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Page 258 Franca et al. Cancer Drug Resist 2019;2:256-70 I http://dx.doi.org/10.20517/cdr.2019.004

Figure 2. Thiopurine pathway. MP: mercaptopurine; MMP: methyl-mercaptopurine; TIMP: thioinosine monophosphate; Me-TIMP:
methyl-thioinosine monophosphate; TGDP: thioguanine diphosphate; TGMP: thioguanine monophosphate; TGTP: thioguanine
triphosphate; TITP: thioinosinetriphosphate; Me-TITP: methylthioinosinetriphosphate; TGN: thioguanine nucleotide; TU acid: thiouric
acid; TXMP: thioxantine monophosphate; AZA: azathioprine; IMPDH: Inosine-5′-monophosphate dehydrogenase; ITPA: inosine
triphosphate pyrophosphatase; GMPS: GMP synthase; GST: glutathione-transferase; NUDT15: nucleotide triphosphate diphosphatase
gene; PACSIN2: Protein kinase C and casein kinase substrate in neurons protein 2; TPMT: thiopurine methyltransferase; XO: xanthine
oxidase. Hatched arrow indicates the infleunce of PACSIN2 on TPMT gene expression and TPMT activity

[9]
to avoid excessive toxicity . Thiopurine active metabolites persist in the blood for a long time in contrast to
MP plasma concentration that rapidly declines after oral administration (MP serum peak is achieved within
2 h, half-life ranges from 20 to 120 min according to patients age and drug formulation): TGN are detected
in RBC by the 3rd day of treatment and reach the steady state around the 3rd week; in IBD patients, clinical
response to thiopurines is further delayed and appears between weeks 8 and 17 of therapy making these
[10]
drugs unsuitable to achieve early disease remission but useful in long-term maintenance treatments . TGN