Inhibition of HIF-1 activation for anti-tumor and anti-inflammatory responses

Patent metadata

Field	Value
Publication number	US-8968702-B2
Application number	US-73171907-A
Country	US
Kind code	B2
Filing date	Mar 30, 2007
Priority date	Mar 30, 2006
Publication date	Mar 3, 2015
Grant date	Mar 3, 2015

Abstract

The presently disclosed subject matter generally relates to methods and compositions for inhibiting the expression and/or activation of hypoxia-inducible factor 1 (HIF-1) genes in a hypoxic cell. More particularly, the methods disclosed herein relate to inhibition of HIF-1 activation in a cell, increasing sensitivity of a tumor cell to radiation and/or chemotherapy, delaying tumor growth, inhibiting tumor blood vessel growth, inhibiting inflammatory responses in a cell through the use of compositions that prevent the nitrosylation of HIF-1, and methods for screening for new inhibitors of HIF-1 activiation. Additionally, the compositions disclosed herein relate to compositions that can be employed in, and are identified by, the disclosed methods.

First claim

What is claimed is:

1. A method for enhancing radiation therapy by inhibiting a macrophage-mediated stabilization of HIF-1 in a tumor undergoing radiation therapy free of cytotoxic chemotherapy, the method comprising:
(i) providing a radiation therapy free of cytotoxic chemotherapy by irradiating a tumor in a subject, wherein the radiation increases the number of tumor-associated macrophages, wherein the tumor-associated macrophages produce nitric oxide through inducible nitric oxide synthase, whereby the nitric oxide stabilizes HIF-1 in the irradiated tumor; and then
(ii) contacting the irradiated tumor having stabilized HIF-1 with a composition comprising a minimally therapeutic dose of an inhibitor of inducible nitric oxide synthase to inhibit HIF-1 stabilization, whereby the minimally therapeutic dose of an inhibitor of inducible nitric oxide synthase is sufficient to prevent production of nitric oxide through inducible nitric oxide synthase in tumor-associated macrophages for a number of days following irradiation,
whereby a macrophage-mediated stabilization of HIF-1 in the tumor is inhibited such that the radiation therapy is enhanced.

2. The method of claim 1 , wherein the subject is a mammal.

3. The method of claim 2 , wherein the mammal is a human.

4. The method of claim 1 , wherein the composition inhibits nitrosylation of Cys520 of SEQ ID NO: 6.

5. The method of claim 1 , wherein the nitric oxide produced by inducible nitric oxide synthase nitrosylates Cys520 of SEQ ID NO: 6, whereby the nitrosylation of Cys520 of SEQ ID NO: 6 stabilizes HIF-1 in the tumor.

6. The method of claim 1 , wherein the tumor is irradiated in step (i), and then after a period of time the tumor is contacted with the composition in step (ii).

Assignees

• Li Chuan-Yuan
• Li Fang
• Sonveaux Pierre
• Dewhirst Mark W
• Univ Duke

Inventors

• Li Chuan-Yuan
• Li Fang
• Sonveaux Pierre
• Dewhirst Mark W

Classifications

• A61K41/0038 Primary

  Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10) · CPC title

• A61K45/06

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title