thioguanine

P2, N=145, Not yet recruiting, St. Jude Children's Research Hospital

P2, N=171, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Jul 2024

P2, N=154, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Aug 2024

P3, N=680, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Jul 2024

P3, N=310, Suspended, Alliance for Clinical Trials in Oncology | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

6TG evidenced a marked anti-angiogenic activity in HUVECs exposed to high glucose and in mice with DR. This seems to be mediated by MC1R and MC5R retinal receptors.

P3, N=1895, Active, not recruiting, National Cancer Institute (NCI)

P2, N=500, Recruiting, National University Hospital, Singapore

P2, N=171, Not yet recruiting, National Cancer Institute (NCI)

P3; Initiation date: Jan 2024 --> Apr 2024

Methionine metabolism and polyamine synthesis can be attractive therapeutic targets in leukemia.

P3, N=4997, Recruiting, Children's Oncology Group | Trial completion date: Jun 2029 --> Mar 2030 | Trial primary completion date: Jun 2029 --> Mar 2030

We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis.

P2, N=154, Not yet recruiting, National Cancer Institute (NCI)

One study reported outcomes for 206 children who received supportive care for VOD/SOS during 6-thioguanine therapy for ALL; only three pts had acute hepatic failure and all pts recovered from VOD/SOS. Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. A lack of consensus regarding VOD/SOS diagnosis in the non-HCT setting may lead to underdiagnosis; therefore, clinicians should be vigilant for VOD/SOS even in non-HCT pts. Though defibrotide is approved for post-HCT VOD/SOS, there is no approved therapy for non-HCT VOD/SOS; future trials should focus on diagnosis and treatment outside the HCT setting, which represents a significant unmet need.

05 and absolute log2FC>1) in the high-resistance group for one or multiple drugs: amsacrine (ams, n = 10), etoposide (eto, n = 10), tioguanine (thio, n = 8) and mitoxantrone (mito, n = 1). Importantly, our analysis indicates that the differential expression of snoRNAs in the resistance groups cannot be solely attributed to host gene expression, implying that targeting pathways involving host genes might not be the most effective approach. Rather than concentrating on pathways involving host genes, our results suggest that understanding the mechanisms of action of snoRNAs could provide promising avenues for developing novel therapeutic targets to enhance drug response in pediatric ALL.

P3, N=6720, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2030 --> Jun 2029 | Trial primary completion date: Mar 2030 --> Jun 2029

P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026

The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1x10 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm). In future studies, we aim to apply this method to investigate TPMT activity in patients' leukocytes.

P3; N=680; Not yet recruiting; Sponsor:National Cancer Institute (NCI)

P3, N=6720, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P3, N=847, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2023 --> Sep 2024

P2, N=78, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Sep 2024

P3, N=5937, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Sep 2024

Cumulative thiopurine dose and duration did not show an association with KSC development. Future KSC risk stratification, based on all available KSC risk factors, may aid in selecting individuals who can benefit most from dermatologic screening programs.

Furthermore, the stability of the drug in whole blood samples under various storage conditions was investigated. The suggested method is suitable for determining 6-thioguanine in whole blood erythrocyte samples for drug level monitoring, thus correct dosing.

TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.

Our results suggest azathioprine could be the preferable anti-cancer drug for the population with NUDT15 variants that could effectively be hydrolyzed as evidenced by molecular docking and dynamic simulation.

Funding 300 doses of immune checkpoint inhibitor 'atezolizumab' are sponsored by Pharmaceutical company Roche as an unrestricted grant...The thiopurines 6-mercaptopurine (6MP) and 6-thioguanine (6TG) are prodrugs that are converted into cytotoxic metabolites that are incorporated into DNA and cause DNA-damage and mutations through futile DNA mismatch repair attempts...Extensive exploratory analyses will include characterization of the tumor mutational and neoantigen landscape on serial biopsies using whole genome sequencing and RNA sequencing. The study was initiated in September 2022, and currently four patients have been included in the study.

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy...We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic-pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.

P2, N=78, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Jun 2024

In this study, we propose an innovative strategy to enhance the knockout efficiency of CRISPR/Cas9 ribonucleoproteins (RNPs) by co-targeting hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway and subsequently treating with 6-thioguanine... Here, we report an innovative method for generating high-efficiency CRISPR/Cas9 RNP knockout pools in patient-derived CRC organoids. We intend to apply this method to verify and further investigate the knockout effects of specific genes of interest identified in arrayed CRISPR RNP screens conducted using our 384-well RNP transfection platform in adherent CRC cell lines. Furthermore, our method is particularly valuable for generating knockout organoids without the need for lentiviral transduction.

Three patients (4%) ceased thiopurine therapy due to thiopurine-related AEs, while no laboratory toxicity required therapy adjustments. Monitoring frequency of every 6 months seems feasible in patients with stable IBD on long-term (median duration > 6 years) maintenance thiopurine therapy and may contribute to reduced patient-burden and health care costs.

Modifications included use of E. coli asparaginase, 6-mercaptopurine instead of thioguanine and use of rituximab among CD20 positive patients. Most patients presented hepatotoxicity (51.6% and 53.7% during induction and consolidation), and treatment-related mortality was 9.5%. Overall, results highlight that implementing a modified CALGB 10403 regimen in Central America is feasible, and it is associated with improvements in clinical outcomes and a manageable safety profile.

P3, N=6720, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2029 --> Mar 2030 | Trial primary completion date: Dec 2029 --> Mar 2030

P2/3, N=793, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting

P3, N=669, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Apr 2024

Its cytotoxic effects are mediated by 6-thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (Odds ratio=8.2, p<0.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype-guided dose adjustment to reduce toxicity.

Under optimum conditions for the determination of 6-TG, a wide linear concentration range from 2.5 to 100 μmol L was observed with a limit of detection (LOD) of 1.57 μmol L. The characteristics of simple operation, high sensitivity and selectivity make this fluorescent nanoprobe a promising candidate for the detection of 6-TG in biological samples, as demonstrated by the application in spiked human serum with recoveries of 97.6 to 104.8%. In general, this proposed method has good potential for the detection of 6-TG in biological samples.