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Publication Number
US-11154520-B2
Publication Date
2021-10-26
Expiration Date
Abstract
The present invention relates to methods and sets of drugs for the effective treatment of metastatic cancer and the administration of a set of drugs that overcome mechanisms of resistance to DNA-damaging agents, thereby sensitizing cancer cells to said DNA-damaging agents. The methods involve the administration of a set of drugs comprising melphalan, BCNU, hydroxocobalamin, and ascorbic acid. In a preferred embodiment, ethanol is also added to the set of drugs and bone marrow toxicity is reversed with an infusion of bone marrow stem cells. The methods also involve the depletion of GSH in tumors and the selective delivery of drugs to solid tumors. The methods also involve preventing the loss of catalase function and preventing oxidant-induced hemolysis and/or methemoglobin formation in subjects treated with oxidant drugs or agents that generate hydrogen peroxide, wherein said methods comprise the systemic administration of ethanol.
Core Innovation
The invention is a method of treating metastatic solid cancers in a subject by administering 1,3-bis(2-chloroethyl)-1-nitrosourea together with hydroxocobalamin and ascorbic acid, or pharmaceutically acceptable salts of any of the foregoing. The treatment is directed to metastatic solid cancers and is presented as a combination therapy that uses hydroxocobalamin and ascorbic acid together with a DNA-crosslinking nitrosourea agent.
In the described regimen, melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea are administered together with hydroxocobalamin and ascorbic acid. The material describes redox-based tumor sensitization in terms of glutathione (GSH) depletion and increased intracellular redox stress, including conversion involving dehydroascorbic acid (DHA) and hydrogen peroxide.
The approach is framed around redox pathways associated with glutathione reductase (GR) inhibition and resulting redox changes that increase tumor cell susceptibility to DNA damage. The partial content also states that selective tumor delivery/uptake is discussed in relation to solid tumor barriers and that illustrative patient examples are provided, including metastatic pancreatic BRCA2.
Claims Coverage
The partial content includes two independent claims. Across the independent claim set, the inventive coverage centers on administering a redox-based combination for treating metastatic solid cancers, with a second independent claim adding melphalan and a melphalan dose range plus concomitant or time-spanning administration.
Combination treatment of metastatic solid cancers with a nitrosourea plus hydroxocobalamin and ascorbic acid
A method of treating metastatic solid cancers in a subject comprising administering 1,3-bis(2-chloroethyl)-1-nitrosourea, hydroxocobalamin, and ascorbic acid, or pharmaceutically acceptable salts of any of the foregoing.
Concomitant or time-spanning combination including melphalan at a defined range with a nitrosourea plus hydroxocobalamin and ascorbic acid
A method of treating metastatic solid cancers in a subject, comprising administering a combination of 1,3-bis(2-chloroethyl)-1-nitrosourea, melphalan, hydroxocobalamin, and ascorbic acid, or pharmaceutically acceptable salts of any of the foregoing, concomitantly or over a period of time; wherein the melphalan dose is in the range of approximately 20 mg/m^2 to approximately 200 mg/m^2.
Overall claim coverage centers on combination treatment of metastatic solid cancers using 1,3-bis(2-chloroethyl)-1-nitrosourea with hydroxocobalamin and ascorbic acid, and further includes a combination with melphalan (20 mg/m^2 to 200 mg/m^2) with concomitant or over-time administration.
Stated Advantages
Overcoming resistance to DNA-damaging agents by sensitizing tumor cells via redox-based mechanisms.
Redox-based tumor sensitization through glutathione depletion and increased intracellular redox stress.
Optionally, reversal of marrow toxicity by infusion of bone-marrow stem cells.
Optionally, preservation of catalase and reduction of hemolysis and methemoglobinemia by including ethanol.
Documented Applications
Treatment of metastatic pancreatic cancer is illustrated, including metastatic pancreatic BRCA2.
Treatment is described for metastatic solid cancers, including pancreatic cancer, ovarian cancer, breast cancer, and prostate cancer.
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