Pharmacokinetics and antitumor properties in tumor-bearing mice of an enediol analogue inhibitor of glyoxalase I.
Pharmacokinetics and antitumor properties in tumor-bearing mice of an enediol analogue inhibitor of glyoxalase I.
复制标题
乙二醛酶 I 烯二醇类似物抑制剂在荷瘤小鼠中的药代动力学和抗肿瘤特性。
DOI：
10.1007/s002800000130
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Eiseman,JL
中科院分区：
文献类型：
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作者：
Sharkey,EM;O'Neill,HB;Kavarana,MJ;Wang,H;Creighton,DJ;Sentz,DL;Eiseman,JL
目的：恩替卡韦类似物S-（N-对氯苯基-N-羟基氨基甲酰基）谷胱甘肽（CHG）是一种强效的、基于机制的竞争性甲基谷胱甘肽解毒酶谷胱甘肽酶I抑制剂。该化合物的[甘氨酰，谷氨酰]二乙酯前药形式（CHG（Et）2）在体外抑制不同肿瘤细胞系的生长，显然是通过诱导细胞内甲基乙二醛水平升高。本研究的目的是评价CHG（Et）2在血浆酯酶缺陷的C57 BL/6（Es-1 e）小鼠中静脉注射（i. v.）或腹膜内（i. p.）在一些实施方案中，施用推注剂量的CHG（Et）2。此外，还评估了CHG（Et）2在这些小鼠中针对小鼠B16黑色素瘤的体内抗肿瘤特性，以及在血浆酯酶缺陷裸小鼠中针对雄激素非依赖性人前列腺PC 3肿瘤和人结肠HT-29腺癌的体内抗肿瘤特性。方法：在以120 mg/kg的最大耐受剂量对两种肿瘤-游离雄性和雌性小鼠以及携带皮下B16肿瘤的雄性和雌性小鼠。通过反相C18高效液相色谱法测定脱蛋白组织样品中CHG（Et）2、CHG和[甘氨酰]单乙酯CHG（Et）的组织浓度随时间的变化。CHG（Et）2以80或120 mg/kg每周静脉推注5 d，持续2周，或使用Alzet微型渗透泵连续输注14 d后，评价CHG（Et）2对荷瘤小鼠的疗效。结果：CHG（Et）2静脉给药后，荷瘤小鼠血浆中CHG（Et）2迅速出现，峰值为40-60 μM，随后呈一级递减，半衰期约为10 min。在B16肿瘤中抑制性CHG的浓度相应增加，在15 min时出现最大浓度，范围为30-60 μ M，120 min后降至约6 μ M的平台值。无瘤雌性小鼠腹腔注射CHG（Et）2后，血浆中未检测到CHG（Et）2及其水解产物。从疗效研究，给药方案被确定，导致抗肿瘤效果与观察到的标准抗肿瘤药物阿霉素（B16肿瘤），顺铂（与PC 3肿瘤），长春新碱（与HT-29肿瘤）。结论：这是第一次证明，一个机制为基础的竞争性抑制剂的glycoprotease I有效地抑制小鼠实体瘤的生长时，提供的二乙基酯前药。
Purpose: The enediol analogueS-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG) is a powerful, mechanism-based, competitive inhibitor of the methylglyoxal-detoxifying enzyme glyoxalase I. The [glycyl,glutamyl]diethyl ester prodrug form of this compound (CHG(Et)2) inhibits the growth of different tumor cell lines in vitro, apparently by inducing elevated levels of intracellular methylglyoxal. The purpose of this study was to evaluate the pharmacokinetic properties of CHG(Et)2in plasma esterase-deficient C57BL/6 (Es-1e) mice after intravenous (i.v.) or intraperitoneal (i.p.) administration of bolus doses of CHG(Et)2. In addition, the in vivo antitumor properties of CHG(Et)2were evaluated against murine B16 melanoma in these mice, and against androgen-independent human prostate PC3 tumor and human colon HT-29 adenocarcinoma in plasma esterase-deficient nude mice.Methods: Pharmacokinetics were evaluated after either i.v. or i.p. administration of CHG(Et)2at the maximally tolerated dose of 120 mg/kg to both tumor-free male and female mice and male and female mice bearing subcutaneous B16 tumors. Tissue concentrations of CHG(Et)2, CHG and the [glycyl]monoethyl ester CHG(Et) were measured as a function of time by reverse-phase C18high-performance liquid chromatography of deproteinized tissue samples. The efficacy of CHG(Et)2in tumor-bearing mice was evaluated after i.v. bolus administration of CHG(Et)2at 80 or 120 mg/kg for 5 days each week for 2 weeks, or after 14 days continuous infusion of CHG(Et)2using Alzet mini-osmotic pumps. Hydroxypropyl-β-cyclodextrin was used as a vehicle in the efficacy studies.Results: Intravenous administration of CHG(Et)2resulted in the rapid appearance of CHG(Et)2in the plasma of tumor-bearing mice with a peak value of 40–60 μM, followed by a first-order decrease with a half-life of about 10 min. There was a corresponding increase in the concentration of inhibitory CHG in the B16 tumors, with a maximum concentration in the range 30–60 μMoccurring at 15 min, followed by a decrease to a plateau value of about 6 μMafter 120 min. Neither CHG(Et)2nor its hydrolysis products were detectable in plasma, after i.p. administration of CHG(Et)2to tumor-free female mice. From the efficacy studies, dosing schedules were identified that resulted in antitumor effects comparable to those observed with the standard antitumor agents Adriamycin (with B16 tumors), cisplatin (with PC3 tumors), and vincristine (with HT-29 tumors).Conclusion:This is the first demonstration that a mechanism-based competitive inhibitor of glyoxalase I effectively inhibits the growth of solid tumors in mice when delivered as the diethyl ester prodrug.