Actinomycin D

Actinomycin D (dactinomycin) is a natural chromopeptide isolated from Streptomyces species, and has one heterocyclic chromophore and two cyclic pentapeptide lactone rings. [1] It is the first antibiotic showing anti-tumor activity, and has been implemented in the clinical practice for years to treat, such as testicular cancer, and choriocarcinoma.[2]

Actinomycin D intercalates into DNA to inhibit the transcription. It forms a very stable complex with DNA, preventing the unwinding of the DNA double-helix, so as to inhibit the DNA-dependent RNA polymerase activity. Actinomycin D is well implemented in mRNA stability assays to inhibit the synthesis of new mRNA, allowing the assessment of mRNA decay by measuring mRNA abundance following transcription inhibition. [3]

The in vitro experiment suggests that actinomycin D is an potent and effective agent to inhibit the proliferation of SMC by preventing cells from getting into S phase. The LD50 (260 lM) determined by measuring the remaining viable cells at various concentrations of actinomycin D was about five orders greater than that of IC50 (0.4 nM), which was calculated by measuring the percentage of cells in S phase following the treatment of actinomycin D. A dose-dependent inhibition by actinomycin D was found in PCNA, Raf and FAK. However, in contrast to those seen on PCNA, Raf and FAK expression, the phosphorylated Erk was significantly up-regulated by actinomycin D. An in vivo study using rat carotid artery as a model was conducted to evaluate if topically applied actinomycin D onto the arterial adventitia of the artery was effective in suppressing the formation of stenosis following a balloon angioplasty. Topical application of pluronic gel containing 80 nM and 80 μM actinomycin D to surround the adventitia of rat carotid arteries, the thickness of the neointima was significantly reduced (45% and 55%, respectively). [4]

Reference:
[1]. Farber S. Chemotherapy in the treatment of leukemia and Wilms' tumor. JAMA. 1966 Nov 21;198(8):826-36. PMID: 4288581.
[2]. Lewis J.L., Jr. Chemotherapy of gestational choriocarcinoma. Obstet. Gynecol. Surv. 1973;28:7478–7480. doi: 10.1097/00006254-197307000-00006.
[3]. Shyu A. B., Greenberg M. E. and Belasco J. G.(1989). The c-fos transcript is targeted for rapid decay by two distinct mRNA degradation pathways. Genes Dev 3(1): 60-72.
[4]. Wu, C. H., Pan, J. S., Chang, W. C., Hung, J. S., & Mao, S. J. T. (2005). The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury. Journal of Biomedical Science, 12(3), 503–512. doi:10.1007/s11373-005-6900-5.

阿克替诺霉素D（也称为达克替诺霉素）是一种从链霉菌属中分离出来的天然色胺肽,含有一个杂环色团和两个五元环戊肽内酯环。它是第一种显示抗肿瘤活性的抗生素,并已经在临床实践中使用多年,用于治疗睾丸癌和绒毛膜癌等疾病。

阿克替诺霉素D插入到DNA中,抑制转录。它与DNA形成非常稳定的复合物,防止DNA双螺旋解开,从而抑制依赖于DNA的RNA聚合酶活性。阿克替诺霉素D在mRNA稳定性测定中得到了很好的应用,以抑制新mRNA的合成,并通过测量转录抑制后mRNA丰度来评估mRNA降解。[3]

实验室内的实验表明,阿克替霉素D是一种有效的药物,可以通过阻止细胞进入S期来抑制平滑肌细胞的增殖。通过测量不同剂量下剩余存活细胞数量确定的LD50（260微摩尔）比IC50（0.4纳摩尔）,即使用阿克替霉素D处理后处于S期的细胞百分比计算得出的值小五个数量级。在PCNA、Raf和FAK中发现了依赖剂量作用。然而,与PCNA、Raf和FAK表达相反,在接受阿克替霉素D处理后磷酸化Erk显著上调。使用大鼠颈动脉作为模型进行体内研究,评估局部应用阿克替霉素D是否能够有效地抑制气囊扩张术后瘢痕形成。将含有80纳摩尔和80微米阿克替霉素D的聚乙二醇凝胶局部涂抹于大鼠颈动脉周围组织中时,新生内膜厚度显着降低（分别为45%和55%）。[4]

参考文献：_x000D_[1]. Farber S. 化疗在治疗白血病和威尔姆斯肿瘤中的应用。JAMA. 1966年11月21日;198(8):826-36. PMID: 4288581._x000D_[2]. Lewis J.L., Jr. 妊娠性绒毛膜癌的化学治疗。Obstet.Gynecol.Surv.1973;28:7478–7480.doi：10.1097/00006254-197307000-00006。_x000D_[3]. Shyu A.B., Greenberg M.E.and Belasco J.G.(1989). c-fos转录本被两种不同的mRNA降解途径快速降解。Genes Dev 3(1):60-72。_x000D_[4]. Wu, C.H., Pan, J.S., Chang, W.C., Hung, J.S.& Mao,S.J.T.(2005).阿克替霉素D预防大鼠颈动脉球囊损伤后新内膜形成的分子机制。生物医学科学杂志,12（3）,503–512。doi：10.1007/s11373-005-6900-5。