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

Abstract

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-carboxamid e (HMMTIC) or temozolomide was studied by reversed-phase 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.

Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors

“…Both 3AB (5 mM) and NU1025 (300 J.M) increased net levels of DNA strand breaks over the entire time period. The time interval during which DNA strand break levels were highest (approximately 2-4 h) correlated with the reported timing of the peak levels of MTIC obtained in culture medium following addition of TM (Tsang et al, 1991 (10-50I1M) required to potentiate TM cytotoxicity compared with the concentrations of the compounds alone required to exert cytotoxic effects (> 1 mM). In comparison, considerable overlap is evident in the concentrations of 3AB and BZ required to exert these two effects.…”

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

“…7 Whereas dacarbazine must be activated by the cytochrome P-450 system in the liver, temozolomide is metabolized to its active form by a nonenzymatic pathway in the blood. 8,9 Thus, we speculate that the response to treatment would be better with temozolomide, compared with dacarbazine, because of elimination of the variable introduced by cytochrome P-450 activation necessary for dacarbazine activity. Further, we hypothesize that the toxicity of dacarbazine is influenced by pharmacogenomic factors introduced by variations in cytochrome P-450 activity among individuals and that toxicity would thus be minimized by use of temozolomide.…”

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules

“…Temozolomide (Temodar, SCH52365, NSC362856), an oral imidazotetrazinone methylating agent, undergoes spontaneous conversion in plasma to its active methylating species, 3-methyl-(triazen-1yl)imidazole-4-carboxamide (MTIC) (Hickman et al, 1985;Stevens et al, 1987;Tsang et al, 1990Tsang et al, , 1991. In both preclinical and clinical investigations, temozolomide has demonstrated markedly schedule-dependent anticancer activity, with more frequent treatment schedules generally producing greater cytotoxicity than less frequent schedules (Stevens et al, 1987).…”