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Use of opioid antagonists to attenuate endothelial cell proliferation and migration

a technology of endothelial cells and opioid antagonists, which is applied in the field of attenuating the migration and/or proliferation of endothelial cells, can solve the problems of patients refusing opioid-based pain management, morphine and other opioid medications can have severe side effects, and complete necrosis of the neoplasm, so as to improve the antiproliferative effect of cancerous cells, increase the therapeutic effect, and improve the antiproliferative

Inactive Publication Date: 2017-09-07
UNIVERSITY OF CHICAGO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method of treating cancer by giving a patient a combination of an opioid antagonist and another therapeutic agent, such as an anticancer drug or antiangiogenic agent. This combination can enhance the effectiveness of the therapeutic agents and reduce the side effects associated with them. The opioid antagonist can also inhibit the growth of tumors and reduce the risk of recurrence after medical intervention. The patent also describes the use of peripheral opioid antagonists to inhibit or reduce opioid-induced angiogenesis and the risk of recurrence of cancer or tumors after medical intervention.

Problems solved by technology

As a significant proportion of neoplasms are dependent on continued angiogenesis, inhibition of angiogenesis blocks neoplasm growth which often leads to complete necrosis of the neoplasm.
Despite wide use in pain management, morphine and other opioid medications can have severe side effects that may be caused by activation of the peripheral receptors.
The side effects can be difficult to manage and can result in the patient refusing opioid-based pain management.

Method used

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  • Use of opioid antagonists to attenuate endothelial cell proliferation and migration
  • Use of opioid antagonists to attenuate endothelial cell proliferation and migration
  • Use of opioid antagonists to attenuate endothelial cell proliferation and migration

Examples

Experimental program
Comparison scheme
Effect test

example 1

al Cell Migration Assay

[0169]The antiangiogenic activity of the peripheral opioid antagonists in accordance with the present invention was evaluated in experiments testing the ability of the antagonist to inhibit or modulation capillary endothelial cell migration using a modified Boyden chamber.

[0170]The endothelial cell migration assay was performed as described by Lingen, M. W., Methods in Molecular Medicine, 78: 337-347 (2003), the disclosure of which is incorporated by reference. Briefly, Human Microvascular Endothelial Cells (HMVEC) (Cell Systems, Kirkland, W A.) were starved overnight in Endothelial Growth Medium (EGM) containing 0.1% bovine serum albumin (BSA). Cells were then trypsinized and resuspended in Dulbecco's Modified Eagle Medium (DME) with 0.1% BSA at a concentration of 1×106 cells / mL. Cells were added to the bottom of a 48-well modified Boyden chamber (NeuroPore Corporation, Pleasanton, Calif.). The chamber was assembled and inverted, and cells were allowed to att...

example 2

al Cell Migration Assay

[0172]Another set of experiments was conducted in accordance with the procedure described in Example 1. In this set of experiments, methylnaltrexone and the combination of methylnaltrexone and morphine was again tested for ability to inhibit endothelial cell migration. The methylnaltrexone concentrations when tested alone varied from 0.001 to 10.0 μM. In combination, the concentrations of methylnaltrexone varied from 0.001 to 10.0 μM, while the morphine concentration remained constant at 0.1 μM as described in Example 1. The results are shown in FIG. 2.

[0173]FIG. 2 shows the combination of methylnaltrexone and morphine decreased migration in a concentration-dependent manner, while methylnaltrexone alone did not affect migration.

example 3

al Cell Migration Induced by DAMGO

[0174]The drugs used in this study were [D-Ala 2, N-McPhe4, Gly5-ol] enkephalin or DAMGO (Sigma, St. Louis, Mo.); naloxone (Sigma, St. Louis, Mo.); N-methylnaltrexone bromide or methylnaltrexone (Mallinckrodt Specialty Chemicals, Phillipsburg, N.J.). The endothelial cell migration assay was performed as previously described (9). Human dermal microvascular endothelial cells (Cell Systems, Kirkland, W A) were starved overnight in media containing 0.1% bovine serum albumin (BSA), harvested, resuspended into Dulbecco's Modified Eagle's media (DME) with 0.1% BSA, and plated on a semi-porous gelatinized membrane in a modified Boyden chamber (Nucleopore Corporation, Pleasanton, Calif.). Test substances were then added to the wells of the upper chamber and cells were allowed to migrate for four hours at 37° C.

[0175]Membranes were recovered, fixed, and stained and the number of cells that had migrated to the upper chamber per ten high power fields counted by...

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PUM

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Abstract

The invention provides methods of attenuating, e.g., inhibiting or reducing, cellular proliferation and migration, particularly endothelial cell proliferation and migration, including that associated with angiogenesis, using opioid antagonists, including, but not limited to, those that are peripherally restricted antagonists.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 14 / 292,816, filed May 30, 2014, now U.S. Pat. No. 9,662,325, which is a continuation-in-part of U.S. application Ser. No. 13 / 972,122, filed Aug. 21, 2013, which is a continuation of U.S. application Ser. No. 11 / 379,010, filed Apr. 17, 2006, now U.S. Pat. No. 8,524,731, which is a continuation-in-part of PCT Application No. PCT / US2006 / 07892 filed on Mar. 7, 2006, which claims benefit under 35 U.S.C. 119(e) of the filing dates of U.S. Ser. Nos. 60 / 659,193 filed on Mar. 7, 2005, 60 / 725,703 filed Oct. 12, 2005, 60 / 731,009 filed on Oct. 28, 2005, and 60 / 760,851 filed Jan. 20, 2006, the entire disclosures of which are incorporated herein by reference.STATEMENT REGARDING FEDERAL SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was supported in part by National Institutes of Health grants: DE12322; DE00470; and DE015830. The United States government has certain rights in this invention.FIELD OF IN...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485A61K31/475A61K31/337A61K39/395A61K31/7068A61K45/06A61K31/517
CPCA61K31/517A61K31/475A61K31/337A61K39/39558A61K31/7068A61K45/06A61K31/485A61K2300/00
Inventor MOSS, JONATHANLINGEN, MARKSINGLETON, PATRICK A.GARCIA, JOE G.N.YUAN, CHUN-SU
Owner UNIVERSITY OF CHICAGO
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