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Review
. 2019 Jun 19;2(2):256-270.
doi: 10.20517/cdr.2019.004. eCollection 2019.

Pharmacogenetics of thiopurines

Raffaella Franca  1 , Giulia Zudeh  2   3 , Sofia Pagarin  4 , Marco Rabusin  4 , Marianna Lucafò  4   5 , Gabriele Stocco  3 , Giuliana Decorti  1   4
Affiliations
Review

Pharmacogenetics of thiopurines

Raffaella Franca et al. Cancer Drug Resist. .

Abstract

Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes. Nevertheless, daily oral thiopurines remain the backbone maintenance or continuation therapy. Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available. Other genes of interest, such as ITPA and PACSIN2, have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols. In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.

Keywords: NUDT15; PACSIN2; Thiopurines; acute lymphoblastic leukemia; inosine triphosphate pyrophosphatase; pharmacogenetics clinical implementation; therapy personalization; thiopurine methyltransferase.

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Conflict of interest statement

All authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Thiopurines chemical structure. A: thioguanine; B: mercaptopurine; C: azathioprine
Figure 2
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
See this image and copyright information in PMC

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