Methylazoxyprocarbazine, the active metabolite responsible for the anticancer activity of procarbazine against L1210 leukemia.
Methylazoxyprocarbazine, the active metabolite responsible for the anticancer activity of procarbazine against L1210 leukemia.
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发表时间：
1989-05
期刊：
影响因子：
11.2
通讯作者：
D. S. Swaffar;Michael G. Horstman;John-Van Jaw;B. Thrall;Gary G Meadows;W. Graydon Harker;Garold S. Yost;J-Y J T-J-Y-J-T-2253625702
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作者：
D. S. Swaffar;Michael G. Horstman;John-Van Jaw;B. Thrall;Gary G Meadows;W. Graydon Harker;Garold S. Yost;J-Y J T-J-Y-J-T-2253625702
丙卡巴嗪是一种 1,2-二取代肼衍生物，用于治疗人类白血病。丙卡巴肼的抗癌活性源自活性中间体的生物活化。它首先被氧化为偶氮丙卡巴肼，并进一步被N-氧化为甲基偶氮氧基丙卡巴肼和苄偶氮氧基丙卡巴肼异构体的混合物。在本研究中，合成并纯化了氧化偶氮丙卡巴嗪异构体。然后使用 3-(4,5-二甲基-噻唑-2-基)-2,5-二苯基-四唑溴化物进行比色测定，在体外评估代谢物对 L1210 鼠白血病细胞系的细胞毒性作用。这项研究的结果表明，甲基偶氮氧基丙卡巴肼异构体是最具细胞毒性的代谢物（IC50，0.2 mM）。苄偶氮氧基异构体具有不显着的细胞毒性作用，两种异构体的混合物具有中等效力。然而，该测定法不能用于确定丙卡巴肼的细胞毒性，因为药物本身（而不是活细胞）会还原染料。软琼脂克隆实验表明，丙卡巴肼仅在浓度（IC50，1.5 mM）高于甲基偶氮氧基丙卡巴肼（IC50，0.15 mM）时才具有细胞毒性。测定了丙卡巴肼及其代谢物对 L1210 荷瘤小鼠存活的影响，甲基偶氮氧基丙卡巴肼再次成为最有效的化合物。这些研究表明，甲基偶氮氧基丙卡巴肼代谢物可能是丙卡巴肼抗癌作用机制中涉及的主要细胞毒性中间体。
Procarbazine is a 1,2-disubstituted hydrazine derivative that is used to treat human leukemias. The anticancer activity of procarbazine results from bioactivation to reactive intermediates. It is first oxidized to azoprocarbazine and further N-oxidized to a mixture of methylazoxyprocarbazine and benzylazoxyprocarbazine isomers. In this study the azoxyprocarbazine isomers were synthesized and purified. The cytotoxic effect of the metabolites on the L1210 murine leukemia cell line were then evaluated in vitro by use of a colorimetric assay using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide. The results of this study showed that the methylazoxyprocarbazine isomer was the most cytotoxic metabolite (IC50, 0.2 mM). The benzylazoxy isomer had an insignificant cytotoxic effect, and a mixture of the two isomers was intermediate in effectiveness. This assay, however, could not be used to determine the cytotoxicity of procarbazine since the drug itself (not the live cells) reduced the dye. A soft-agar clonogenic assay demonstrated that procarbazine was cytotoxic only at higher concentrations (IC50, 1.5 mM) than methylazoxyprocarbazine (IC50, 0.15 mM). The effect of procarbazine and its metabolites on the survival of L1210 tumor-bearing mice was determined, and methylazoxyprocarbazine was again the most effective compound. These studies demonstrate that the methylazoxyprocarbazine metabolite is probably the major cytotoxic intermediate involved in the mechanism of anticancer action of procarbazine.