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Tioguanine: Wikis

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Tioguanine
Systematic (IUPAC) name
2-amino-7H-purine-6-thiol
Identifiers
CAS number 154-42-7
ATC code L01BB03
PubChem 2723601
DrugBank APRD00290
Chemical data
Formula C 5H5N5S 
Mol. mass 167.193 g/mol
Pharmacokinetic data
Bioavailability 30% (range 14% to 46%)
Metabolism Intracellular
Half life 80 minutes (range 25-240 minutes)
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes oral
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Tioguanine (INN), formerly thioguanine (BAN), is a drug that is used in the treatment of cancer.[1]

It belongs to the family of drugs called antimetabolites. It is a guanine analog.

Contents

Uses

Its principal use is in acute leukaemias and chronic myeloid leukaemia.

It has been investigated for use in treatment of psoriasis.[2]

Pharmacology

As a guanine analogue, it is transformed inside the cell into 6-thioguanilyic acid (TGMP), which, by pseudofeedback interference with purine biosynthesis, interferes with the synthesis of guanine nucleotides. Some of its activity may also be due to the incorporation of thioguanine nucleotides into both RNA and DNA, but the end-result is inducing cell cycle arrest and apoptosis. It is metabolized via methylation by thiopurine methyltransferase.

Mechanism of cell cycle arrest and cell death

After incorporation into DNA, the thiocarbonyl of thioguanine has a tendency to be methylated. This produces a base similar to 6-O-methylguanine.

During a second round of replication, the mismatch repair system will recognize the mismatch between the methylated base and cytosine. The attempt to repair such a mismatch is abortive since no nucleotides can be properly matched with the methylated base. This leads to persistent 100-200 base single strand breaks. Such a genotoxic stress will trigger cell cycle arrest and cell death. In this regard, thioguanine and mercaptopurine, although categorized as antimetabolites, exert their functions more like a genotoxic methylating agents, such as temozolomide, which methylates DNA and generate 6-O-methylguanine and cytosine mismatch.

The ability of thioguanine and mercaptopurine to trigger genotoxic stress is also exemplified by their treatment-related acute myeloid leukemia (AML), which is uncommon for antimetabolites, but common for alkylating agents and topoisomerase inhibitors.

References

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