Assessment of Mercaptopurine (6MP) Metabolites and 6MP Metabolic Key-Enzymes in Childhood Acute Lymphoblastic Leukemia

Abstract

Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this pathway still remains unclear. This study attempted to determine which components of 6MP metabolism in leukemic blasts and red blood cells are important for 6MP's sensitivity and toxicity. In addition, changes in the enzymatic activities and metabolite levels during the treatment were analyzed. In a cohort (N=236) of pediatric ALL patients enrolled in the Dutch ALL-9 protocol, we studied the enzymes inosine-5'-monophosphate dehydrogenase (IMPDH), thiopurine S-methyltransferase (TPMT), hypoxanthine guanine phosphoribosyl transferase (HGPRT), and purine nucleoside phosphorylase (PNP) as well as thioguanine nucleotides (TGN) and methylthioinosine nucleotides (meTINs). Activities of selected enzymes and levels of 6MP derivatives were measured at various time points during the course of therapy. The data obtained and the toxicity related parameters available for these patients were correlated with each other. We found several interesting relations, including high concentrations of two active forms of 6MP--TGN and meTIN--showing a trend toward association with better in vitro antileukemic effect of 6MP. High concentrations of TGN and elevated activity of HGPRT were found to be significantly associated with grade III/IV leucopenia. However, a lot of data of enzymatic activities and metabolite concentrations as well as clinical toxicity were missing, thereby limiting the number of assessed relations. Therefore, although a complex study of 6MP metabolism in ALL patients is feasible, it warrants more robust and strict data collection in order to be able to draw more reliable conclusions.

Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis

“…In a pooled analysis of 22 reports [ 40 , 46 , 48 , 56 , 57 , 58 , 65 , 67 , 70 , 72 , 73 , 75 , 84 , 85 , 91 , 92 , 94 , 96 , 98 , 103 , 105 , 107 ], 6-TGN concentrations were significantly higher in patients with leukopenia (mean difference of 127.06 pmol/8 × 10 8 RBC (95% CI 70.88; 183.24; p < 0.01)). We could observe a considerable heterogeneity between studies ( p < 0.01; I 2 = 90%).…”

Acral Skin Rash Caused by Altered Mercaptopurine Metabolism in Maintenance Therapy for B-Cell Acute Lymphoblastic Leukemia

“…Furthermore, the timing of the rash resolution corresponded well with the addition of allopurinol and the improvement of the mercaptopurine metabolites. Symptoms occurring sometime after first exposure to 6-MP could be explained by the fact that skewed metabolism can be shown to be idiosyncratic, with manifestations occurring at any time during maintenance therapy 19,20. Other explanations of this could be that the duration of 6-MP exposure was longer during maintenance.…”

Red Blood cell IMPDH activity in adults and children with or without azathioprine: Relationship between thiopurine metabolites, ITPA and TPMT activities

“…Few studies have been reported on the influence of the activity of the IMPDH on the metabolism of thiopurine drugs, and none have been conducted on the activity of IMPDH in the erythrocytes in the context of autoimmune diseases. Although considered as the limiting enzyme in the formation of 6‐TGN, we did not find any association between RBC IMPDH activity and 6‐TGN, regardless of the population studied.…”