Skip to main content
SpringerLink
Log in

Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide

  • Original Articles
  • Triazenes, Imidazotetrazinone, Cytotoxicity, Metabolism
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

The present study tested the hypothesis that the experimental antineoplastic imidazotetrazinone temozolomide degrades in the biophase to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) and exerts its cytotoxicity via this species. MTIC is a metabolite of the antimelanoma agent dacarbazine and is thought to be responsible for the antineoplastic activity of the latter. Cytotoxicity in vitro was investigated in TLX5 murine lymphoma cells. MTIC and temozolomide were cytotoxic in the absence of mouse-liver microsomes, whereas dacarbazine required metabolic activation. The generation of MTIC from either dacarbazine, its primary metabolite 5-[3-(hydroxymethyl)-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) or temozolomide was studied by reversedphase high-performance liquid chromatography in incubation mixtures under the conditions of the cytotoxicity assay. MTIC was found in incubations of temozolomide with or without microsomes. Dacarbazine yielded MTIC (and HMMTIC) only when microsomes were included in the incubation mixture. Although the mode of action of temozolomide seems to be similar to that of dacarbazine, the results obtained in this study show that these agents differ markedly in their ability to generate the active species MTIC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AUC:

area under the curve

HMMTIC:

5-[3-(hydroxymethyl)-3-methyl-triazen-1-yl]imidazole-4-carboxamide

HPLC:

highperformance liquid chromatography

MTIC:

3-methyl-(triazen-1-yl)imidazole-4-carboxamide

References

  1. Baig GU, Stevens MFG (1987) Antineoplastic imidazotetrazines: 12. Reaction of mitozolomide and its 3-alkyl congeners with oxygen, nitrogen, halogen and carbon nucleophiles. J Chem Soc Perkin Trans I 48: 3389

    Google Scholar 

  2. Bill CA, Gescher A, Hickman JA (1988) Effects ofN-methylformamide on the growth, cell cycle, and glutathione status of murine TLX5 lymphoma cells. Cancer Res 48: 3389

    Google Scholar 

  3. Boyle W (1968) An extension of the51Cr release assay for the estimation of mouse cytotoxins. Transplantation 6: 761

    Google Scholar 

  4. Connors TA, Goddard PM, Merai K, Ross WCJ, Wilman DEV (1976) Tumour inhibitory triazenes. Structural requrements for an active metabolite. Biochem Pharmacol 25: 241

    Google Scholar 

  5. Gescher A, Thradgill MD (1987) The metabolism of triazene antitumor drugs. Pharmacol Ther 32:191

    Google Scholar 

  6. Horspool KR, Quarterman CP, Slack JA, Gescher A, Stevens MFG, Lunt E (1989) Metabolism and murine pharmacokinetics of the 8-(N, N-dimethylcarboxamide) analogue of the experimental antitumor drug mitozolomide (NSC353451). Cancer Res 49: 5023

    Google Scholar 

  7. Kolar GF, Maurer M, Wildschütte M (1980) 5-(3-Hydroxymethyl)-3-methyl-triazeno-imidazole-4-carboxamide is a metabolite of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DIC, dacarbazine, NSC-45388). Cancer Lett 10:235

    Google Scholar 

  8. Rutty CJ (1983) The species-dependent pharmacokinetics of dacarbazine. Br J Cancer 48:140

    Google Scholar 

  9. Shealey YF, Struck RF, Holum LB, Montgomery JA (1961) Synthesis of potential antitumor agents: XXIX. 5-Diazoimidazole-4-carboxamide and 5-diazo-v-triazole-4-carboxamide. J Org Chem 26: 2396

    Google Scholar 

  10. Shealey YF, Krauth CA, Montgomery JA (1962) Imidazoles: I. Coupling reactions of diazoimidazole-4-carboxamide. J Org Chem 27:2150

    Google Scholar 

  11. Slack JA, Goddard C, Stevens MFG, Baig GU, Griffin MJ (1986) Analysis and murine pharmacokinetics of the new antitumour agent CCRG 81 045. J Pharm Pharmacol 38:63

    Google Scholar 

  12. Stevens MFG, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, Newton CG (1984) Antineoplastic imidazotetrazines: 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)-imidazo-[5,l-d]-1,2,3,5-tetrazin-4(3H)one-a novel broad spectrum antitumor agent. J Med Chem 27:196

    Google Scholar 

  13. Stevens MFG, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA, Newton C, Lunt E, Fizames C, Lavelle F (1987) Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5, l-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 47:5846

    Google Scholar 

  14. Tisdale MJ (1985) Induction of haemoglobin synthesis in the human leukaemia cell line K562 by monomethyl triazenes and imidazotetrazinones. Biochem Pharmacol 34:2077

    Google Scholar 

  15. Tsang LH, Farmer PB, Gescher A, Slack JA (1990) Characterisation of urinary metabolites of temozolomide in humans and mice and evaluation of their cytotoxicity. Cancer Chemother Pharmacol (in press)

  16. Vaughan K, Stevens MFG (1978) Monoalkyltriazenes. Chem Soc Rev 7:277

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, B4 7ET, Birmingham, U.K.

    Lincoln L. H. Tsang, Charmaine P. Quarterman, Andreas Gescher & John A. Slack

Authors
  1. Lincoln L. H. Tsang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charmaine P. Quarterman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Gescher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John A. Slack
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Part XXIII in the series: Antitumour imidazotetrazines (for part XXII, See Tsang et al. [15]

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsang, L.L.H., Quarterman, C.P., Gescher, A. et al. Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. Cancer Chemother. Pharmacol. 27, 342–346 (1991). https://doi.org/10.1007/BF00688855

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00688855

Keywords

Search

Navigation