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AssigneesThe Rockefeller University, Board of Trustees operating Michigan State University
InventorsSanford M. Simon, Melvin M. S. Schindler
Estimating the term…
The predominant effect of pH change on multidrug resistance (MDR) independent of active drug efflux has been demonstrated in tumor cells through studies of the drugs doxorubicin and daunomycin. Specifically, the distribution of both drugs was monitored in fibroblasts and myeloma cells to examine the role of pH in drug partitioning. The invention comprises in one aspect the treatment of MDR by administering a therapeutically effective amount of a pH modulator. Diagnostic utilities are contemplated and extend to drug discovery assays and methods for measuring monitoring the status of the onset or development of pH-related conditions such as MDR, as well as the measurement of intracellular drug accumulation. Therapeutic compositions include a composition comprising a pH modulator alone or in combination with the dose-limited therapeutic agent(s), and a pharmaceutically acceptable excipient, are also contemplated.
A method for measuring the development or onset of pH-dependent multidrug resistance in a tumor cell in which such multidrug resistance is suspected, comprising determining whether there is a defect in the pH regulatory mechanism of an intracellular vesicular compartment of the cell;
A method for screening potential drugs to identify candidate drugs for treating pH-dependent multidrug resistance in mammals comprising:
An assay system for screening a potential drug for the treatment of pH-dependent multidrug resistance (MDR) in mammals comprising a mammalian tumor cell susceptible to or experiencing MDR, a pH indicator, and a means for determining whether there is a defect in the pH regulatory mechanism of an intracellular vesicular compartment of the mammalian tumor cell.
A method for treating pH-dependent multidrug resistance in a mammalian tumor cell comprising administering to the tumor cell a pH modulator in an amount effective for disrupting a secretary pathway in the tumor cell and thereby alleviate the multidrug resistance in the tumor cell.
A therapeutic composition for the treatment of multidrug resistance in a mammal comprising, in unit dose form, a modulator of cellular pH and a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.