2-Amino-1,7-dihydro-6H-purin-6-thion

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, dampen the solid spill material with 5% ammonium hydroxide, then transfer the dampened material to a suitable container. Use absorbent paper dampened with 5% ammonium hydroxide to pick up any remaining material. Your contaminated clothing and the absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with 5% ammonium hydroxide followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

INDUCTION OF 6-THIOGUANINE RESISTANCE WAS STUDIED IN HUMAN CELLS TREATED WITH THE DIRECT-ACTING CARCINOGEN N-ACETOXY-2-ACETYLAMINOFLUORENE. AT 2.5-7.5 MUMOL INDUCTION OF RESISTANT CLONES WAS LINEAR & FOLLOWED 1-HIT KINETICS, WHILE AT 10 MUMOL THE YIELD OF RESISTANT CLONES WAS HIGHER & APPEARED TO RESULT FROM COMBINATION OF 1-HIT & 2-HIT KINETICS.

6-MERCAPTOPURINE & 6-THIOGUANINE SYNERGISTICALLY INHIBITED MILK XANTHINE OXIDASE.

PRETREATMENT OF L1210 LEUKEMIA CELLS WITH METHOTREXATE ENHANCED CYTOTOXICITY OF 6-THIOGUANINE. METHOTREXATE PRETREATMENT & ENHANCEMENT OF 6-THIOGUANINE CYTOTOXICITY FOLLOWING METHOTREXATE EXPOSURE IS NOT ASSOC WITH 6-THIOGUANINE INCORPORATION INTO DNA, BUT RATHER WITH INCORPORATION OF 6-THIOGUANINE INTO RNA. THIS DRUG SEQUENCE MAY BE BENEFICIAL IN CLINICAL TREATMENT OF LEUKEMIA.

As with other thiopurines, thioguanine has been associated with several forms of hepatotoxicity, including mild, transient and asymptomatic rises in serum aminotransferase levels, an acute hepatic injury developing during the first year of starting therapy, and a chronic hepatic injury marked by variable degrees of peliosis hepatis, veno-occlusive disease and/or nodular regenerative hyperplasia. Chronic injury typically arises 1 to 5 years after starting thioguanine and can present insidiously with signs and symptoms of portal hypertension.

Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides.

Bone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising).

Gastrointestinal ulceration (black, tarry stools); hepatotoxicity, hepatic fibrosis, or toxic hepatitis (Yellow eyes or skin); stomatitis, dose-related (sores in mont and on lips).

Hyperuricemia or uric acid nephropathy (joint pain, lower back or side pain, swelling of feet or lower legs); unsteadiness when walking. Note: Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown, which leads to elevated serum uric acid concentrations.

Immunosuppression, leukopenia, or infection (usually asymptomatic; less frequently, fever or chills, cough or hoarseness, lower back or side pain, painful or difficult urination); thrombocytopenia (usually asymptomatic; less frequently, unusual bleeding or bruising; black, tarry stool; blood in urine or stools). Note: Bone marrow depression usually occurs over 2 to 4 weeks, although a rapid fall in leukocyte count may occur within 1 to 2 weeks.

For more Human Toxicity Excerpts (Complete) data for THIOGUANINE (9 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Thioguanine

vLess-DILI-concern

2

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

...PREGNANT RATS /INJECTED IP/ WITH 10 MG/KG. COMPLETE RESORPTION WAS FOUND WITH TREATMENT ON 7TH & 8TH DAY WHILE UNSPECIFIED TYPES OF MALFORMATION OR RUNTING WERE FOUND AFTER TREATMENT ON THE 4TH & 5TH OR 11TH & 12TH DAYS.

TOXIC SIGNS ARE HEMATOLOGIC DEPRESSION CHARACTERIZED BY GRADUAL ONSET, WHICH MAY PERSIST FOR SEVERAL DAYS AFTER CESSATION OF THERAPY. LEUKOPENIA, ANEMIA, & LESS SEVERE THROMBOCYTOPENIA OCCUR. GI TOXICITY INCL FREQUENT NAUSEA, VOMITING, & ANOREXIA. STOMATITIS & DIARRHEA ARE RARE. REVERSIBLE CHOLESTATIC JAUNDICE IS FAIRLY FREQUENT. /MERCAPTOPURINE, USP/

WHEN RATS WERE GIVEN THIOGUANINE (8 MG/100 G BODY WT) FOR 2 OR 3 DAYS THE ADRENAL CORTEX SHOWED HEMORRHAGIC NECROSIS. THE FIRST EFFECTS APPEARED TO BE ON THE ENDOTHELIAL LINING OF CAPILLARIES IN ZONA FASCICULATA RESULTING IN PLATELET AGGREGATION. PARENCHYMAL CELL INJURY MANIFESTED BY MITOCHONDRIAL SWELLING, DILATION & VESICULATION OF ENDOPLASMIC RETICULUM AS WELL AS MORE SEVERE STRUCTURAL ALTERATIONS SEEM TO OCCUR AS A LATE CONSEQUENCE. THE THIOGUANINE-INDUCED ADRENOCORTICAL NECROSIS COULD BE PREVENTED BY HYPOPHYSECTOMY.

AT 4 MG/KG, ORALLY, FOR 14 DAYS, THIOGUANINE DECR BLOOD ASPARTATE AMINOTRANSFERASE, ALANINE AMINOTRANSFERASE, & ALKALINE PHOSPHATASE ACTIVITIES IN MICE.

28 HR AFTER EXPOSURE TO 6-THIOGUANINE MORPHOLOGICAL CHANGES IN CHROMOSOMES OF CHINESE HAMSTER OVARY FIBROBLASTS IN THE G2 PHASE OF THE CELL CYCLE WERE EVIDENT. IT WAS DETERMINED THAT CHROMOSOMAL EFFECT IS A DOSE-RELATED EFFECT, APPEARING AS SHARP CURLING OR "KINKING" AT LOWER THIOGUANINE CONCENTRATIONS & UNILATERAL CHROMATID DAMAGE & GROSS CHROMOSOME DISRUPTION AT HIGHER THIOGUANINE CONCENTRATIONS. SINCE APPEARANCE OF UNILATERAL CHROMATID DAMAGE PARALLELED THE APPEARANCE OF THIOGUANINE-INDUCED CYTOTOXICITY IN TERMS OF TIME & DOSE, & SINCE THE SEVERE DISRUPTION OF G2 PREMATURELY CONDENSED CHROMOSOMES IS CONSISTENT WITH THIOGUANINE-INDUCED G2 ARREST SEEN IN OTHER SYSTEMS, IT WAS CONCLUDED THAT UNILATERAL CHROMATID DAMAGE IS CENTRALLY INVOLVED IN THE DELAYED CYTOTOXICITY OF THIOGUANINE IN CHINESE HAMSTER OVARY CELLS.

Rat (ip): LD50 300 mg/kg

Oral, mouse: LD₅₀ = 160 mg/kg.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl thioguanine, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

6-THIOGUANINE RESISTANCE IS USED AS GENETIC MARKERS FOR MUTAGEN SCREENING... CHINESE HAMSTER CELLS V-79 ARE DESCRIBED AS CONVENIENT SYSTEMS FOR DETECTION OF MUTAGENS IN VITRO & IN SITU.

MEDICATION

For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.