thioguanine

The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM.DPWG classifies genotyping for TPMT and NUDT15 "essential" before thiopurine initiation.

The thiopurines 6-mercaptopurine and 6-thioguanine (TG) are analogs of guanine and are used in the treatment of hematological malignancies and immune-mediated inflammatory diseases. dMeTG could also be detected in patient samples, although in low amounts and primarily in samples with high DNA-TG levels. The developed method for the quantitation of dMeTG and dTG can be used in further studies to investigate the role of DNA-MeTG in the mechanism of action of thiopurines, including its antileukemic efficacy and effects on acquired mutations.

Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.

Sequential 6-TG administration capitalizes on salvage pathway activation in MTX-resistant LC and may represent a promising therapeutic strategy to overcome MTX resistance.

P3, N=5949, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

Mercaptopurine (MP)-based maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL). Dose escalation is unlikely to improve myelosuppression but will increase the risk of hepatotoxicity. Low-dose mercaptopurine combined with allopurinol can improve efficacy and reduce the risk of hepatotoxicity.

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2025 --> Sep 2026

P2/3, N=1708, Not yet recruiting, Children's Oncology Group | Initiation date: Sep 2025 --> Mar 2026

We used ACGBEmax to generate HPRT variants, identifying mutations conferring resistance to 6-thioguanine. Additionally, we performed in situ mutagenesis of Ctnnb1 in mouse liver, identifying both known and potential oncogenic mutations. Our results prove that ACGBEmax is a powerful tool for generating a wide spectrum of mutation types at specific gene loci, highlighting its significant potential for applications in functional screening and the directed evolution of protein variants.

One mother underwent antileukemic treatment including thioguanine during early pregnancy; the other received 6-mercaptopurine for Crohn's disease throughout gestation. Each underwent allogeneic hematopoietic stem cell transplantation and is currently in remission. These findings suggest a possible link between prenatal thiopurine exposure and leukemogenesis.

P3, N=6430, Recruiting, Mats Heyman | Trial completion date: Jun 2032 --> Jun 2033 | Trial primary completion date: Jun 2027 --> Jun 2033

P3, N=280, Active, not recruiting, Children's Oncology Group | Trial completion date: Jul 2025 --> Jun 2026