The Thiopurine Tale: An Unexpected Journey

Abstract

Exactly 70 years ago mercaptopurine (1951) was discovered by Gertrude Elion as a novel treatment option for acute leukemia. A total of three thiopurines (also thioguanine (1950) and azathioprine (1957)) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For the discovery of thiopurines and other antimetabolite drugs she was rewarded in 1988, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Till today thiopurine (based) therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

Drug rediscovery in gastroenterology: from off-label to on-label use of thioguanine in inflammatory bowel disease

“…The thiopurine derivatives (AZA, MP and TG) were developed by Gertrude Elion and George Hitchings in the 1950s primarily as antiproliferative agents for therapy of neoplastic diseases such as leukaemia 31. Subsequently, it was demonstrated that the drug metabolism of these agents was complex, involving multiple enzymes 32–34.…”

Therapeutic Drug Monitoring for IBD Children on Thioguanine

“…We were interested to read the recent JPN report titled “Safety of Thioguanine in Pediatric Inflammatory Bowel Disease: A Multi‐Center Case Series” by the Working Group for Collaborative Paediatric IBD Research in the Netherlands on the efficacy and safety of thioguanine in children (1). Thioguanine is formally licensed for use in adult inflammatory bowel disease (IBD) patients in Netherlands (2).…”

6-Thioguanosine Monophosphate Prodrugs Display Enhanced Performance against Thiopurine-Resistant Leukemia and Breast Cancer Cells

“…Since their development in the 1950s, thiopurines have a history as anticancer and immunosuppressant drugs. , 6-Mercaptopurine (6-MP), its derivative azathioprine (AZA), and 6-thioguanine (6-TG) have remained in broad use for the treatment of acute lymphoblastic leukemia in children and for inflammatory diseases, such as inflammatory bowel disease (IBD). , Although thiopurine therapy is often linked to toxicity and poor response, clinical guidelines are supportive of its use for maintenance therapy. , Thiopurines are precursors of the actual bioactive compounds (“prodrugs”) and must be converted by enzymes of the purine salvage pathway to the metabolically active thioguanine nucleotides (TGN). Whereas several enzymatic steps are involved in the case of 6-MP and AZA, 6-TG activation requires only the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) that catalyzes its conversion to 6-thioguanosine monophosphate (6-TGMP) (Figure ).…”

“…Since their development in the 1950s, thiopurines have a history as anticancer and immunosuppressant drugs. 1 , 2 6-Mercaptopurine (6-MP), its derivative azathioprine (AZA), and 6-thioguanine (6-TG) have remained in broad use for the treatment of acute lymphoblastic leukemia in children and for inflammatory diseases, such as inflammatory bowel disease (IBD). 3 , 4 Although thiopurine therapy is often linked to toxicity and poor response, clinical guidelines are supportive of its use for maintenance therapy.…”