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Cancer Chemotherapy and Pharmacology

, Volume 27, Issue 5, pp 342–346 | Cite as

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

  • Lincoln L. H. Tsang
  • Charmaine P. Quarterman
  • Andreas Gescher
  • John A. Slack
Original Articles Triazenes, Imidazotetrazinone, Cytotoxicity, Metabolism

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.

Keywords

Lymphoma Liquid Chromatography Cancer Research Metabolic Activation Lymphoma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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

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Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Lincoln L. H. Tsang
    • 1
  • Charmaine P. Quarterman
    • 1
  • Andreas Gescher
    • 1
  • John A. Slack
    • 1
  1. 1.Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences InstituteAston UniversityBirminghamU.K.

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