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AntifolatesObsoleteRational designNeeds review

Aminopterin

Also known as 4-aminopteroyl-glutamic acid

A folic acid antagonist first given to a child with acute leukaemia in December 1947. A 2012 account says methotrexate, which one review calls its methyl derivative, has comparable effectiveness with fewer adverse effects.

From discovery to approval

  1. 1947 · First described

    A 2022 commentary cites a 1947 paper by Seeger, Smith and Hultquist, 'Antagonist for pteroylglutamic acid' (title only), for the newly synthesised antifolate aminopterin. A 2012 account says Farber asked Yellapragada SubbaRow's team at American Cyanamid to develop antifolates, including aminopterin.[2][3][4][5][6]

  2. 1947 · First use in people

    A 2012 account says Farber's team began daily aminopterin on 16 December 1947 for an eight-year-old boy with acute leukaemia; the series of 16 children was reported in 1948.[2]

  3. No approval is recorded on this site.

How it works

In a 1998 laboratory comparison with other antifolate analogues, aminopterin was shown to inhibit dihydrofolate reductase, to be carried into cells by the reduced folate transport system and to be a substrate for folylpolyglutamate synthetase.[1]

Where it came from and why

Farber had given folic acid conjugates to patients with leukaemia and saw the disease accelerate, clinically and at autopsy. A 2012 account says he inferred that reducing folate might suppress malignant cells and restore normal bone marrow, and asked for antagonists of folic acid.

Sidney Farber and colleagues in Boston gave folic acid to 90 patients with late-stage cancers, including acute leukaemia; a 2012 account says folic acid accelerated the leukaemic process, with sudden mortality in all patients [2]. A 2022 commentary adds that the acceleration was seen both clinically and at autopsy [3]. Farber inferred that lowering folate might suppress malignant cells [2].

At his request, a team led by Yellapragada SubbaRow at the American Cyanamid Company developed folic acid antagonists, including aminopterin [2]. On 16 December 1947 Farber's team began daily aminopterin for an eight-year-old boy with acute leukaemia and a temperature of 106 degrees Fahrenheit; four months later he was reported in clinical and haematological remission [2].

The team went on to treat 16 critically ill children: 10 had remissions, 2 did not and 4 died within a few months, and the 1948 paper described five of the ten [2]. The remissions were temporary and came with serious toxicity, including mouth ulceration, internal bleeding and bone marrow depletion [2]. In a 1949 follow-up of about 60 children treated with aminopterin or related antifolates, more than half had important remissions, but Farber remained cautious and called for less toxic related compounds [2].

Cancers

  • Acute leukaemia in children

    Ten of 16 critically ill children had temporary remissions in Farber's 1948 series, according to a 2012 account.[2]

  • Refractory acute leukaemia in adults and children

    A phase II trial of weekly oral aminopterin in 46 patients with refractory acute leukaemia reported clinically significant responses in 6 of 22 children with acute lymphoblastic leukaemia.[7]

Family and partners

Drugs derived from it: Methotrexate, Pralatrexate

Worth knowing

  • Farber's folic acid experiment in patients with late-stage cancers accelerated leukaemia; a 2012 account says this led him to look for antagonists of folic acid.[2]
  • A 2022 commentary reports that 16 children were treated with aminopterin in Farber's 1948 series, that 10 entered transient remissions and that the longest complete remission off therapy was 47 days.[3]
  • A 2013 paper states that antifolates were the first class of antimetabolites to enter the clinic, with the introduction of aminopterin in 1947 and, shortly after, methotrexate.[6]
  • A 2005 phase II trial of weekly oral aminopterin concluded that it deserved further study as an alternative to methotrexate, citing more reliable bioavailability and greater cellular accumulation and metabolism.[7]
  • A 2012 account says methotrexate has comparable effectiveness but fewer adverse effects than aminopterin and remains a standard component of treatment of acute lymphoblastic leukaemia.[2]

On this site

References

  1. Sirotnak FM, DeGraw JI, Colwell WT, Piper JR. A new analogue of 10-deazaaminopterin with markedly enhanced curative effects against human tumor xenografts in mice. Cancer Chemother Pharmacol. 1998;42(4):313-8. PubMedDOI
  2. Spain PD, Kadan-Lottick N. Observations of unprecedented remissions following novel treatment for acute leukemia in children in 1948. J R Soc Med. 2012;105(4):177-81. PubMedDOI
  3. Izraeli S. The first achievement of complete remission in childhood leukemia by treatment with the folic acid antagonist aminopterin. Haematologica. 2022;107(4):782. PubMedDOI
  4. SEEGER DR, SMITH JM Jr, HULTQUIST ME. Antagonist for pteroylglutamic acid. J Am Chem Soc. 1947;69(10):2567. PubMedDOI
  5. Farber S, Diamond LK, Mercer RD, Sylvester RF Jr, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med. 1948;238(23):787-93. PubMedDOI
  6. Visentin M, Unal ES, Zhao R, Goldman ID. The membrane transport and polyglutamation of pralatrexate: a new-generation dihydrofolate reductase inhibitor. Cancer Chemother Pharmacol. 2013;72(3):597-606. PubMedDOI
  7. Cole PD, Drachtman RA, Smith AK, Cate S, Larson RA, Hawkins DS, et al. Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res. 2005;11(22):8089-96. PubMedDOI