of claim 1 , wherein the IL-6/STAT3 signaling pathway antagonist comprises at least one of an antibody, peptide, or small molecule.

7. The method of claim 1 , wherein the IL-6/STAT3 signaling pathway antagonist is an HMG CoA reductase inhibitor.

8. The method of claim 1 , wherein the IL-6/STAT3 signaling pathway antagonist is a STAT3 inhibitor.

9. The method of claim 1 , the PPARy agonist being administered to the skin cancer in a topical formulation.

Assignees

• Univ Case Western Reserve

Inventors

• Lu Kurt Q
• Cooper Kevin D

Classifications

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K31/426

  1,3-Thiazoles · CPC title