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In vitro cytotoxicity analysis on patient-derived PBMCs to predict 6-mercaptopurine therapy response in children with acute lymphoblastic leukemia

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Title In vitro cytotoxicity analysis on patient-derived PBMCs to predict 6-mercaptopurine therapy response in children with acute lymphoblastic leukemia
 
Creator Velugonda, Nagaraj
Chaithanya, Krishna
Patchva, Dorababu
Manda, Sasidhar V
Gundeti, Sadashivudu
 
Subject 6-thioguanine
ALL
Methyl-mercaptopurine
Myelotoxicity
Thioguanine nucleotide
 
Description 371-379
6-Mercaptopurine (6-MP) is a critical medication used in the remission-maintenance phase of pediatric acute lymphoblastic leukemia (ALL). Mercaptopurine has a narrow therapeutic index with treatment-related toxicities and resistance as major challenges. In addition to well-documented pharmacogenetic determinants, various other molecular mechanisms are known to influence 6-MP adherence. A predictive therapy response analysis encompassing all these molecular factors would help in accomplishing personalized 6-MP therapy goals to mitigate relapse and toxicity. We aim to study in vitro 6-MP cytotoxicity results in correlation with the erythrocyte 6-MP metabolite profile to predict survival in pediatric ALL. Peripheral blood samples were collected from 56 children with ALL and 10 healthy individuals. In vitro cytotoxicity was performed on patient-derived peripheral blood mononuclear cells (PBMCs) (n=30) using the WST-1 assay. Erythrocyte methyl-mercaptopurine (MMP) and thioguanine (TG) levels were measured using UPLC-MS/MS. Thiopurine methyl transferase (TPMT) pharmacogenetic variants (rs1800460, rs1800462, and rs1142345) were analyzed using TaqMan probe-based genotyping assay. Subjects were stratified into sensitive, responders, and non-responder groups based on the cytotoxicity assay results. Non-responders showed higher erythrocyte MMP levels (P = 0.023), and the sensitive group had higher TG levels (P = 0.008). Non-responders had a diminished overall survival compared to sensitive and responder groups (P = 0.043). In vitro cytotoxicity assay on patient-derived PBMCs provides a plausible platform for predicting 6-MP therapy response and relapse/ death in children with ALL.
 
Date 2024-05-16T06:18:09Z
2024-05-16T06:18:09Z
2024-05
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://nopr.niscpr.res.in/handle/123456789/63901
https://doi.org/10.56042/ijbb.v61i6.9295
 
Language en
 
Publisher NIScPR-CSIR,India
 
Source IJBB Vol.61(06) [June 2024]