Thiopurines: Factors influencing toxicity and response

Thiopurines are the backbone of current anti-leukemia regimens and have also been effective immunosuppressive agents for the past half a century. Extensive research on their mechanism of action has been undertaken, yet many issues remain to be addressed to resolve unexplained cases of thiopurine toxicity or treatment failure. The aim of this review is to summarize current knowledge of the mechanism of thiopurine action in experimental models and put into context with clinical observations. Clear understanding of their metabolism will contribute to maximizing efficacy and minimizing toxicity by individually tailoring therapy according to the expression profile of relevant factors involved in thiopurine activation pathway.

Graphical abstractWhen inside the cell 6-TG is converted directly by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) through addition of ribose-5-phosphate to 6-thioguanosine-5′-monophosphate (TGMP), 6-MP is converted first to 6-thioinosine-5′-monophosphate (TIMP) by HGPRT then to 6-thioxanthine-5′-monophosphate (TXMP) by inosine monophosphate dehydrogenase (IMPDH) and finally to TGMP by guanosine monophosphate synthetase (GMPS). Both 6-MP and 6-TG and their respective monophosphates (TIMP and TGMP) are extensively inactivated inside the cell by thiopurine-S-methyltransferase (TPMT). Methylthioinosine monophosphate (meTIMP) is a strong inhibitor of DNPS. The remaining TGMP is converted to 6-thioguanosine-5′-diphosphate (TGDP), reduced to deoxy-6-thioguanosine-5′-diphosphate (dTGDP) by ribonucleotide reductase (RR) and phosphorylated by nucleoside diphosphate kinase (NDPK) to dTGTP, a DNA polymerase substrate.Figure optionsDownload full-size imageDownload as PowerPoint slide