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Bending the Curve Trial by Trial
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Nitrosoureas, triazenes, alkyl sulfonates, aziridines and related alkylatorsIn useSyntheticNeeds review

Temozolomide

Also known as Temodar, Temodal, CCRG 81045, M&B 39831, NSC 362856, methazolastone, malkazole

An oral imidazotetrazine prodrug that delivers a methyl group to DNA. Combined with radiotherapy it is established as first-line treatment for glioma, according to its inventors' 2023 review.

From discovery to approval

  1. 1980 · First described

    According to the inventors' 2023 review, research student Robert Stone made the first imidazotetrazines at Aston University, Birmingham, in 1979, and his laboratory book of 29 April 1980 records the first synthesis of temozolomide. A 1983 patent announced temozolomide and mitozolomide; the first paper, on mitozolomide, appeared in 1984.[1][2][3]

  2. 1987 · First use in people · 7 years after first description

    The inventors' 2023 review states that temozolomide was introduced into a phase 1 clinical trial in 1987; the trial was published in 1992. Its predecessor mitozolomide had entered clinical trials in 1983.[1]

  3. 1999-08-11 · FDA accelerated · 19 years after first description

    Adult patients with refractory anaplastic astrocytoma, i.e. patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine (NDA 21-029). The letter states approval under 21 CFR Subpart H (accelerated approval) with Phase 4 commitments under 21 CFR 314.510. The letter prints no date; 11 August 1999 is the original-approval action date shown by Drugs@FDA and openFDA.[4]

  4. 2005-03-15 · FDA converted · 25 years after first description

    Patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment (NDA 21-029/S-008). The letter says the NDA was approved under 21 CFR 314 Subpart H and that approval of the supplement fulfils the commitments made under 21 CFR 314.510; it does not use the word 'converted', which is the record type chosen on that basis.[5]

How it works

A prodrug converted in the body to a triazene (MTIC) and then to an alkyldiazonium ion that transfers a methyl group to DNA, especially the O6 position of guanine. Being monofunctional, it cannot cross-link DNA, unlike mitozolomide.[1]

Where it came from and why

The inventors write that no specific biological insight motivated the work, which came from an interest in the chemistry of nitrogen-rich molecules. The compounds later proved to be prodrugs of triazenes, related to the active metabolite of dacarbazine.

This account follows the 2023 review by Malcolm Stevens and Richard Wheelhouse, who worked on the drug themselves. They write that no specific biological insight motivated the synthesis of the ring system behind temozolomide; it grew from an interest in the chemistry of nitrogen-rich molecules [1]. The first examples were made in 1979 by research student Robert Stone at Aston University in Birmingham, and his laboratory book dated 29 April 1980 records the first synthesis of temozolomide [1].

The first compound studied in detail was mitozolomide, because of its spectacular activity in mouse tumour models, and it went into clinical trials in the United Kingdom in 1983 [1]. Phase 1 evaluation found severe, unpredictable and irreversible thrombocytopenia, and its sponsor, May & Baker, reluctantly abandoned further work on this structural type in 1985 [1].

Temozolomide was then selected from a box of assorted imidazotetrazines for further study. As a methylating agent it could not cross-link DNA, so a better safety profile was predicted [1]. It entered a phase 1 trial in 1987, and the results published in 1992 showed that a five-day schedule was well tolerated and that the oral dose was fully bioavailable [1]. Cancer Research Campaign UK licensed it to Schering-Plough in 1993, and it was marketed first in the United States in 1999 as Temodar [1].

Cancers

  • Glioblastoma

    The US Food and Drug Administration approved temozolomide in 2005 for newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. A randomised trial of 573 patients compared radiotherapy with and without temozolomide.[6]

  • Anaplastic astrocytoma

    A multicentre phase II trial at first relapse enrolled 162 patients in the intent-to-treat population; the FDA's 1999 approval covered refractory anaplastic astrocytoma.[7]

  • Recurrent glioblastoma

    A randomised phase II study compared temozolomide with procarbazine in 225 patients with glioblastoma at first relapse.[8]

  • Melanoma

    A randomised phase III trial of 305 patients compared temozolomide with dacarbazine; the phase I trial had recorded responses in melanoma (see the facts).[9]

  • Mycosis fungoides

    The phase I trial abstract reports a complete response lasting 7 months in one patient with mycosis fungoides. The inventors' 2023 review says two complete responses were seen in mycosis fungoides; the two accounts differ.[10]

Worth knowing

  • In the randomised trial of radiotherapy with or without temozolomide in 573 patients with newly diagnosed glioblastoma, median survival was 14.6 months with temozolomide and 12.1 months without (unadjusted hazard ratio 0.63; 95% CI 0.52 to 0.75; P < 0.001), and two-year survival was 26.5% and 10.4%.[6]
  • Among 206 assessable cases, the MGMT promoter was methylated in 45%; in those patients median survival was 21.7 months with temozolomide plus radiotherapy and 15.3 months with radiotherapy alone (P = 0.007).[11]
  • Mitozolomide, the first imidazotetrazine studied clinically, caused severe unpredictable and irreversible thrombocytopenia in phase 1, and its sponsor abandoned further work on this structural type in 1985.[1]
  • The phase I trial found that myelotoxicity was dose-limiting, recommended 150 mg per square metre orally for 5 days for the first course, and recorded responses in 4 of 23 patients with melanoma (2 complete, 2 partial; 17%).[10]
  • In the 2000 comparison with procarbazine in 225 patients with glioblastoma at first relapse, the 6-month progression-free survival rate was 21% with temozolomide and 8% with procarbazine (P = 0.008).[8]

On this site

References

  1. Stevens MFG, Wheelhouse RT. Antitumour imidazotetrazines: past, present… and future?. RSC Chem Biol. 2023;4(10):736-741. PubMedDOI
  2. Stevens MF, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, et al. Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent. J Med Chem. 1984;27(2):196-201. PubMedDOI
  3. Tsang LL, Quarterman CP, Gescher A, Slack JA. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother Pharmacol. 1991;27(5):342-6. PubMedDOI
  4. US Food and Drug Administration, Center for Drug Evaluation and Research. Approval letter, NDA 21-029, Temodar (temozolomide) capsules, Schering Corporation; signed by Robert Temple, Director, Office of Drug Evaluation I. The letter states that approval is effective on the date of the letter and prints no date; the Drugs@FDA overview and openFDA list the original-approval action date as 11 August 1999. Source
  5. US Food and Drug Administration, Center for Drug Evaluation and Research. Approval letter, NDA 21-029/S-008, Temodar (temozolomide) capsules, Schering Corporation; electronic signature of Richard Pazdur dated 3/15/05. Source
  6. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96. PubMedDOI
  7. Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999;17(9):2762-71. PubMedDOI
  8. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000;83(5):588-93. PubMedDOI
  9. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158-66. PubMedDOI
  10. Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer. 1992;65(2):287-91. PubMedDOI
  11. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. PubMedDOI