Combined administration of integrin receptor antagonists for Anti-angiogenic therapy

Inactive Publication Date: 2011-12-29
CALIFORNIA NORTHSTATE COLLEGE OF PHARMACY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]The teachings provided herein generally relate to pharmaceutical compositions and methods comprising an αvβ3 antagonist for use in inhibiting, preventing, or reversing angiogenesis and treating cancer when used in combination with an α2β1 antagonist and in a pharmaceutically acceptable carrier. In some embodiments, the teachings are directed to a pharmaceutical formulation comprising an αvβ3 antagonist, a

Problems solved by technology

Unfortunately, however, a particularly effective method of using an agent or combination of agents remain to be discovered that, at least, (i) inhibits or prevents angiogenesis; (ii) treats solid tumors to contain and / or reduce tumor size; and (iii) inhibits or prevents the tumor invasion that leads to metastasis within a subject.
As such, a combination of select inhibitors could possibly limit this process.

Method used

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  • Combined administration of integrin receptor antagonists for Anti-angiogenic therapy
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  • Combined administration of integrin receptor antagonists for Anti-angiogenic therapy

Examples

Experimental program
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example 1

A Human Model was Prepared to Correlate Angiogenesis with the Extracellular Matrix

[0079]In this study, we investigated the correlation between sprout angiogenesis and the integrity of an extracellular matrix (ECM) environment using in vivo and in vitro angiogenesis models. We used an αvβ3 antagonist and an α2β1 antagonist in the model, where the αvβ3 antagonist was the disintegrin echistatin, and the α2β1 antagonist was the disintegrin VP12 (ECL12).

Materials

[0080]A 3-D ECM model was prepared. Gelatin-coated, microcarrier beads (Cytodex-3) were purchased from Pharmacia (Uppsala, Sweden). Sterile, native bovine dermal collagen containing 95% type I collagen and 5% type III collagen (Vitrogen) was obtained from Collagen Biomaterials (Palo Alto, Calif.). Dimethyl dichlorosilane, aprotinin, dibutyryl cyclic AMP, hydrocortisone, trypsin, soybean trypsin inhibitor, and EDTA were obtained from Sigma Chemical Co. (St. Louis, Mo.). Endothelial cell basal medium (EBM), endothelial cell growth ...

example 2

Cell Migration and Capillary Sprout Formation was Identified in Fibrin Gels and Type I Collagen Gels in the Human Model

[0083]FIGS. 1A-1C illustrate a study of human microvascular endothelial cell angiogenesis, according to some embodiments. A microcarrier, in vitro angiogenesis assay, previously designed to investigate bovine pulmonary artery endothelial cell angiogenic behavior in bovine fibrin gels, was modified for the study of human microvascular endothelial cell angiogenesis. The HDMEC were isolated from human neonatal foreskins and used, as described above, and images were captured at various magnifications, where the effect of angiogenic factors on sprout angiogenesis was quantified visually by counting the number and percent of EC-beads with capillary sprouts.

[0084]FIG. 1A shows the process in Step I, where human fibrinogen, isolated as previously described, was dissolved in M199 medium at a concentration of 1 mg / ml (pH 7.4) and sterilized by filtering through a 0.22 micron ...

example 3

Integrin Receptors were Identified Using Porcine Cutaneous Wounds and Immunofluorescence Staining

[0089]Porcine cutaneous wounds were harvested at various times and then immunoprobed for expression of integrin receptors. See Xu, J and Clark, R. The Journal of Cell Biology 132:239-249(1996). Briefly, full-thickness wounds were made with an 8-mm punch on the backs of White Yorkshire pigs and harvested at the times indicated. Specimens were bisected; one half was fixed in formalin and stained with MASSON trichrome, the other half was frozen in liquid nitrogen for immunofluorescence studies. Anti-laminin antibodies (Gibco BRL) conjugated with biotin were used to identify wound vasculature. All antibodies were used at dilutions that gave maximal specific fluorescence and minimal background fluorescence on frozen tissue specimens. Bound antibody was detected by the avidin-biotin-complex (ABC) technique. Stained specimens were observed and photographed using a NIKON Microphot FXA epifluores...

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Abstract

The teachings provided herein generally relate to a combination therapy and are directed to pharmaceutical compositions and methods for administering a combination of an αvβ3 antagonist with an α2β1 antagonist to a subject. The methods are for use in inhibiting, preventing, or reversing angiogenesis, as well as in treating cancer. In some embodiments, the compositions and methods include a combined administration of echistatin and VP12 (ECL12).

Description

BACKGROUND[0001]1. Field of the Invention[0002]The teachings provided herein relate to pharmaceutical compositions comprising an αvβ3 antagonist for use in inhibiting angiogenesis and treating cancer when used in combination with an α2β1 antagonist and in a pharmaceutically acceptable carrier.[0003]2. Description of Related Art[0004]Solid tumor growth is generally considered to be angiogenesis-dependent, such that the control of neovascularization in cancerous tissue is one of the goals of cancer research. As such, various potential angiogenesis inhibitors have been investigated in the treatment of solid tumors and metastasis using anti-angiogenic therapy. Unfortunately, however, a particularly effective method of using an agent or combination of agents remain to be discovered that, at least, (i) inhibits or prevents angiogenesis; (ii) treats solid tumors to contain and / or reduce tumor size; and (iii) inhibits or prevents the tumor invasion that leads to metastasis within a subject....

Claims

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Application Information

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IPC IPC(8): A61K38/17A61P35/00
CPCA61K38/1703A61K38/36A61K45/06A61K38/1767A61K2300/00A61P35/00
Inventor FENG, XIAODONG
Owner CALIFORNIA NORTHSTATE COLLEGE OF PHARMACY
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