Drug Information

Drug (ID: DG00179) and It's Reported Resistant Information

• Name: Fludarabine
• Synonyms: FaraA; Fludarabina; Fludarabinum; Fluradosa; Fludarabina [Spanish]; Fludarabine [INN]; Fludarabinum [Latin]; SQ Fludarabine; Fludara, Fludarabine; Fludarabine (INN); Fluradosa (TN); F-Ara-A; (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol; (2R,3S,4S,5R)-2-(6-amino-2-fluoropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol; 2-F-ara-A; 2-Fluoro Ara-A; 2-Fluoro-9-beta-D-arabinofuranosyladenine; 9-beta-D-Arabinofuranosyl-2-fluoroadenine; 9-beta-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine; 9H-Purin-6-amine, 9-beta-D-arabinofuranosyl-2-fluoro-(9CI)
• Indication:
  In total 1 Indication(s)
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [2]
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Chronic lymphocytic leukemia [ICD-11: 2A82]; [3]
  Chronic myeloid leukemia [ICD-11: 2A20]; [4]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [6]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Liver cancer [ICD-11: 2C12]; [5]
• Target: Adenosine deaminase (ADA); ADA_HUMAN; [1]
• Formula: C10H12FN5O4
• IsoSMILES: C1=NC2=C(N=C(N=C2N1[C@H]3[C@H]([C@@H]([C@H](O3)CO)O)O)F)N
• InChI: 1S/C10H12FN5O4/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,14,15)/t3-,5-,6+,9-/m1/s1
• InChIKey: HBUBKKRHXORPQB-FJFJXFQQSA-N
• PubChem CID: 657237
• ChEBI ID: CHEBI:94701
• TTD Drug ID: D0F2XQ
• VARIDT ID: DR00434
• DrugBank ID: DB01073

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-29a [4]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-29a can activate p53 and induce apoptosis in a p53-dependent manner.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cysteine and glycine-rich protein 1 (CSRP1) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Rap1 signaling pathway; Activation; hsa04015
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: JAK-STAT signaling pathway; Activation; hsa04630
• In Vivo Model: Patient-derived advanced AML model; Homo sapiens
• Experiment for Drug Resistance: OncoPredict assay
• Mechanism Description: Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future.

Chronic lymphocytic leukemia [ICD-11: 2A82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 17p13 (Unclear) [3]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Structural variation; Copy number loss
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: FISH assay
• Experiment for Drug Resistance: Multivariable Andersen-Gill regression analysis; VH sequencing assay
• Mechanism Description: Expansion of the clone with del(17p13) was observed in all patients during treatment, indicating in vivo resistance to therapy.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [4]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: High levels of miR-181a and miR-221 also point to cell cycle progression as both miRNAs repress CDkN1B (p27) expression in hematologic diseases and p27 was also found down-regulated in resistant cells.

Key Molecule: hsa-mir-221 [4]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: High levels of miR-181a and miR-221 also point to cell cycle progression as both miRNAs repress CDkN1B (p27) expression in hematologic diseases and p27 was also found down-regulated in resistant cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protocadherin Fat 1 (FAT1) [7]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT/STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: White blood cell count assay
• Mechanism Description: FAT1 and its mutational inactivation have been linked to activation of the WNT pathway in solid tumors and to chemoresistance in chronic lymphocytic leukemia and could serve as an attractive therapeutic target.

Key Molecule: Cellular tumor antigen p53 (TP53) [8]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: Genes belonging to the DNA damage response and cell cycle control (TP53, ATM, POT1, BIRC3) happen to be more frequently mutated in uCLL cases. However, DNA-damaging chemotherapy results in the development of chemo-resistance in most of the cases, which has been initially attributed to the selection of driver mutations affecting genes of the DNA-damage response pathways, such as TP53 and ATM.

Key Molecule: Serine-protein kinase ATM (ATM) [8]

• Resistant Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Inhibition; hsa04218
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Mechanism Description: Genes belonging to the DNA damage response and cell cycle control (TP53, ATM, POT1, BIRC3) happen to be more frequently mutated in uCLL cases. However, DNA-damaging chemotherapy results in the development of chemo-resistance in most of the cases, which has been initially attributed to the selection of driver mutations affecting genes of the DNA-damage response pathways, such as TP53 and ATM.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [1]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Key Molecule: hsa-mir-181 [1]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [1]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [1]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [1]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CLL B cells; Lymph; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181a and miR-181b directly inhibit the expression of BCL-2, MCL-1 and XIAP by binding to the target sequence, sensitizes CLL cells to fludarabine-induced apoptosis.

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CXC chemokine receptor type 4 (CXCR4) [6]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to fludarabine in the waldenstrom macroglobulinemia.

Liver cancer [ICD-11: 2C12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Xin actin-binding repeat-containing protein 2 (XIRP2) [5]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Molecule Alteration: Mutation; I828V
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNU475 cells; Liver; Homo sapiens (Human); CVCL_0497
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: CCK-8 assays demonstrated that HCC cells carrying the?XIRP2?mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the?XIRP2?wildtype. The?XIRP2?mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of?XIRP2?resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the?XIRP2?mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin.

References

• Ref 1: miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes. Carcinogenesis. 2012 Jul;33(7):1294-301. doi: 10.1093/carcin/bgs179. Epub 2012 May 18.
• Ref 2: Cysteine- and glycine-rich protein 1 predicts prognosis and therapy response in patients with acute myeloid leukemia. Clin Exp Med. 2024 Mar 28;24(1):57.
• Ref 3: Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica. 2007 Sep;92(9):1242-5. doi: 10.3324/haematol.10720. Epub 2007 Aug 1.
• Ref 4: Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia. Mol Cancer. 2010 May 20;9:115. doi: 10.1186/1476-4598-9-115.
• Ref 5: Identification of Clinical Value and Biological Effects of XIRP2 Mutation in Hepatocellular Carcinoma. Biology (Basel). 2024 Aug 19;13(8):633.
• Ref 6: Genomics, Signaling, and Treatment of Waldenstr m Macroglobulinemia .J Clin Oncol. 2017 Mar 20;35(9):994-1001. doi: 10.1200/JCO.2016.71.0814. Epub 2017 Feb 13. 10.1200/JCO.2016.71.0814
• Ref 7: Mutational spectrum of adult T-ALL. Oncotarget. 2015 Feb 20;6(5):2754-66. doi: 10.18632/oncotarget.2218.
• Ref 8: FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017 Jun;16(6):991-1001. doi: 10.1158/1535-7163.MCT-16-0876.