Abstract
Drug-resistant tumor cells are rendered drug-sensitive by administering to the tumor cells a pump-affecting compound which suppresses the pumping action of P-glycoprotein on the tumor cells. In the case where the tumor cells have higher .beta.-glucuronidase activity than that of the surrounding tissues, the pump-affecting compound is in the form of a .beta.-D-glucuronide.
Filing date: Oct 13, 1989
Issue date: Apr 9, 1991
Inventor: David Rubin
Primary Examiner: Michael Rafa
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What is claimed is:
1. A method of rendering drug-resistant tumor cells drug-sensitive, comprising selectively administering only to said tumor cells a sufficient amount of a pump-affecting compound to suppress the pumping action of P-glycoprotein on said tumor cells, said amount being less than that amount necessary for such pump-affecting compound itself to kill said tumor cells.
2. The method according to claim 1 wherein cells have higher .beta.-glucuronidase activity than that of the surrounding tissues and said pump-affecting compound is in the form of a .beta.-D-glucuronide.
3. The method according to claim 2 wherein the tumor cells are hyperacidified and the .beta.-D-glucuronide compound is administered to the patient, whereby the .beta.-glucuronidase activity of the hyperacidified tumor cells causes deconjugation of the glucuronide compound at the site of the tumor cells and release of the pump-affecting compound thereat.
4. The method according to claim 3 wherein the tumor selectivity of the process is improved and the risk of deconjugation of the glucuronide compound at the site of non-tumor tissues is diminished comprising administering to the patient an alkalinizing agent in an amount sufficient to maintain the pH level of the non-tumor tissues of the patient at approximately 7.4 during the glucuronide treatment.
5. The process according to claim 4 wherein the glucuronide compound is one in which the aglycone exerts a higher pump-affecting effect in an acid environment than in an alkaline environment or is water-insoluble or only poorly water-soluble in an acid environment and more water-soluble in an alkaline environment.
6. A process according to claim 2 wherein the glucuronide compound is selected from the group consisting of 2,4-dinitrophenol-.beta.-D-glucuronic acid; 2,4-dinitrocresol -.beta.-D-glucuronic acid; 4-chloro-m-cresol-.beta.-D-glucuronic acid; 4,6-dinitro-o-cresol-.beta.-D-glucuronic acid; podophyllotoxin -.beta.-D-glucuronic acid; p-iodophenol-.beta.-D-glucuronic acid; mandelonitrile-.beta.-D-glucuronic acid; 1-hydroxy-mandelonitrile -.beta.-D-glucuronic acid and methacrylonitrile-.beta.-D-glucuronic acid.
7. The process in accordance with claim 3 wherein said step of hyperacidifying the tumor cells comprises administering a hyperglycemic agent in an amount sufficient to hyperacidify the tumor cells.
8. A process in accordance with claim 2 wherein said alkalinizing agent is administered orally or intravenously.
9. A process in accordance with claim 4 further including the step of inducing hyperthermia at least at the site of the tumor being treated to an extent sufficient to substantially increase .beta.-glucuronidase activity at the site without substantially affecting the overall health of the patient at least at the time of maximum glucuronide concentration at the tumor.
10. A process in accordance with claim 9 wherein said hyperthermia is induced locally at the tumor by administration of the glucuronide of a pyrogen, by microwave treatment, or by passage of electrical current through the body.
11. A process in accordance with claim 1 wherein said pump-affecting compound is one which interferes with the production of adenosine triphosphate in the tumor cells.
12. A method for the treatment of patients having tumors with .beta.-glucuronidase activity, comprising administering to such patients a .beta.-D-glucuronic acid conjugate of a compound having pump-affecting properties, in an amount sufficient to suppress the pumping of P-glycoprotein on said tumor cells, said amount being less than that amount necessary for said conjugate itself to kill said tumor cells, and, while the tumors are being contacted by said compound, administering an effective amount of a chemotherapeutic agent other than a .beta.-D-glucuronic acid conjugate.
13. A method in accordance with claim 12, further including the step of, prior to administering said glucuronic acid conjugates, causing the tumors to become hyperacidified and causing the healthy tissues of the remainder of the patient to become alkalinized.
14. A method in accordance with claim 12, wherein said chemotherapeutic agent is selected from the group consisting of 5-fluorouracil, p-hydroxyanaline mustard, methotrexate, floxuridine, cytarabine, melphalan, hydroxyurea, adriamycin, thiouracil, chlorophenol, methacrylonitrile, fluoroacetic acid, melphalan, dinitrocresol, vinblastine, vincristine, daunomycin, and dinitrophenol.