THIOGUANINE ANHYDROUS

US Previously Marketed

First approved in 1966

Details

Stereochemistry	ACHIRAL
Molecular Formula	C5H5N5S
Molecular Weight	167.192
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC2=C(N=CN2)C(=S)N1

InChI

InChIKey=WYWHKKSPHMUBEB-UHFFFAOYSA-N

InChI=1S/C5H5N5S/c6-5-9-3-2(4(11)10-5)7-1-8-3/h1H,(H4,6,7,8,9,10,11)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00352
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/12429slr021_tabloid_lbl.pdf

Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). 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. Thioguanine is used for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. It is marketed under the trade name Lanvis and Tabloid among others.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
DNA 278 Target ID: DNA Sources: http://www.drugbank.ca/drugs/DB00352	Interacts 323
Leukemia cells 2 Target ID: CHEMBL614844 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7967706	Inhibitor 8297	20.0 µM [IC50]
Inosine-5'-monophosphate dehydrogenase (IMPDH) 11 Target ID: CHEMBL2111369 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/12429s022lbl.pdf	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute non-lymphocytic leukemia 10 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/12429slr021_tabloid_lbl.pdf	Primary		Approved 8429	TABLOID Approved Use Indications and Usage for Thioguanine a) Acute Nonlymphocytic Leukemias TABLOID brand Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity. The response to this agent depends upon the age of the patient (younger patients faring better than older) and whether Thioguanine is used in previously treated or previously untreated patients. Reliance upon Thioguanine alone is seldom justified for initial remission induction of acute nonlymphocytic leukemias because combination chemotherapy including Thioguanine results in more frequent remission induction and longer duration of remission than Thioguanine alone. b) Other Neoplasms TABLOID brand Thioguanine is not effective in chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, or solid tumors. Although Thioguanine is one of several agents with activity in the treatment of the chronic phase of chronic myelogenous leukemia, more objective responses are observed with MYLERAN® (busulfan), and therefore busulfan is usually regarded as the preferred drug. Launch Date 1966

C_max

Value	Dose	Co-administered	Analyte	Population
313 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/11422012	40 mg/m² 1 times / day multiple, oral dose: 40 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:		THIOGUANINE plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
586 pM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/11422012	40 mg/m² 1 times / day multiple, oral dose: 40 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:		THIOGUANINE plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27463047	40 mg 1 times / day multiple, oral dose: 40 mg route of administration: Oral experiment type: MULTIPLE co-administered:		THIOGUANINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED

Doses

Dose	Population	Adverse events
20 mg 1 times / day multiple, oral (median) Dose: 20 mg, 1 times / day Route: oral Route: multiple Dose: 20 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17943403/	unhealthy, 16–82 years n = 135 Health Status: unhealthy Condition: inflammatory bowel disease Age Group: 16–82 years Sex: M+F Population Size: 135 Sources: https://pubmed.ncbi.nlm.nih.gov/17943403/	Other AEs: Pain, Nausea and vomiting... Other AEs: Pain (grade 1-2, 9.6%) Nausea and vomiting (grade 1-2, 20%) Leukopenia (grade 1-2, 11.8%) Thrombocytopenia (grade 1-3, 3.7%) Hepatotoxicity (grade 1-2, 24.4%) Headache (grade 1-2, 8.9%) Anemia (grade 1-3, 8.9%) Gamma-glutamyltransferase increased (grade 1-4, 16.3%) Diarrhea (grade 2, 1.4%) Skin toxicity (grade 1-2, 11.8%) Hair loss (grade 1, 5.2%) Infection (grade 1-3, 26.7%) Blood urea nitrogen increased (grade 1, 1.4%) Neurotoxicity (grade 1-2, 1.4%) Hemorrhage (grade 3, 0.7%) Stomatitis (grade 1, 0.7%) Creatinine increased (grade 2, 0.7%) Cardiac arrhythmias (grade 1, 0.7%) Constipation (grade 1, 0.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/17943403/
40 mg 1 times / day multiple, oral (median) Dose: 40 mg, 1 times / day Route: oral Route: multiple Dose: 40 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17943403/	unhealthy, 16–82 years n = 296 Health Status: unhealthy Condition: inflammatory bowel disease Age Group: 16–82 years Sex: M+F Population Size: 296 Sources: https://pubmed.ncbi.nlm.nih.gov/17943403/	Disc. AE: Pain, Nausea and vomiting... AEs leading to discontinuation/dose reduction: Pain (grade 1-3, 6.1%) Nausea and vomiting (grade 1-2, 4.4%) Leukopenia (grade 1-3, 2.7%) Thrombocytopenia (grade 1-3, 2.7%) Hepatotoxicity (grade 1-2, 2.4%) Headache (grade 1-2, 1.7%) Anemia (grade 1-4, 0.7%) Gamma-glutamyltransferase increased (grade 2-3, 1%) Diarrhea (grade 2-4, 1%) Skin toxicity (grade 1, 0.7%) Hair loss (grade 1, 0.7%) Cardiac dysfunction (grade 3, 0.3%) Pericarditis (grade 2, 0.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/17943403/
40 mg 1 times / day multiple, oral Dose: 40 mg, 1 times / day Route: oral Route: multiple Dose: 40 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12622758/	unhealthy, 22–61 years n = 37 Health Status: unhealthy Condition: Crohn's disease Age Group: 22–61 years Sex: M+F Population Size: 37 Sources: https://pubmed.ncbi.nlm.nih.gov/12622758/	Disc. AE: Pancreatitis, Headache... Other AEs: Headache, Nausea... AEs leading to discontinuation/dose reduction: Pancreatitis (2.7%) Headache (5.4%) Pneumonia (2.7%) Leucopenia (5.4%) Other AEs: Headache (45.9%) Nausea (27%) Vomiting (5.4%) Pruritus (8.1%) Arthralgia (8.1%) Alopecia (8.1%) Dysaesthesia (2.7%) Eczema (10.8%) Exanthema (5.4%) Photosensitivity allergic reac (5.4%) Erythema nodosum (2.7%) Rotavirus infection (2.7%) Respiratory tract infections (29.7%) Urinary tract infections (10.8%) Genital candidiasis (5.4%) Herpes labialis (2.7%) Transaminases increased (5.4%) Leucopenia (8.1%) Anaemia (2.7%) Thrombopenia (2.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/12622758/
1200 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 1200 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 1200 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/7105383/	unhealthy, 37-70 years n = 4 Health Status: unhealthy Condition: colorectal carcinoma Age Group: 37-70 years Sex: M+F Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/7105383/	Disc. AE: Creatinine increased... Other AEs: Leukopenia... AEs leading to discontinuation/dose reduction: Creatinine increased (25%) Other AEs: Leukopenia (25%) Sources: https://pubmed.ncbi.nlm.nih.gov/7105383/
300 mg/m2 1 times / week multiple, intravenous MTD Dose: 300 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 300 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/7521908/	unhealthy, Patients < 21 years n = 31 Health Status: unhealthy Condition: advanced malignancies Age Group: Patients < 21 years Population Size: 31 Sources: https://pubmed.ncbi.nlm.nih.gov/7521908/	Other AEs: Neutropenia, Anemia... Other AEs: Neutropenia (grade 3, 16.1%) Anemia (grade 3, 16.1%) Thrombocytopenia (grade 3, 16.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/7521908/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 UGT1A9 116 UGT2B7 146	TPMT 5 MRP4 77 MRP5 40

Drug as perpetrator

Target	Modality	Activity
UGT1A9 121	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11488768/ Page: 4.0	no
UGT2B7 157	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11488768/ Page: 4.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/11488768/ Page: 4.0	weak

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
MRP4 77	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12435799/ Page: 1.0	major	tGMP 2
MRP5 40	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12435799/ Page: 1.0	minor	tGMP 2
TPMT 5	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012429s028lbl.pdf#page=3 Page: 3.0	yes		yes (pharmacogenomic study) Comment: patients with reduced TPMT receiving usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012429s028lbl.pdf#page=3 Page: 3.0

PubMed

Title	Date	PubMed
Recent advances in the pharmacogenomics of thiopurine methyltransferase.	2001	11908768
Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation.	2001	11782291
Favorable outcome for children and adolescents with T-cell lymphoblastic lymphoma with an intensive ALL-type therapy without local radiotherapy.	2001	11757713
Pharmacogenetics: the therapeutic drug monitoring of the future?	2001	11735602
Pharmacokinetic considerations in the treatment of inflammatory bowel disease.	2001	11707060
Remission induction therapy: the more intensive the better?	2001 Aug	11587366
Continuing therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of methotrexate, 6-mercaptopurine and 6-thioguanine.	2001 Dec	11908928
Renal cell carcinoma as a secondary malignancy after treatment of acute promyelocytic leukemia.	2001 Dec	11902306
Toxoplasma gondii: mechanism of the parasitostatic action of 6-thioxanthine.	2001 Dec	11888251
Why measure thiopurine methyltransferase activity? Direct administration of 6-thioguanine might be the alternative for 6-mercaptopurine or azathioprine.	2001 Dec	11758505
Mechanisms of tolerance to DNA damaging therapeutic drugs.	2001 Dec	11751422
Comparative pharmacokinetics of oral 6-mercaptopurine and intravenous 6-mercaptopurine riboside in children.	2001 Dec	11737747
[Primary pulmonary manifestation of extramedullary acute myelocytic leukemia].	2001 Jun	11458438
6-Thioguanine in children with acute lymphoblastic leukaemia: influence of food on parent drug pharmacokinetics and 6-thioguanine nucleotide concentrations.	2001 Jun	11422012
The mouse guanylate kinase double mutant E72Q/D103N is a functional adenylate kinase.	2001 Nov	11742110
Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine.	2001 Nov	11683683
Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine.	2001 Nov	11681411
Treatment of psoriasis. Part 2. Systemic therapies.	2001 Nov	11606913
Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.	2001 Nov	11600468
Loss of DNA mismatch repair imparts defective cdc2 signaling and G(2) arrest responses without altering survival after ionizing radiation.	2001 Nov 15	11719462
Substitution F569S converts UapA, a specific uric acid-xanthine transporter, into a broad specificity transporter for purine-related solutes.	2001 Nov 2	11697902
FAB M4 and high CD14 surface expression is associated with high cellular resistance to Ara-C and daunorubicin: implications for clinical outcome in acute myeloid leukaemia.	2001 Oct	11860442
Managing the glucocorticoid dependent inflammatory bowel disease patient.	2001 Oct	11726077
Acute arterial occlusion as the presenting feature in acute promyelocytic leukaemia.	2001 Oct	11722402
Co-amplification of dhfr and a homologue of hmsh3 in a Chinese hamster methotrexate-resistant cell line correlates with resistance to a range of chemotherapeutic drugs.	2001 Oct	11710632
6-mercaptopurine metabolite levels in children with inflammatory bowel disease.	2001 Oct	11698762
Targeting DNA mismatch repair for radiosensitization.	2001 Oct	11677655
Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells.	2001 Oct	11577013
Hypoxia-induced enrichment and mutagenesis of cells that have lost DNA mismatch repair.	2001 Oct 15	11606400
Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial.	2001 Sep 1	11520775
Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents.	2001 Sep 27	11593426
Novel glutathione-dependent thiopurine prodrugs: evidence for enhanced cytotoxicity in tumor cells and for decreased bone marrow toxicity in mice.	2002 Apr	11907160
Photodynamic therapy of DNA mismatch repair-deficient and -proficient tumour cells.	2002 Apr 8	11953861
Specific [(3)H]-guanosine binding sites in rat brain membranes.	2002 Feb	11861325
Diversity of the apoptotic response to chemotherapy in childhood leukemia.	2002 Feb	11840289
Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.	2002 Feb	11840287
Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues.	2002 Feb 1	11802779
Aphidicolin induces 6-thioguanine resistant mutants in human diploid fibroblasts.	2002 Feb 20	11827715
The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics.	2002 Jan	11966406
Inflammatory bowel disease.	2002 Jan	11778131
HPLC determination of thiopurine nucleosides and nucleotides in vivo in lymphoblasts following mercaptopurine therapy.	2002 Jan	11751539
Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome.	2002 Jan 1	11756178
Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal nocturnal hemoglobinuria.	2002 Jan 1	11756148
Flow cytometric determination of HPRT-variants in human peripheral blood lymphocytes.	2002 Jan 29	11804605
Genetic toxicology studies with glutaraldehyde.	2002 Jan-Feb	11807929
Hypomethylation and multiple sclerosis, the susceptibility factor?	2002 Mar	11927101
Pharmacological characterization of the ATP-dependent low K(m) guanosine 3',5'-cyclic monophosphate (cGMP) transporter in human erythrocytes.	2002 Mar 1	11911846
Childhood hyperuricemia and acute renal failure resulting from a missense mutation in the HPRT gene.	2002 Mar 15	11891689
X-ray induced mutation in Syrian hamster fetal cells.	2002 Mar 20	11890930
Implication of protein kinase C in the regulation of DNA mismatch repair protein expression and function.	2002 May 17	11880362

Patents

Sample Use Guides

In Vivo Use Guide

Single Agent Chemotherapy: Usual Initial dose: 2 mg/kg/day orally. If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg per day. The total daily dose may be given at one time. As a part of combination therapy for induction of remission in patients with acute nonlymphocytic leukemia: 75 to 200 mg/m2/day in 1 to 2 divided doses for 5 to 7 days or until remission is attained.

Route of Administration: Oral

In Vitro Use Guide

Maximum cytotoxicity against leukemic cells from patients with ALL occured at 0.5 uM

Name

Type

Language

THIOGUANINE ANHYDROUS

Common Name

English

THIOGUANINE, ANHYDROUS

Common Name

English

NSC-752

Code

English

Tioguanine [WHO-DD]

Common Name

English

6-THIOGUANINE

Systematic Name

English

2-AMINOPURINE-6(1H)-THIONE

Systematic Name

English

tioguanine [INN]

Common Name

English

TIOGUANINE

Official Name

English

6H-PURINE-6-THIONE, 2-AMINO-1,7-DIHYDRO-

Systematic Name

English

THIOGUANINE [HSDB]

Common Name

English

THIOGUANINE [MI]

Common Name

English

NSC-76504

Code

English

Classification Tree Code System Code

NDF-RT

N0000180853