生物活性

• 靶点	Ribonucleotide Reductase IC50:65nM

• 描述Clofarabine (CAFdA or CL-F-Ara-a) is a deoxyadenosine analogue compound that has been used in treatment for relapsed or refractory acute lymphoblastic leukemia (see https://www.fda.gov/). Clofarabine can inhibit DNA synthesis through both inhibition of ribonucleotide reductase activity and DNA polymeraseαactivity. The first, clofarabine is phosphorylated by deoxycytidine kinase to clofarabine triphosphate. Clofarabine triphosphate can compete with dATP for incorporation into A sites of the extending DNA strand catalyzed by both human DNA polymeraseα. The second, clofarabine triphosphate is a potent inhibitor of ribonucleotide reductase and thus depletes the dNTP pool primarily of dCTP and dATP. And this further facilitates clofarabine triphosphate incorporated into the DNA^[1]. Though inhibition of DNA synthesis is mainly contributed to the anti-tumor effect, the cytotoxicity of clofarabine can be implemented through induction of DNA damage and mitochondrial damage on CLL cells, thus triggering the apoptosis^[2].
• 作用机制Clofarabine can inhibit DNA synthesis and DNA strands extension through both inhibition of ribonucleotide reductase and DNA polymeraseα.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A549 cells	-	Function assay	5 days	Cytostatic activity against human A549 cells after 5 days by SRB assay, GI50=0.086 μM	21711054
  BT549 cells	-	Cytotoxicity assay	5 days	Cytotoxicity against human BT549 cells after 5 days by SRB assay, GI50=0.065 μM	19929004
  CCRF-CEM cell lines	-	Cytotoxicity assay	-	Compound was tested for cytotoxicity against CCRF-CEM cell lines, IC50=0.05 μM	1732556

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• 动物研究
  剂量	Mice[3] (i.p.): min = 20 mg/kg, max = 600 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Mice[3] Dose 20 mg/kg Administration i.p. CL/F 2.707 L/h/kg K21 1.886 (1/h) V1/F 28.37 L/kg AUC0→t 6.124 mg/L/h K12 0.255 (1/h) T1/2α 0.356 h K10 0.095 (1/h) T1/2β 2.395 h

• 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
  NCT00042341	Leukemia, Lymphoblastic, Acute... more >>, Pediatric Collapse <<	Phase 2	Completed	-	United States, California ... more >> Children's Hospital Los Angeles, California, United States, 90027 Children's Hospital Orange County, California, United States Children's Hospital San Diego, California, United States United States, Colorado Children's Hospital Denver, Colorado, United States, 80218 United States, Illinois Children's Memorial Hospital Chicago, Illinois, United States, 60614 United States, Maryland Johns Hopkins Children's Center Baltimore, Maryland, United States United States, Missouri Children's Hospital St. Louis, Missouri, United States United States, New York Memorial Sloan-Kettering New York, New York, United States United States, Pennsylvania Children's Hospital Philadelphia, Pennsylvania, United States Children's Hospital Pittsburgh, Pennsylvania, United States, 15213 United States, Tennessee St. Jude Children's Research Hospital Memphis, Tennessee, United States United States, Texas Cook's Children's Medical Center Fort Worth, Texas, United States, 76104 Texas Children's Cancer Center Houston, Texas, United States The University of Texas M.D. Anderson Cancer Center Houston, Texas, United States Collapse <<
  NCT00042354	Leukemia, Myelocytic, Acute, P... more >>ediatric Collapse <<	Phase 2	Completed	-	United States, Arkansas ... more >> Arkansas Children's Hospital Little Rock, Arkansas, United States, 72202 United States, California Children's Hospital Los Angeles, California, United States, 90027 Children's Hospital Orange County, California, United States Children's Hospital San Diego, California, United States United States, Colorado Children's Hospital Denver, Colorado, United States United States, Connecticut University of Connecticut Health Center Hartford, Connecticut, United States, 06106 United States, Illinois Children's Memorial Hospital Chicago, Illinois, United States, 60614 United States, Maryland Johns Hopkins Children's Center Baltimore, Maryland, United States, 21231 United States, Missouri Children's Hospital St. Louis, Missouri, United States United States, Nebraska University of Nebraska Medical Center Omaha, Nebraska, United States, 67198 United States, New York Memorial Sloan-Kettering New York, New York, United States United States, Pennsylvania Children's Hospital Philadelphia, Pennsylvania, United States Children's Hospital Pittsburgh, Pennsylvania, United States, 15213 United States, Tennessee St. Jude Children's Research Hospital Memphis, Tennessee, United States United States, Texas Children's Medical Center Dallas, Texas, United States Cook's Children's Medical Center Fort Worth, Texas, United States, 76104 Texas Children's Cancer Center Houston, Texas, United States The University of Texas M.D. Anderson Cancer Center Houston, Texas, United States Collapse <<
  NCT00593645	Myelodysplastic Syndromes ... more >> Acute Myeloid Leukemia Collapse <<	Phase 2	Terminated(toxicities were wor... more >>se than expected) Collapse <<	-	United States, Missouri ... more >> Ravi Vij, M.D. St. Louis, Missouri, United States, 63110 Collapse <<

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• 参考文献

• [1] Xie KC, Plunkett W, et al. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine. Cancer Res. 1996 Jul 1;56(13):3030-7.

  [2] Genini D, Adachi S, et al. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood. 2000 Nov 15;96(10):3537-43.

  [3] Luan JJ, Zhang YS, et al. Dosing-time contributes to chronotoxicity of clofarabine in mice via means other than pharmacokinetics. Kaohsiung J Med Sci. 2016 May;32(5):227-34.