Definition
- 6-Thioguanine (6-TG) is a purine analogue antimetabolite.
- It is a thiolated derivative of guanine that incorporates into DNA and RNA and inhibits purine nucleotide synthesis.
- Classified as an antimetabolite chemotherapeutic agent (purine antagonist).
Mechanism of Action
- Converted intracellularly to thioguanine nucleotides (TGNs).
- TGNs:
- Incorporate into DNA and RNA, causing mispairing and cytotoxicity.
- Inhibit de novo purine synthesis via feedback inhibition.
- Cytotoxic effect mainly occurs in the S-phase of the cell cycle.
Clinical Uses
- Acute myeloid leukemia (AML) – used in combination chemotherapy regimens.
- Historically used in acute lymphoblastic leukemia (ALL), but less common now (replaced by mercaptopurine).
- Not generally used for maintenance therapy due to hepatic toxicity.
- Oral agent.
- Metabolized by thiopurine S-methyltransferase (TPMT) and NUDT15.
- Genetic polymorphisms in TPMT and NUDT15 greatly affect toxicity risk → dose reduction needed in poor metabolizers.
Toxicities (Pharmacist-Relevant)
| Toxicity | Notes |
|---|---|
| Myelosuppression | Dose-limiting; risk ↑ with TPMT/NUDT15 deficiency |
| Hepatotoxicity | Risk of veno-occlusive disease (VOD) and sinusoidal obstruction syndrome; higher than mercaptopurine |
| GI toxicity | Nausea, vomiting, mucositis |
| Long-term risk | Mutagenic and potentially carcinogenic |
Monitoring
- CBC: baseline and at least weekly during therapy.
- LFTs: monitor for hepatotoxicity and VOD.
- Consider TPMT and NUDT15 genotyping/phenotyping prior to initiation.
- Monitor for signs of infection due to immunosuppression.
Pharmacist Considerations
- Drug Interactions:
- Allopurinol/febuxostat inhibit xanthine oxidase → do not significantly affect 6-TG metabolism (unlike 6-MP).
- Avoid hepatotoxic drugs concurrently.
- Counseling:
- Take orally, consistent timing.
- Report jaundice, abdominal pain, fever, or bleeding.
- Therapeutic Drug Monitoring (TGN levels) may be used in some centers.
In short: 6-TG is a purine antimetabolite used mainly in AML, metabolized by TPMT/NUDT15, with dose-limiting myelosuppression and high risk of hepatotoxicity (VOD), requiring careful genetic screening and monitoring.