生物活性

• 靶点	Adenosine Deaminase IC50:0.18μM(in MM1.S cells)

• 描述Adenosine Deaminase (ADA) is a housekeeping enzyme in purine metabolism that is unique and essential in the differentiation and maturation of the immune system and thus can be the cause of human severe combined immune deficiency. Cladribine is a well-known ADA inhibitor against lymphoproliferative disorders with IC50 for U266, RPMI8226, or MM1.S cells approximately 2.43, 0.75, or 0.18 μM respectively. In U266 cells, cladribine treatment gradually increased the percentage of cells in the G1 phase from 42% to 45%, 62%, 66% at 24, 48, 72 hrs, respectively. And the percentage of cells in S phase reduced from 50% to 36%, 26%, 23% at 24, 48, 72 hrs, respectively. The percentage of cells in G2/M phase increased from 8% to 19% at 24 hrs and then decreased to 11% at 72 hrs. Cladribine also induced the cells' apoptosis with percentages of 5%, 15%, 21% and 33% when U266 cells were untreated or treated with 2, 5, 10 μM of cladribine, respectively. In RPMI8226 cells, 2μM cladribine treatment led to 14% increasing of cells in G1 phase and 18% decreasing in S phase at 24 hrs. And the percentages of apoptosis cells were improved in a dose-dependent manner when treated with 0.5, 1, 2 μM of cladribine, respectively. Similar cell cycle induction results with treatment of 0.5μM cladribine and apoptosis induction results with treatment of 0.1, 0.2, 0.5μM cladribine were observed in MM1.S cells. Furthermore, treatment of 0.2μM cladribine could be effective in reducing P-STAT3 in MM1.S cells while the concentrations were 1 μM in RPMI8226 and 2 μM in U266 cells^[1]. When applied the cladribine in four patients with systemic mastocytosis (SM), the IC50 for HMC-1.1 and HMC-1.2 cells were 300 nM and 10 nM respectively, suggesting that the codon 816 mutant may improve the responses to this drug. Cell apoptosis were also induced when treated with 0.5 and 1 μM of cladribine, the survival of HMC-1.2 cells was much stronger. The expression of apoptosis related CD95 in HMC-1.2 cells were also substantially promoted by 0.5 μM cladribine with stimulation index (SI) raised from 1 to 3 and with that of CD164 raised from 1 to 2. The expression SI of CD87 only in HMC-1.1 cells were raised from 1 to 5, while no effect on CD87 was observed in HMC-1.2 cells^[6].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  BT549 cells	-	Cytotoxicity assay	3 days	Cytotoxicity against human BT549 cells after 3 days by MTT assay, IC50=0.123 μM	21711054
  CCRF-CEM cell lines	-	Cytotoxicity assay	-	Compound was tested for cytotoxicity against CCRF-CEM cell lines, IC50=0.003 μM	1732556
  CCRF-CEM cells	-	Cytotoxicity assay	72 h	Cytotoxicity against human CCRF-CEM cells after 72 hrs by MTT assay, IC50=0.0005 μM	21840722

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• 动物研究
  剂量	Mice: 60 mg/kg[3] (s.c.); 20 mg/kg[3] (p.o.); 0.5 mg/kg[4] (i.p.)
  给药途径	s.c., p.o., i.p.
  动物药代数据	Animal Mice[5] Dose 30 mg/kg (male) Administration p.o. AUC24h 4108 h·ng/ml Cz 52.7 ng/ml Tmax 1 h Cmax 4580 ng/ml

• 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
  NCT02096055	Leukemia	Phase 2	Active, not recruiting	April 2026	United States, Texas ... more >> University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT00691652	Lymphoma	Phase 1 Phase 2	Terminated	-	United States, Oregon ... more >> Knight Cancer Institute at Oregon Health and Science University Portland, Oregon, United States, 97239-3098 Collapse <<
  NCT00117598	Lymphoma	Phase 3	Completed	-	-

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• 参考文献

• [1] Ma J. Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma. BMC Cancer. 2011 Jun 16;11:255. doi: 10.1186/1471-2407-11-255.

  [2] Guchelaar HJ, Vermes I, et al. Apoptosis-and necrosis-inducing potential of cladribine, cytarabine, cisplatin, and 5-fluorouracil in vitro: a quantitative pharmacodynamic model. Cancer Chemother Pharmacol. 1998;42(1):77-83.

  [3] Scheible H, Laisney M, et al. Comparison of the in vitro and in vivo metabolism of Cladribine (Leustatin, Movectro) in animals and human. Xenobiotica. 2013 Dec;43(12):1084-94.

  [4] Hayes CD, Dey D, et al. Chronic cladribine administration increases amyloid beta peptide generation and plaque burden in mice. PLoS One. 2012;7(10):e45841.

  [5] Cladribine

  [6] Böhm A. In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V. Exp Hematol. 2010 Sep;38(9):744-55. doi: 10.1016/j.exphem.2010.05.006. Epub 2010 May 27.

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