Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. 1999 Nov; 81(6): 1022–1030.
PMCID: PMC2362937

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies


Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100–250 mg m−2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m−2 day−1. Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax ~1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m−2 day−1 for 5 days, every 28 days, is recommended for phase II studies. © 1999 Cancer Research Campaign

Keywords: oral, cytotoxic, chemotherapy, pharmacokinetics, dose escalation

Full Text

The Full Text of this article is available as a PDF (95K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bleehen NM, Newlands ES, Lee SM, Thatcher N, Selby P, Calvert AH, Rustin GJ, Brampton M, Stevens MF. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol. 1995 Apr;13(4):910–913. [PubMed]
  • Bower M, Newlands ES, Bleehen NM, Brada M, Begent RJ, Calvert H, Colquhoun I, Lewis P, Brampton MH. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol. 1997;40(6):484–488. [PubMed]
  • Catapano CV, Broggini M, Erba E, Ponti M, Mariani L, Citti L, D'Incalci M. In vitro and in vivo methazolastone-induced DNA damage and repair in L-1210 leukemia sensitive and resistant to chloroethylnitrosoureas. Cancer Res. 1987 Sep 15;47(18):4884–4889. [PubMed]
  • D'Atri S, Piccioni D, Castellano A, Tuorto V, Franchi A, Lu K, Christiansen N, Frankel S, Rustum YM, Papa G, et al. Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: studies with blasts of leukaemic patients. Ann Oncol. 1995 Apr;6(4):389–393. [PubMed]
  • Denny BJ, Wheelhouse RT, Stevens MF, Tsang LL, Slack JA. NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry. 1994 Aug 9;33(31):9045–9051. [PubMed]
  • Dhodapkar M, Rubin J, Reid JM, Burch PA, Pitot HC, Buckner JC, Ames MM, Suman VJ. Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Clin Cancer Res. 1997 Jul;3(7):1093–1100. [PubMed]
  • Friedman HS, Dolan ME, Pegg AE, Marcelli S, Keir S, Catino JJ, Bigner DD, Schold SC., Jr Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res. 1995 Jul 1;55(13):2853–2857. [PubMed]
  • Kim HK, Lin CC, Parker D, Veals J, Lim J, Likhari P, Statkevich P, Marco A, Nomeir AA. High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma. J Chromatogr B Biomed Sci Appl. 1997 Dec 5;703(1-2):225–233. [PubMed]
  • Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH, et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer. 1992 Feb;65(2):287–291. [PMC free article] [PubMed]
  • Newlands ES, O'Reilly SM, Glaser MG, Bower M, Evans H, Brock C, Brampton MH, Colquhoun I, Lewis P, Rice-Edwards JM, et al. The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer. 1996 Dec;32A(13):2236–2241. [PubMed]
  • O'Reilly SM, Newlands ES, Glaser MG, Brampton M, Rice-Edwards JM, Illingworth RD, Richards PG, Kennard C, Colquhoun IR, Lewis P, et al. Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer. 1993;29A(7):940–942. [PubMed]
  • Plowman J, Waud WR, Koutsoukos AD, Rubinstein LV, Moore TD, Grever MR. Preclinical antitumor activity of temozolomide in mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 1994 Jul 15;54(14):3793–3799. [PubMed]
  • Shen F, Decosterd LA, Gander M, Leyvraz S, Biollax J, Lejeune F. Determination of temozolomide in human plasma and urine by high-performance liquid chromatography after solid-phase extraction. J Chromatogr B Biomed Appl. 1995 May 19;667(2):291–300. [PubMed]
  • Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res. 1987 Nov 15;47(22):5846–5852. [PubMed]
  • Tsang LL, Farmer PB, Gescher A, Slack JA. Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemother Pharmacol. 1990;26(6):429–436. [PubMed]
  • Wedge SR, Porteous JK, Newlands ES. 3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. Br J Cancer. 1996 Oct;74(7):1030–1036. [PMC free article] [PubMed]
  • Wedge SR, Porteous JK, Newlands ES. Effect of single and multiple administration of an O6-benzylguanine/temozolomide combination: an evaluation in a human melanoma xenograft model. Cancer Chemother Pharmacol. 1997;40(3):266–272. [PubMed]
  • Wedge SR, Porteous JK, Glaser MG, Marcus K, Newlands ES. In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs. 1997 Jan;8(1):92–97. [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...