Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Invest New Drugs. 2011 Oct;29(5):1102-10. doi: 10.1007/s10637-010-9473-8. Epub 2010 Jun 22.
We have examined the cellular action of SN 28049 (N-[2-(dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide), a DNA binding drug with curative activity against the Colon 38 transplantable murine carcinoma, on human tumour cells. Its action has been compared with that of two topoisomerase II-targetted drugs, etoposide and doxorubicin.
The NZM3 melanoma and HCT116 colon carcinoma cell lines, each expressing wild-type p53, were cultured and responses were compared by flow cytometry, electrophoresis, microscopy, and growth of tumour xenografts.
Responses of NZM3 cells to all three drugs, as measured by histone H2AX γ-phosphorylation, induction of the p53 pathway and cell cycle arrest, were comparable and typical of those of topoisomerase II poisons. Xenografts of NZM3 cells responded to SN 28049 with a tumour growth delay of 16 days. In contrast, HCT116 cells had an attenuated DNA damage response to the drugs and SN 28049 had no in vivo activity, consistent with low topoisomerase II activity. However, SN 28049 inhibited HCT116 cell growth in vitro and activated the p53 pathway to induce a state with G(2)/M-phase DNA content, low mitotic index and a high proportion of binucleate cells. Treated cells expressed cyclin E and the senescence marker β-galactosidase but showed low expression of cyclin B and survivin. In comparison, etoposide caused little p53 expression or cycle arrest, and doxorubicin had an intermediate effect.
The action of SN 28049 in NZM3 cells is typical of a topoisomerase II poison, but the low topoisomerase IIα activity of HCT116 cells allowed the detection of a second antiproliferative action of SN 28049 in which cells undergo post-mitotic cycle arrest and induction of p53.
我们研究了 SN 28049（N-[2-（二甲氨基）乙基]-2,6-二甲基-1-氧代-1,2-二氢苯并[b]-1,6-萘啶-4-甲酰胺）的细胞作用，这是一种对结肠 38 可移植鼠癌具有治疗活性的 DNA 结合药物，对人类肿瘤细胞进行了研究。将其作用与两种拓扑异构酶 II 靶向药物依托泊苷和阿霉素进行了比较。
培养 NZM3 黑色素瘤和 HCT116 结肠癌细胞系，每个细胞均表达野生型 p53，并通过流式细胞术、电泳、显微镜和肿瘤异种移植的生长来比较反应。
NZM3 细胞对所有三种药物的反应，如组蛋白 H2AX γ-磷酸化、p53 通路的诱导和细胞周期阻滞的测量，都是可比的，并且与拓扑异构酶 II 毒物的反应典型。NZM3 细胞的异种移植物对 SN 28049 的肿瘤生长延迟了 16 天。相比之下，HCT116 细胞对药物的 DNA 损伤反应减弱，SN 28049 没有体内活性，这与低拓扑异构酶 II 活性一致。然而，SN 28049 抑制了体外 HCT116 细胞的生长，并激活了 p53 通路，诱导 G（2）/M 期 DNA 含量、低有丝分裂指数和高双核细胞比例的状态。处理后的细胞表达细胞周期蛋白 E 和衰老标志物β-半乳糖苷酶，但细胞周期蛋白 B 和生存素的表达水平较低。相比之下，依托泊苷引起的 p53 表达或细胞周期阻滞很少，阿霉素的作用介于两者之间。
SN 28049 在 NZM3 细胞中的作用是典型的拓扑异构酶 II 毒物，但 HCT116 细胞的低拓扑异构酶 IIα活性允许检测到 SN 28049 的第二种抗增殖作用，其中细胞经历有丝分裂后细胞周期阻滞和 p53 的诱导。
