The TPMT and NUDT15 genes influence the side effects of 6-MP medications. Patients who have variations in both genes are at a higher risk of experiencing toxicity. High levels of 6-TGN are associated with TPMT variants, whereas low levels are linked to NUDT15 variants. This could facilitate more precise monitoring of toxicity.

Among the pharmacogenetic factors influencing toxicity of commonly used B-ALL treatments, variants in the TPMT and NUDT15 genes, both involved in the metabolism of 6-mercaptopurine, represent the most robust and clinically validated predictors. Emerging evidence also links additional genetic variants to toxicities associated with other key agents used in ALL treatment regimens, including variants in SLCO1B1 associated with methotrexate-related gastrointestinal toxicity and variants in CEP72 associated with vincristine-induced neuropathy. The integration of pharmacogenomic biomarkers into clinical protocols, enabling genotype-guided dose adjustment, may represent a valuable strategy to avoid toxicity and improve overall cancer outcomes. However, further studies and innovative approaches are required to validate emerging biomarkers and facilitate their translation into routine clinical practice.

Furthermore, pharmacogenomic analysis identified candidate small molecules, such as MK-886 and mercaptopurine, as potential therapeutic options. Our findings transition HCCS from a computational biomarker to a functionally validated regulator of breast cancer cell survival. By linking its systemic immunometabolic impact with its direct role in cell cycle control, this study identifies HCCS as a promising therapeutic target and a reliable prognostic indicator in BRCA.

Clinical variables included the median weekly 6-mercaptopurine (6-MP) dose (mg/m2, time-weighted) and duration of 6-MP dose interruptions...This real-world study demonstrates that suboptimal median 6-MP dosing and prolonged dose interruptions during maintenance are significantly associated with thiopurine resistance and MMR deficiency-related mutational signatures at relapse. These findings underscore the importance of optimised dose intensity and minimal interruptions during maintenance therapy in paediatric B-ALL.

A total of 270 patients with CD receiving azathioprine or mercaptopurine monotherapy were retrospectively enrolled. SIGNIFICANCE STATEMENT: This study identifies plasma histidine as a pharmacometabolic biomarker of thiopurine response in Crohn disease. By linking baseline amino acid metabolism to variability in therapeutic efficacy, these findings highlight metabolic status as a determinant of drug response and support metabolomics in precision pharmacotherapy.

Our findings support a role for ITPA and NUDT15 variants in modulating 6-MP dose requirements, while single-variant associations with MTX pharmacokinetics and toxicity were limited and not supported. These results underscore the complexity of antimetabolite pharmacogenetics and suggest that integrative polygenic approaches may better capture clinically relevant pharmacogenetic risk.

Tyrosine kinase inhibitors (TKI) are often used in combination with other chemotherapeutic nucleoside/nucleobase analogues, such as gemcitabine and 6-mercaptopurine, in the treatment of various cancers...Gefitinib, which was one of the most effective inhibitors of ENT1, also inhibited ENBT1 with a similar affinity...These data suggest that TKI inhibit multiple purine transporters, likely via interactions with their common purine ring binding domain. However, interactions between TKI and other nucleoside/nucleobase analogue drugs that are substrates for these systems are not likely to be a significant concern at the doses commonly used therapeutically.

This evaluation indicates that NUDT15 variations are more prevalent than TPMT among Indian patients. Consequently, the genotyping of TPMT and NUDT15 before MP treatment may assist in determining the appropriate dosage of MP to prevent life-threatening infections.

Allopurinol co-treatment reduces toxicity while maintaining therapeutic efficacy at lower 6-MP doses. The proposed model warrants prospective evaluation for clinical relevance confirmation.

Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade.

Approximately 28% of patients carried TPMT and/or NUDT15 variants associated with non-wild-type enzymatic activity, increasing the risk of mercaptopurine-induced myelotoxicity. Preemptive genotyping is essential to reduce toxicity, optimize treatment, and advance precision medicine in this population. Additionally, the two TPMT variants p.G126A and p.D137Y, currently not classified within Clinical Pharmacogenetics Implementation Consortium-defined star alleles, highlight the need for functional validation and potential clinical classification to improve pharmacogenetic interpretation in diverse populations.

Propolis serves as a prospective chemotherapeutic adjuvant that enhances the anticancer efficacy of 6-MP and 5-FU, allowing dose reduction, minimizing toxicity, and potentially overcoming drug resistance in breast cancer treatment. However, the therapeutic use of this synergistic technique requires confirmation via pharmacokinetic profiling, extensive vivo research, and considered clinical trials.