Abstract
Hyperacidified tumors having high .beta.-glucuronidase activity can be treated with glucuronides with aglycones toxic to the tumor cells with great safety toward the rest of the body by first administering an alkalinizing agent in an amount sufficient to maintain the pH level of non-tumor tissues at approximately 7.4 during the glucuronide treatment. This will cause inactivation of .beta.-glucuronidase activity in the rest of the body. When nitrile-containing aglycones are used sodium thiosulfate is also administered to avoid cyanide poisoning. A loading dose of glucuronide greater than 2 mMoles per kilogram body weight is first administered with additional administration of one third the initial dose each hour as long as .beta.-glucuronidase activity remains at the tumor site. Bacterial cells having .beta.-glucuronidase activity may also be diagnosed and treated in accordance with the present invention.
Filing date: Oct 13, 1981
Issue date: Nov 6, 1984
Inventor: David Rubin
Assignees: Adolf Schwimmer, Irwin S. Schwartz, David Rubin, Century Science Corp.
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What is claimed is:
1. In a process of selectively delivering the aglycone of a glucuronide compound to tumor cells having higher .beta.-glucuronidase activity than that of the surrounding tissues by hyperacidifying the tumor cells and then administering to the patient a glucuronide compound, the aglycone of which is to be delivered to the tumor cells, 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 aglycone thereat, the improvement wherein the tumor selectivity of the process is improved and the risk of deconjugtion 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, and the improvement further comprising administering said glucuronide in an initial dosage of at least 2 mMols per kg of body weight but not exceeding the maximum safe toxicity dosage.
2. A process in accordance with claim 1, wherein said compound is one in which the aglycone is toxic to tumor cells and exerts a higher toxic effect in an acid environment than in an alkaline environment or is water-soluble in an alkaline environment and water-insoluble or only poorly water-soluble in an acid environment.
3. A process in accordance with claim 2, wherein said glucuronide compound is selected from the group consisting of 2,4-dinitrophenol-.beta.-D-glucuronic acid; 4-chloro-m-cresol-.beta.-D-glucuronic acid; 4,6-dinitro-o-cresol-.beta.-D-glucuronic acid; 4-chloro-3,5-xylanol-.beta.-D-glucuronic acid; chlorothymol-.beta.-D-glucuronic acid; 5-chloro-7-iodo-8-quinolinol-.beta.-D-glucuronic acid; podophyllotoxin-.beta.-D-glucuronic acid; 2-phenyl-6-chlorophenol-.beta.-D-glucuronic acid; p-iodophenol .beta.-D-glucuronic acid; and phenylsulfazole-.beta.-D-glucuronic acid.
4. A process in accordance with claim 1, wherein said step of hyperacidifying the tumor cells comprises administering a hyperglycaemic agent in an amount sufficient to hyperacidify the tumor cells.
5. a process in accordance with claim 1, wherein said alkalinizing agent is administered orally or intravenously.
6. A process in accordance with claim 1, wherein said alkalinizing agent is administered prior to administration of said glucuronide compound, said glucuronide compound being administered after the pH of the urine of the patient is determined to be approximately 7.4 and wherein administration of said alkalinizing agent continues during administration of said glucuronide compound.
7. A process in accordance with the claim 1 wherein the aglycone of said glucuranide compound is nitrile containing and further including the step of administering to the patient an amount of sodium thiosulfate sufficient to serve as antidote for cyanide poisoning.
8. A process in accordance with claim 1, 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.
9. A process in accordance with claim 8, 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.
10. A process in accordance with claim 1 further including the step of administering estrogen or testosterone substantially simultaneously with the administration of said glucuronide.
11. A process in accordance with claim 1 wherein said initial dosage of glucuronidase is followed by administration of a dosage thereof equalling about one third of said initial dosage each hour following said initial dosage for a period of about 24 hours.
12. A process in accordance with claims 1 or 11 wherein said glucuronide administration is repeated 2-5 days after said first administration, when an abrupt increase of .beta.-glucuronidase activity is noted in the patient.
13. A process in accordance with claim 1 wherein throughout said treatment the patient is also treated to alleviate or avoid ammonia intoxication.