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Bending the Curve Trial by Trial
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AntifolatesUsed in a few countriesRational designNeeds review

Raltitrexed

Also known as Tomudex, ZD1694, ICI D1694

A thymidylate synthase inhibitor developed for advanced colorectal cancer. No US approval record was found; the UK label (revised March 2024) lists palliative treatment where fluorouracil and folinic acid regimens are not tolerated or inappropriate.

From discovery to approval

  1. 1991 · First described

    A 1991 Cancer Research paper described ICI D1694, a water-soluble folate-based thymidylate synthase inhibitor designed as a less toxic, more potent analogue of the earlier compound N10-propargyl-5,8-dideazafolic acid. A 1995 abstract gives the same chemical name for ZD1694, which a 1997 review gives as the former name of raltitrexed.[2][3][4][5]

  2. No approval is recorded on this site.

How it works

A folate analogue that directly and specifically inhibits thymidylate synthase, the enzyme needed to make the thymidine nucleotide used in DNA synthesis. It enters cells through the reduced folate carrier and is retained as polyglutamate forms.[1]

Where it came from and why

A 1997 review says raltitrexed was rationally designed to inhibit one molecular target, thymidylate synthase, in a disease that had gone over 40 years without a new drug, and notes a convenient dosing schedule.

Cancers

  • Advanced colorectal cancer

    A randomised phase III study of 439 previously untreated patients compared raltitrexed 3.0 mg/m2 every 3 weeks with fluorouracil plus leucovorin and found no statistically significant difference in time to progression or survival.[6]

  • Adjuvant stage III colon cancer

    In the PETACC-1 trial of 1,921 randomised patients, raltitrexed failed to show non-inferiority to fluorouracil plus leucovorin and the trial closed early.[7]

Worth knowing

  • The UK summary of product characteristics (revised March 2024) lists palliative treatment of advanced colorectal cancer where 5-fluorouracil and folinic acid based regimens are either not tolerated or inappropriate, and gives 25 June 2000 as the date of first authorisation.[1]
  • A 1997 review reports a response rate of 26% and median survival of 11.2 months in a phase II study of 177 patients with advanced colorectal cancer at 3 mg/m2.[5]
  • PETACC-1 closed prematurely when 17 raltitrexed-related deaths (1.9%) were reported; in the 993 eligible patients who started and completed the allocated treatment, the relapse-free survival hazard ratio was 1.16 (90% CI 0.99 to 1.37).[7]
  • A 1995 report says ZD1694 (Tomudex) entered phase III studies in November 1993; the first randomised analysis showed response in 19.8% of patients on Tomudex and 12.7% on fluorouracil plus leucovorin (P = 0.059), with shorter hospital time, less mucositis and leucopenia, and a higher incidence of reversible grade 3 or 4 transaminase increases.[6]

References

  1. Hospira UK Ltd. Tomudex 2 mg powder for solution for infusion: summary of product characteristics (date of revision of the text 03/2024; date of first authorisation 25 June 2000). electronic Medicines Compendium, product 5500. Read 26 October 2026. Source
  2. Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, et al. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res. 1991;51(20):5579-86. PubMed
  3. Freemantle SJ, Jackman AL, Kelland LR, Calvert AH, Lunec J. Molecular characterisation of two cell lines selected for resistance to the folate-based thymidylate synthase inhibitor, ZD1694. Br J Cancer. 1995;71(5):925-30. PubMedDOI
  4. Jackman AL, Farrugia DC, Gibson W, Kimbell R, Harrap KR, Stephens TC, et al. ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer. Eur J Cancer. 1995;31A(7-8):1277-82. PubMedDOI
  5. Judson IR. 'Tomudex' (raltitrexed) development: preclinical, phase I and II studies. Anticancer Drugs. 1997;8 Suppl 2:S5-9. PubMedDOI
  6. Cunningham D, Zalcberg JR, Rath U, Olver I, Van Cutsem E, Svensson C, et al. 'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group. Eur J Cancer. 1995;31A(12):1945-54. PubMedDOI
  7. Popov I, Carrato A, Sobrero A, Vincent M, Kerr D, Labianca R, et al. Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1). Eur J Cancer. 2008;44(15):2204-11. PubMedDOI