Tioguanine

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	C5H5N5S
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.

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