ANTITUMOR IMIDAZOTETRAZINES .23. COMPARISON OF THE CYTOTOXICITY INVITRO OF TEMOZOLOMIDE AND DACARBAZINE, PRODRUGS OF 3-METHYL-(TRIAZEN-1-YL)IMIDAZOLE-4-CARBOXAMIDE
ANTITUMOR IMIDAZOTETRAZINES .23. COMPARISON OF THE CYTOTOXICITY INVITRO OF TEMOZOLOMIDE AND DACARBAZINE, PRODRUGS OF 3-METHYL-(TRIAZEN-1-YL)IMIDAZOLE-4-CARBOXAMIDE
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DOI：
10.1007/bf00688855
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发表时间：
1991-01-01
影响因子：
3
通讯作者：
SLACK, JA
中科院分区：
文献类型：
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作者：
TSANG, LLH;QUARTERMAN, CP;SLACK, JA
本研究验证了实验性抗肿瘤药物咪唑四氮酮替莫唑胺在生物相中降解为3-甲基-（三氮-1-基）咪唑-4-羧酰胺（MTIC）并通过该物种发挥其细胞毒性的假设。MTIC是抗黑色素瘤药物达卡巴嗪的代谢物，被认为是后者抗肿瘤活性的原因。研究了TLX5小鼠淋巴瘤细胞的体外细胞毒性。在缺乏小鼠肝微粒体的情况下，MTIC和替莫唑胺具有细胞毒性，而达卡巴嗪需要代谢激活。在细胞毒性实验条件下，用反相高效液相色谱法研究了达卡巴嗪及其主要代谢物5-[3-（羟甲基）-3-甲基-三氮杂-1-基]-咪唑-4-羧酰胺（HMMTIC）或替莫唑胺在培养混合物中生成MTIC的过程。在替莫唑胺有或没有微粒体的孵育中发现MTIC。达卡巴嗪只有在培养液中加入微粒体时才产生MTIC（和HMMTIC）。虽然替莫唑胺的作用方式似乎与达卡巴嗪相似，但本研究的结果表明，这些药物在产生活性物质MTIC的能力上存在显著差异。
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 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.