Increasing cancer patient survival time by administration of dithio-containing compounds
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Publication Number
US-11471431-B2
Publication Date
2022-10-18
Expiration Date
Abstract
The present invention discloses and claims compositions, methods of treatment, and kits which cause an increase in the time of survival in cancer patients, wherein the cancer: (i) overexpresses thioredoxin or glutaredoxin and/or (ii) exhibits evidence of thioredoxin- or glutaredoxin-mediated resistance to one or more chemotherapeutic interventions. The present invention also discloses and claims methods and kits for the administration of said compositions to properly treat cancer patients. Additionally, the present invention discloses and claims methods and kits for quantitatively determining the level of expression of thioredoxin or glutaredoxin in the cancer cells of a cancer patient, methods of using those determined levels in the initial diagnosis and/or planning of subsequent treatment methodologies for said cancer patient, as well as ascertaining the potential growth “aggressiveness” of the particular cancer and treatment responsiveness of the particular type of cancer. Further, the present invention discloses and claims novel pharmaceutical compositions, methods, and kits used for the treatment of patients with medical conditions and disease where there is the overexpression of thioredoxin and/or glutaredoxin, and wherein this overexpression is associated with deleterious physiological effects in the patients.
Core Innovation
The patent addresses the thioredoxin (TX)/glutaredoxin (GRX) redox systems and their roles in cancer drug resistance, including apoptosis resistance and reduced treatment efficacy of chemotherapy and radiation. It provides medicinal pharmacological inactivation or modulation of the TX/GRX system using oxidative metabolism-affecting Formula (I) compounds, with particular emphasis on disodium 2,2'-dithio-bis-ethane sulfonate (Tavocept, dimesna, BNP7787). The stated objective is to reverse drug-resistant properties associated with TX/GRX and to improve survival after administration of chemotherapeutic agents and/or radiation.
The disclosed invention relates to methods for treatment of a subject suffering from cancer who has previously received administration of one or more chemotherapeutic agents, where the cancer either overexpresses thioredoxin or glutaredoxin and/or exhibits evidence of thioredoxin-mediated or glutaredoxin-mediated resistance to chemotherapy agents. The thioredoxin or glutaredoxin overexpression is quantitatively determined by fluorescence in situ hybridization (FISH), nucleic acid microarray analysis, immunohistochemistry (IHC), or radioimmunoassay (RIA). A medically-sufficient dose of disodium 2,2'-dithio-bis-ethane sulfonate is administered in an amount sufficient to provide therapeutic benefit following prior chemotherapeutic administration.
Additional embodiments describe methods for maintaining or stimulating pluripotent, multipotent, and unipotent normal stem cell function and methods for maintaining or stimulating erythropoietin function or synthesis, each in a patient or subject suffering from cancer who has previously received administration of one or more chemotherapeutic agents. In these embodiments, eligibility is limited by cancer selection, thioredoxin or glutaredoxin overexpression, quantitative determination by FISH, nucleic acid microarray analysis, IHC, or RIA, and an administration-sequencing condition for prior taxane versus platinum agents when both were used.
Claims Coverage
The independent claims cover post-chemotherapy cancer treatment, maintaining or stimulating pluripotent, multipotent, and unipotent normal stem cell function, and maintaining or stimulating erythropoietin function or synthesis. Across these claims, the inventive features consistently include administering disodium 2,2'-dithio-bis-ethane sulfonate after prior chemotherapy, eligibility based on thioredoxin or glutaredoxin overexpression and/or resistance, quantitative determination using specified analytical methodologies, and a taxane-before-platinum administration sequence when both classes are used.
Cancer treatment after prior chemotherapy with disodium 2,2'-dithio-bis-ethane sulfonate
A method for treatment of a subject suffering from cancer who has previously received administration of one or more chemotherapeutic agents, comprising administration of a medically-sufficient dose of disodium 2,2'-dithio-bis-ethane sulfonate in an amount sufficient to provide a therapeutic benefit following the time the subject has previously received administration of chemotherapeutic agents.
Eligibility by thioredoxin or glutaredoxin overexpression and quantified resistance determination
The cancer either overexpresses thioredoxin or glutaredoxin and/or exhibits evidence of thioredoxin-mediated or glutaredoxin-mediated resistance, and said thioredoxin or glutaredoxin overexpression and/or said thioredoxin-mediated or glutaredoxin-mediated treatment resistance is quantitatively determined by fluorescence in situ hybridization (FISH), nucleic acid microarray analysis, immunohistochemistry (IHC), or radioimmunoassay (RIA).
Taxane-before-platinum administration sequence when both are used
If the prior chemotherapeutic agents received by the subject included taxane and platinum agents, administration of the taxane-containing chemotherapy agent occurred prior to the administration of the platinum-containing chemotherapy agent.
Maintaining or stimulating normal stem cell function using disodium 2,2'-dithio-bis-ethane sulfonate
A method for maintaining or stimulating pluripotent, multipotent, and unipotent normal stem cell function in a patient suffering from cancer who has previously received administration of one or more chemotherapeutic agents, comprised of administration of a medically-sufficient dose of disodium 2,2'-dithio-bis-ethane sulfonate.
Maintaining or stimulating erythropoietin function or synthesis using disodium 2,2'-dithio-bis-ethane sulfonate
A method for maintaining or stimulating erythropoietin function or synthesis in a subject suffering from cancer who has previously received administration of one or more chemotherapeutic agents, comprised of administration of a medically-sufficient dose of disodium 2,2'-dithio-bis-ethane sulfonate.
Taken together, the independent claims require post-chemotherapy administration of disodium 2,2'-dithio-bis-ethane sulfonate with eligibility determined by quantitative assessment of thioredoxin and/or glutaredoxin overexpression or thioredoxin- or glutaredoxin-mediated resistance using FISH, nucleic acid microarray analysis, IHC, or RIA. When prior regimens include both taxane and platinum agents, the claims require taxane administration prior to platinum administration. Additional independent-claim scope includes maintaining or stimulating normal stem cell function or maintaining or stimulating erythropoietin function or synthesis.
Stated Advantages
Reverse drug-resistant properties associated with thioredoxin/glutaredoxin and improve survival following chemotherapy.
Increase survival in NSCLC (notably adenocarcinoma) when Formula (I) compounds are used with chemotherapy.
Therapeutic benefit following prior chemotherapy administration.
Maintaining or stimulating pluripotent, multipotent, and unipotent normal stem cell function.
Maintaining or stimulating erythropoietin function or synthesis.
Documented Applications
Treatment of subjects suffering from cancer after previously receiving administration of one or more chemotherapeutic agents, with eligibility based on thioredoxin or glutaredoxin overexpression and quantitatively determined resistance.
Maintaining or stimulating pluripotent, multipotent, and unipotent normal stem cell function in a cancer patient previously treated with chemotherapeutic agents by administering disodium 2,2'-dithio-bis-ethane sulfonate.
Maintaining or stimulating erythropoietin function or synthesis in a cancer subject previously treated with chemotherapeutic agents by administering disodium 2,2'-dithio-bis-ethane sulfonate.
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