Method of treatment employing cardiac glycoside
Inventors
ADDINGTON, Otis C. • Yang, Peiying • Newman, Robert A.
Assignees
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Publication Number
US-9846156-B2
Publication Date
2017-12-19
Expiration Date
Abstract
A method of treatment employing cardiac glycoside is disclosed. A prognostic assay and kit and method of use thereof are provided. The kit and assay are used to determine the likelihood of a diseased cell or tissue having a therapeutic response to treatment with a cardiac glycoside in a disease having an etiology associated with excessive cell proliferation. The kit and assay are used to determine the ratio of isoforms of the α subunit of Na, K-ATPase obtained from the diseased cell or tissue. The kit can be used to predict the therapeutic responsiveness of cancer or tumor in a subject to treatment with a cardiac glycoside. The kit and assay can be incorporated in a method of treating a disease or disorder having an etiology associated with excessive cell proliferation with a composition comprising a cardiac glycoside.
Core Innovation
The invention relates to a prognostic assay and kit for diseases having an etiology associated with excessive cell proliferation. The assay determines a ratio of Na,K-ATPase α-subunit isoforms, specifically a measured amount of the α13 isoform and the α11 isoform in diseased tissue or cells, and computes an α13:α11 ratio. The determination is used to predict a therapeutic response or indicate administration of a composition comprising cardiac glycoside.
The method includes obtaining a sample of diseased tissue from a subject and performing assays on the sample to measure α13 and α11 isoforms. The disclosed assay formats include Western Blot, immunohistochemical staining, enzyme linked immunoabsorbent assay, Northern blot assay for measurement of mRNA to different Na,K-ATPase subunit isoforms, and a protein tissue assay or a cell lysate array assay to determine the content of the α13 isoform and α11 isoform present in the diseased tissue.
When the diseased tissue has an α13:α11 ratio at or below a threshold, a cardiac glycoside-containing composition is administered, with the cardiac glycoside selected from oleandrin, cinobufatalin, cinobufagin, resibufogenin, and bufalin. The disclosure also describes specific kit embodiments and components for detecting α13 and α11, and correlations between the isoform ratio and therapeutic responsiveness, with sensitivity associated with higher α13:α11 ratio.
Claims Coverage
The document provides two independent claims that center on assaying Na,K-ATPase α-subunit isoform content and indicating administration of a cardiac glycoside composition when an α13:α11 ratio meets a specified criterion. The inventive features are the isoform assay of diseased tissue, the α13:α11 ratio threshold used to indicate or determine administration, and the selection of a cardiac glycoside composition limited to specified compounds, with the second independent claim further limiting the subject to a mammal.
Isoform assay-guided treatment using α13:α11 ratio threshold
Obtaining a sample of diseased tissue from a subject; performing on the sample a Western Blot assay, an immunohistochemical staining assay, an enzyme linked immunoabsorbent assay, a Northern blot assay for measurement of mRNA to different Na,K-ATPase subunit isoforms, a protein tissue assay, or a cell lysate array assay to determine the content of an α13 isoform and an α11 isoform of the α-subunit of Na,K-ATPase present in the diseased tissue; and administering to the subject a composition comprising cardiac glycoside when the diseased tissue has a ratio of α13 isoform to α11 isoform of the α-subunit of Na,K-ATPase of ≥0.3.
Indicating administration and administering cardiac glycoside composition for mammal based on α13:α11 ratio
Indicating administration of the composition when the diseased tissue has a ratio of α13 isoform to α11 isoform of the α-subunit of Na,K-ATPase of ≥0.3; and administering to the subject a composition comprising cardiac glycoside wherein the cardiac glycoside is selected from the group consisting of oleandrin, cinobufatalin, cinobufagin, resibufogenin, and bufalin; wherein the subject is a mammal.
Both independent claims implement treatment based on a determined α13:α11 ratio of Na,K-ATPase α-subunit isoforms in diseased tissue and administer a cardiac glycoside composition selected from oleandrin, cinobufatalin, cinobufagin, resibufogenin, and bufalin. The first independent claim additionally specifies assay formats on the diseased tissue sample, while the second independent claim focuses on indicating administration and limiting the subject to a mammal.
Stated Advantages
Predicting or indicating a therapeutic response using a Na,K-ATPase α-subunit isoform ratio (α13:α11).
Indicating administration of cardiac glycoside therapy when a diseased tissue meets an α13:α11 ratio criterion.
Documented Applications
Prognostic assay and treatment indication for diseases with etiology associated with excessive cell proliferation, including diseases described as cancer/tumor and other excessive-proliferation disorders.
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