The thiopurines: An update

Abstract

The thiopurine drugs, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) are commonly used cytotoxic agents. A derivative of 6-MP, azathioprine, is commonly used as an immunosuppressant. A prominent route for the metabolism of these agents is mediated by the enzyme thiopurine methyltransferase (TPMT). This enzyme exhibits considerable inter-individual variation in activity, partly due to the presence of common genetic polymorphisms, which influence cytotoxicity of the thiopurine drugs. Variations in the number of tandem repeats in the 5' promoter region have also been shown to influence TPMT expression in vitro. In this article, we review the impact of variations in TPMT activity on sensitivity to the thiopurine drugs in vitro and also in vivo in terms of their clinical efficacy and toxicity. A possible relationship between TPMT and secondary malignancies is also reviewed.

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

“…The use of thiopurine drugs such as azathioprine and 6-mercaptopurine has become quite common in the treatment of inflammatory bowel disease, transplantation and acute leukemias (3,8) . Despite their effectiveness, these drugs may cause drug-induced toxicity with risk of death by myelosuppression, even when used in standard doses (16,18) .…”

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O6- methylguanine-DNA methyltransferase (MGMT).

“…Thioguanosine monophosphate is further metabolised to thioguanosine di-and tri-phosphate, and subsequently incorporated into DNA and RNA. 2 …”

A role for ITPA variants in the clinical course of pulmonary Langerhans' cell histiocytosis?

“…Aberrant enzyme activity of either TPMT or ITPase gives rise to a broad spectrum of adverse drug reactions (ADR) associated with thiopurines, ranging from therapeutic failure to life-threatening leukopenia [3,4].…”