Abstract
The metabolism of tumor cells which have .beta.-glucuronidase activity is inhibited by administering to a patient a conjugate of glucuronic acid and a thiocarbamate compound of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.1 -C.sub.6 cycloaliphatic, and M is selected from the group consisting of hydrogen, an electropositive, ionically bonded metal, and the radical ##STR2## and R.sup.3 and R.sup.4 are selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.1 -C.sub.6 cycloaliphatic groups.
Filing date: Dec 22, 1992
Issue date: Aug 31, 1993
Inventor: David Rubin
Assignees: Adolph Schwimmer, David Rubin
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What is claimed is:
1. A method for selectively treating tumor cells which have .beta.-glucuronidase activity to inhibit the metabolism of said tumor cells comprising administering to a patient suffering from said tumor cells an effective amount of a conjugate made by conjugating glucuronic acid or a pharmaceutically acceptable ester or salt thereof to a thiol chelating compound of the formula: ##STR7## wherein R.sup.1 and R.sup.2 are selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.6 cycloaliphatic groups, and M is selected from the group consisting of hydrogen, an electropositive, ionically bonded pharmaceutically acceptable metal, and the radical ##STR8## wherein R.sup.3 and R.sup.4 are selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.6 cycloaliphatic groups.
2. The method according to claim 1 wherein the conjugate is formed from the triacetylated form of glucuronic acid.
3. The method according to claim 2 wherein the conjugate is administered orally.
4. The method according to claim 1 wherein the thiol chelating compound is selected from the group consisting of diethyldithiocarbamate and pharmaceutically acceptable salts thereof.
5. The method according to claim 1 wherein, prior to administration of said conjugate, the patient is administered 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 treatment with said conjugate.
6. The method according to claim 1 wherein, prior to administering said conjugate, the tumor cells are hyperacidified.
7. The method according to claim 1 further including the step of inducing hyperthermia at least at the site of the tumor being treated to an extent sufficient to increase substantially .beta.-glucuronidase activity at the site without substantially affecting the overall health of the patient at the time of maximum conjugate concentration at the tumor.
8. The method according to claim 7 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.
9. The method according to claim 1 further including the step of administering estrogen or testosterone substantially simultaneously with administration of said conjugate, wherein the tumor is not estrogen- or testosterone-dependent.
10. A composition for selectively treating tumor cells which have .beta.-glucuronidase activity comprising a pharmaceutically acceptable carrier and an effective amount of a conjugate made by conjugating a glucuronide compound selected from the group consisting of glucuronic acid and pharmaceutically acceptable esters and salts thereof to a thiol chelating compound of the formula: ##STR9## wherein R.sup.1 and R.sup.2 are selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.6 cycloaliphatic groups, and M is selected from the group consisting of hydrogen, an electropositive, ionically bonded pharmaceutically acceptable metal, and the radical ##STR10## wherein R.sup.3 and R.sup.4 are selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.6 cycloaliphatic groups.
11. The composition according to claim 10 wherein the glucuronide compound is a triacetylated glucuronic acid.
12. The composition according to claim 11 wherein the glucuronide compound is methyl-(tri-O-acetyl-.alpha.-D-glucopyranosyl)bromide uronate.
13. The composition according to claim 10 wherein the thiol chelating compound is selected from the group consisting of diethyldithiocarbamate and pharmaceutically acceptable salts thereof.
14. The composition according to claim 10 wherein the carrier is suitable for parenteral administration.
15. The composition according to claim 11 wherein the carrier is suitable for oral administration.
16. The method according to claim 1 wherein the tumor cells are selected from the group consisting of solid breast tumors, bronchogenic carcinoma, and lymphomas.
17. The method according to claim 16 wherein the tumor cells are solid breast tumors.
18. The method according to claim 1 wherein the conjugate is administered in sufficient amount to provide from about 19 mg/kg body weight to about 2000 mg/kg body weight of the thiol chelating compound.