生物活性

• 描述Topoisomerase II (topo II) is an enzyme essential for chromosome segregation and DNA supercoiling homeostasis^[3]. Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA^[4]. In vitro, P-glycoprotein (Pgp)-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin^[4]. Amonafide produces protein-associated DNA cleavage, single-strand breaks (SSB) and DPC and DNA double-strand cleavage. Amonafide (400 nM-2.4 μM) reduces the colony-forming ability of the leukemic cell lines in a dose-dependent manner^[5]. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with drug resistance (MDR). Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of ∼ 40% in a recent Phase II trial in sAML^[4].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00273884	Acute Myeloid Leukemia	Phase 2	Completed	-	-
  NCT00074100	Breast Cancer	Phase 2	Completed	-	United States, New York ... more >> Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10021 Collapse <<
  NCT00087854	Prostate Cancer	Phase 1 Phase 2	Completed	-	United States, California ... more >> USC Norris Comprehensive Cancer Center Los Angeles, California, United States, 90033 United States, Maryland Cancer Center at John Hopkins Baltimore, Maryland, United States, 21231 United States, Missouri Barnard Cancer Center St.Louis, Missouri, United States, 63110 United States, New Jersey Cancer Institute of New Jersey New Brunswick, New Jersey, United States, 08901 United States, New York Herbert Irving Cancer Center New York, New York, United States, 10032-3789 United States, Ohio The Cleveland Clinic Cleveland, Ohio, United States, 44195 United States, Pennsylvania Fox Chase Cancer Center Philadelphia, Pennsylvania, United States, 19111-2497 United States, Washington Seattle Cancer Care Alliance Seattle, Washington, United States, 98109 Collapse <<

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• 参考文献

• [1] Hsiang YH, Jiang JB, et al. Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs. Mol Pharmacol. 1989 Sep;36(3):371-6.

  [2] Andersson BS, Beran M, et al. In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC308847) in human leukemia. Cancer Res. 1987 Feb 15;47(4):1040-4.

  [3] Lee JH, Wendorff TJ, Berger JM. Resveratrol: A novel type of topoisomerase II inhibitor. J Biol Chem. 2017 Dec 22;292(51):21011-21022. doi: 10.1074/jbc.M117.810580. Epub 2017 Oct 26. PMID: 29074616; PMCID: PMC5743075.

  [4] Allen SL, Lundberg AS. Amonafide: a potential role in treating acute myeloid leukemia. Expert Opin Investig Drugs. 2011 Jul;20(7):995-1003. doi: 10.1517/13543784.2011.585756. Epub 2011 May 19. PMID: 21591994.

  [5] Andersson BS, Beran M, Bakic M, Silberman LE, Newman RA, Zwelling LA. In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC 308847) in human leukemia. Cancer Res. 1987 Feb 15;47(4):1040-4. PMID: 3026621.

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