Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, Cancer Pharmacology Laboratory, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Cancer Chemother Pharmacol. 2012 Jun;69(6):1423-31. doi: 10.1007/s00280-012-1851-9. Epub 2012 Feb 25.
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 GI(50) 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 C(max), AUC, F values, and greater bioavailability, although the suspension formulation resulted in a later T(max) and a slightly longer T(1/2). 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.
ML-970（AS-I-145；NSC 716970）是一种吲哚甲酰胺，作为 CC-1065 和 duocarmycin 的毒性较低的类似物合成，duocarmycin 是一种结合 A-T 丰富的 DNA 小沟并使 DNA 烷基化的天然产物。NCI60 筛选表明，ML-970 具有很强的细胞毒性活性，平均 GI（50）为 34 nM。本研究的目的是定义这种新型抗癌剂的药理学特性。
我们建立了该化合物的 HPLC 方法，研究了其稳定性、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 37°C 下孵育 8 小时后，大部分仍保持完整。该化合物与血浆蛋白广泛结合。ML-970 仅被 S9 制剂中存在的酶轻微代谢，且尿液或粪便中未明显排泄。虽然混悬剂制剂导致 T（max）稍晚且 T（1/2）稍长，但溶液制剂提供了更高的 C（max）、AUC、F 值和更大的生物利用度。为了确定该化合物的命运，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肠肝循环。
本研究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 相比骨髓毒性较低的原因。
