Method for the treatment of tumors with .beta.-glucuronidase activity dependent pharmaceuticals

• US 4,337,760 A
• Filed: 10/31/1979
• Issued: 07/06/1982
• Est. Priority Date: 10/13/1978
• Status: Expired due to Term

• Current Assignee: Century Science Corporation
• Original Assignee: Adolf Schwimmer, David Rubin, Irwin Steven Schwartz
• Inventors: Rubin, David
• Primary Examiner(s): Recla, Henry J.
• Assistant Examiner(s): Wallen, T. J.
• Application Number:
  US06/089,888
• Time in Patent Office: 979 Days
• Field of Search: 128/1 R, 128/804, 424/127
• US Class Current: 604/500
• CPC Class Codes: A61K 2123/00 Preparations for testing in vivo
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: C07H 15/18 Acyclic radicals, substituted by carbocyclic rings
• CPC Class Codes: C07H 15/203 Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• CPC Class Codes: C12Q 1/34 involving hydrolase
• CPC Class Codes: C12Q 2334/00 O-linked chromogens for determinations of hydrolase enzymes, e.g. glycosidases, phosphatases, esterases
• CPC Class Codes: C12Q 2334/40 Triphenylmethane dye chromogens, e.g. fluorescein derivatives
• CPC Class Codes: G01N 2333/924 acting on glycosyl compounds (3.2)
• CPC Class Codes: G01N 33/5091 for testing the pathological state of an organism

Abstract

Hyperacidified tumors having high β-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 β-glucuronidase activity in the rest of the body. When nitrile-containing aglycones are used sodium thiosulfate is also administered to avoid cyanide poisoning. Novel glucuronides are disclosed the aglycones of which exert a higher toxic effect in an acid environment or are water-soluble only in an alkaline environment. Such compounds have particular utility with the above process. By substituting radioisotopes into the aglycone, diagnosis and in situ radiation therapy may be accomplished. Bacterial cells having β-glucuronidase activity may also be diagnosed and treated in accordance with the present invention. A urine test is disclosed to determine the amount of free glucuronic acid in the urine which is an indication of the presence of a tumor in the body having high β-glucuronidase activity. Novel methods of synthesizing the glucuronide used in the present invention are also disclosed.

Claims

1. In a process of selectively delivering the aglycone of a glucuronide compound to tumor cells having higher β

-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 β

-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 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.

2. 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. Process in accordance with claim 2, wherein said glucuronide compound is selected from the group consisting of 2,4-dinitrophenol-β

-D-glucuronic acid;

4-chloro-m-cresol-β

-D-glucuronic acid;

4,6-dinitro-o-cresol-β

-D-glucuronic acid;

4-chloro-3,5-xylanol-β

-D-glucuronic acid;

chlorothymol-β

-D-glucuronic acid;

5-chloro-7-iodo-8-quinolinol-β

-D-glucuronic acid;

podophyllotoxin-β

-D-glucuronic acid;

2-phenyl-6-chlorophenol-β

-D-glucuronic acid;

p-iodophenol β

-D-glucuronic acid; and

phenylsulfazole-β

-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 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 β

-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.