Fludarabine is a purine analog that inhibits DNA synthesis[1]. Fludarabine inhibits cytokine-induced activation of STAT1 and STAT1-dependent gene transcription in normal quiescent or activated lymphocytes[2]. Fludarabine is an anti-tumor agent used to treat leukemia and lymphoma[3].
In vitro, treatment of MEC-2 cells with Fludarabine (100μM) for 72h significantly reduced cell viability, induced cytochrome c release and DNA cleavage[4]. Treatment of chronic lymphocytic leukemia (CLL) cells with Fludarabine (3, 10, 30μM) for 24-72h induced apoptosis in a dose- and time-dependent manner, increased intracellular phosphorylation of H2A histone family member X (H2AX), and led to DNA damage[5].
In vivo, treatment of BCL-1-bearing F1 mice with Fludarabine (0.8mg/kg) by intraperitoneal injection reduced the incidence of graft-versus-host disease (GVHD) in mice and maintained the anti-leukemic effect after leukemic cell transplantation[6]. Treatment of SCID beige mice with Fludarabine (200mg/kg) by intraperitoneal injection for 6 weeks promoted the engraftment of acute myeloid leukemia (AML) cell lines[7].
References:
[1] Wang Y, Chen X, Tang N, et al. Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis[J]. International Journal of Molecular Sciences, 2024, 25(7): 4134.
[2] Battle T E, Frank D A. STAT1 mediates differentiation of chronic lymphocytic leukemia cells in response to Bryostatin 1[J]. Blood, 2003, 102(8): 3016-3024.
[3] Ricci F, Tedeschi A, Morra E, et al. Fludarabine in the treatment of chronic lymphocytic leukemia: a review[J]. Therapeutics and clinical risk management, 2009: 187-207.
[4] Huang C, Tu Y, Freter C E. Fludarabine-resistance associates with ceramide metabolism and leukemia stem cell development in chronic lymphocytic leukemia[J]. Oncotarget, 2018, 9(69): 33124.
[5] El-Mabhouh A A, Ayres M L, Shpall E J, et al. Evaluation of bendamustine in combination with fludarabine in primary chronic lymphocytic leukemia cells[J]. Blood, The Journal of the American Society of Hematology, 2014, 123(24): 3780-3789.
[6] Weiss L, Abdul-Hai A, Or R, et al. Fludarabine in combination with cyclophosphamide decreases incidence of GVHD and maintains effective graft-versus-leukemia effect after allogeneic stem cell transplantation in murine lymphocytic leukemia[J]. Bone marrow transplantation, 2003, 31(1): 11-15.
[7]Pievani A, Michelozzi I M, Rambaldi B, et al. Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice[J]. Scientific RepoRts, 2018, 8(1): 9125.
Fludarabine是一种抑制DNA合成的嘌呤类似物[1]。Fludarabine抑制细胞因子诱导的正常静止或激活淋巴细胞中STAT1和STAT1依赖性基因转录的激活[2]。Fludarabine是一种抗肿瘤剂，用于治疗白血病和淋巴瘤[3]。
在体外，Fludarabine（100μM）处理MEC-2细胞72h，显著降低了细胞的活力，诱导了细胞色素c释放和DNA裂解[4]。Fludarabine（3、10、30μM）处理慢性淋巴细胞白血病（CLL）24-72h，剂量和时间依赖性地诱导了细胞凋亡，增加了细胞内H2A组蛋白家族成员X（H2AX）磷酸化，导致了DNA损伤[5]。
在体内，Fludarabine（0.8mg/kg）通过腹膜内注射治疗B型淋巴细胞白血病（BCL-1）携带F1小鼠，降低了小鼠移植物抗宿主病（GVHD）的发生率，并在白血病细胞移植后保持了抗白血病作用[6]。Fludarabine（200mg/kg）通过腹腔注射治疗SCID beige小鼠6周，促进了急性髓系白血病（AML）细胞系的植入[7]。