Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent.
Preclinical pharmacology of novel indolecarboxamide ML-970, an investigative anticancer agent.
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DOI：
10.1007/s00280-012-1851-9
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发表时间：
2012-06
影响因子：
3
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Rayburn E;Wang W;Li M;Zhang X;Xu H;Li H;Qin JJ;Jia L;Covey J;Lee M;Zhang R
ML-970（AS-I-145; NSC 716970）是一种吲哚甲酰胺，作为CC-1065和倍癌霉素的毒性较低的类似物合成，倍癌霉素是一种天然产物，可结合富含A-T的DNA小沟并使DNA烷基化。NCI 60筛选显示ML-970具有强效细胞毒活性，平均GI 50为34 nM。本研究的目的是确定这种新型抗癌药物的药理学特性。我们建立了该化合物的HPLC方法，检查了其稳定性、蛋白结合和S9酶代谢，并使用两种不同制剂在两种小鼠品系中进行了该化合物的药代动力学研究。ML-970在血浆中相对稳定，在小鼠血浆中于37°C孵育8小时后基本完整。该化合物与血浆蛋白广泛结合。ML-970仅被S9制备液中存在的酶代谢至最低程度，未通过尿液或粪便排泄。溶液制剂提供了更高的Cmax、AUC、F值和更大的生物利用度，尽管混悬液制剂导致Tmax较晚和T1/2略长。为了确定化合物的命运，我们完成了组织分布的深入研究;结果表明，该化合物经历了广泛的肝肠循环。从本研究中获得的结果将与该化合物的进一步开发相关，并可能解释该类似物与CC-1065相比具有较低的骨髓毒性。
ML-970 (AS-I-145; NSC 716970) is an indolecarboxamide synthesized as a less toxic analog of CC-1065 and duocarmycin, a natural product that binds the A-T-rich DNA minor groove and alkylates DNA. The NCI60 screening showed that ML-970 had potent cytotoxic activity, with an average GI50 of 34 nM. The aim of this study is to define the pharmacological properties of this novel anticancer agent. We established an HPLC method for the compound, examined its stability, protein binding, and metabolism by S9 enzymes, and conducted pharmacokinetic studies of the compound in two strains of mice using two different formulations. ML-970 was relatively stable in plasma, being largely intact after an 8-h incubation in mouse plasma at 37°C. The compound was extensively bound to plasma proteins. ML-970 was only minimally metabolized by the enzymes present in S9 preparation and was not appreciably excreted in the urine or feces. The solution formulation provided higher Cmax, AUC, F values, and greater bio-availability, although the suspension formulation resulted in a later Tmax and a slightly longer T1/2. To determine the fate of the compound, we accomplished in-depth studies of tissue distribution; the results indicated that the compound undergoes extensive enterohepatic circulation. The results obtained from this study will be relevant to the further development of the compound and may explain the lower myelotoxicity of this analog compared to CC-1065.
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影响因子：
5.7
作者：
Kiakos, Konstantinos;Sato, Atsushi;Hartley, John A.
通讯作者：
Hartley, John A.
影响因子：
4.5
作者：
Agrawal, S;Zhang, XS;Zhang, RW
通讯作者：
Zhang, RW
DOI：
10.1111/j.1440-1681.1995.tb01949.x
发表时间：
1995-11-01
影响因子：
2.9
作者：
PAXTON, JW
通讯作者：
PAXTON, JW
影响因子：
7.3
作者：
Sato, A;McNulty, LA;Lee, M
通讯作者：
Lee, M
影响因子：
2.7
作者：
MacMillan, Karen S.;Lajiness, James P.;Boger, Dale L.
通讯作者：
Boger, Dale L.