Skip to content
Bending the Curve Trial by Trial
?

Purine analoguesIn useRational design

Mercaptopurine

Also known as 6-mercaptopurine, 6-MP, Purinethol

A purine analogue taken by mouth. Made and tested in a nucleic acid antagonist programme by 1951 and reported in leukaemia in 1953; its 2024 US label lists maintenance treatment of acute lymphoblastic leukaemia.

From discovery to approval

  1. c. 1951 · Earliest report found

    In Elion's 1988 Nobel lecture, 6-mercaptopurine and 6-thioguanine came from a screen of over 100 purines in Lactobacillus casei: replacing oxygen with sulfur at the 6-position of hypoxanthine and guanine gave inhibitors of purine use. She places this by 1951.[2][3][4][5]

  2. 1953-09-11 · FDA regular · 2 years after first description

    Mercaptopurine tablets (Purinethol), NDA 009053, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history. The original label and letter are not available there, so the indication at approval is not stated here. The type regular is an inference: no accelerated-approval wording was found. The 2024 label lists maintenance treatment of acute lymphoblastic leukaemia.[5]

How it works

Activated inside cells to metabolites including thioguanine nucleotides, whose incorporation into DNA or RNA causes cell-cycle arrest and cell death; they also inhibit de novo purine synthesis. The label says it is not known which effect is mainly responsible.[1]

Where it came from and why

Hitchings theorised that antagonists of the nucleic acid bases might stop rapidly dividing cells, such as bacteria, tumours and protozoa, and Elion was assigned to work on purines, pteridines and some other condensed pyrimidine systems. Tests at the Sloan-Kettering Institute found activity against a wide range of rodent tumours and leukaemias.

Gertrude Elion joined the Wellcome Research Laboratories in 1944 and recalls that Hitchings theorised that antagonists of the nucleic acid bases might stop rapidly dividing cells; her assignment was to work on purines, pteridines and some other condensed pyrimidine systems [2]. They relied mainly on the bacterium Lactobacillus casei to test compounds, and by 1951 they had made and tested over 100 purines [2]. Replacing oxygen with sulfur at the 6-position of guanine and hypoxanthine produced inhibitors of purine use [2].

Elion's account says 6-mercaptopurine and 6-thioguanine were tested at the Sloan-Kettering Institute and were active against a wide spectrum of rodent tumours and leukaemias, and that Burchenal then proceeded to a clinical trial in children with acute leukaemia [2]. His 1953 paper is titled a clinical evaluation of a new antimetabolite in the treatment of leukaemia and allied diseases [3].

She writes that the only drugs then available for these children were methotrexate and steroids, that median life expectancy was between 3 and 4 months, and that 6-mercaptopurine could produce complete remissions although most children later relapsed [2]. She adds that the FDA approved the drug for this use in 1953, a little more than two years after its synthesis and microbiological investigation [2]; the Drugs@FDA record gives 11 September 1953 for the original approval [5].

Cancers

  • Acute lymphoblastic leukaemia

    The 2024 US label lists maintenance treatment of adult and pediatric acute lymphoblastic leukaemia as part of a combination regimen; the 1953 clinical evaluation covered leukaemia and allied diseases (title only).[1]

  • Acute leukaemia in children

    According to Elion's 1988 account, the first clinical trial was in children with acute leukaemia.[2]

Worth knowing

  • Elion's Nobel lecture says the addition of 6-mercaptopurine to the antileukaemia drugs increased median survival in these children to 12 months, and that a few stayed in remission for years with 6-mercaptopurine and steroids.[2]
  • Elion cites Clarke's finding that mouse tumours treated with 6-mercaptopurine, although not completely regressed, could not be transplanted into other mice.[4]
  • A 1993 review reports that intravenous mercaptopurine, though still an investigative drug, had been used for 40 years and was being given extensively to children with previously untreated acute lymphoid leukaemia in frontline protocols.[6]
  • The Drugs@FDA history lists the original application (NDA 009053) as approved on 11 September 1953, classed as a new molecular entity with priority review; the original label is not available there.[5]
  • Elion also describes how azathioprine, a prodrug of 6-mercaptopurine, arose from attempts to protect the sulfur group, and how Schwartz and Dameshek studied 6-mercaptopurine's effect on the immune response in 1958.[2]

On this site

References

  1. U.S. Food and Drug Administration. Purinethol (mercaptopurine) tablets, prescribing information, NDA 009053 supplement 044 (action date 9 July 2024). Source
  2. Elion GB. The purine path to chemotherapy. Nobel Lecture, 8 December 1988. NobelPrize.org (lecture text, 22 pages). Source
  3. BURCHENAL JH, MURPHY ML, ELLISON RR, SYKES MP, TAN TC, LEONE LA, et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood. 1953;8(11):965-99. PubMedDOI
  4. CLARKE DA, PHILIPS FS, STERNBERG SS, STOCK CC, ELION GB, HITCHINGS GH. 6-Mercaptopurine: effects in mouse sarcoma 180 and in normal animals. Cancer Res. 1953;13(8):593-604. PubMed
  5. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 009053 (mercaptopurine; Purinethol). Page read 2026-10-26. Source
  6. Pinkel D. Intravenous mercaptopurine: life begins at 40. J Clin Oncol. 1993;11(9):1826-31. PubMedDOI