Drug Information

Drug (ID: DG00032) and It's Reported Resistant Information

• Name: Topotecan
• Synonyms: Hycamptamine; Hycamptin; Hycamtamine; Topotecane; Topotecanum; Topotecan lactone; SKF 104864; SKF-S 104864; TOPOTECAN, HYCAMTIN; Topotecan (BAN); Topotecan [INN:BAN]; Topotecane [INN-French]; Topotecanum [INN-Latin]; Topotecan Monohydrochloride, (S)-Isomer; (4S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; (S)-10-((Dimethylamino)methyl)-4-ethyl-4,9-dihydroxy-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione; (S)-10-[(DIMETHYLAMINO)METHYL]-4-ETHYL-4,9-DIHYDROXY-1H-PYRANO[3',4':6,7]INOLIZINO[1,2-B]-QUINOLINE-3,14(4H,12H)-DIONE; (S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]-quinoline-3,14(4H,12H)-dione; (S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 9-Dimethylaminomethyl-10-hydroxycamptothecin
• Indication:
  In total 3 Indication(s)
  Ovarian cancer [ICD-11: 2C73]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
  Lung cancer [ICD-11: 2C25]; Phase 1; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Peritoneal cancer [ICD-11: 2C51]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [3]
• Target: DNA topoisomerase I (TOP1); TOP1_HUMAN; [1]
• Formula: C23H23N3O5
• IsoSMILES: CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=CC5=C(C=CC(=C5CN(C)C)O)N=C4C3=C2)O
• InChI: 1S/C23H23N3O5/c1-4-23(30)16-8-18-20-12(9-26(18)21(28)15(16)11-31-22(23)29)7-13-14(10-25(2)3)19(27)6-5-17(13)24-20/h5-8,27,30H,4,9-11H2,1-3H3/t23-/m0/s1
• InChIKey: UCFGDBYHRUNTLO-QHCPKHFHSA-N
• PubChem CID: 60700
• ChEBI ID: CHEBI:63632
• TTD Drug ID: D02PMO
• VARIDT ID: DR00044
• DrugBank ID: DB01030

Type(s) of Resistant Mechanism of This Drug

  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

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-17-92 [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Z138c cells; Blood; Homo sapiens (Human); CVCL_B077
• In Vivo Model: CB-17/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: Xenograft experiments assay
• Mechanism Description: The protein phosphatase PHLPP2, an important negative regulator of the PI3k/AkT pathway, was a direct target of miR-17 92 miRNAs, miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3k/AkT pathway activation.

Kidney cancer [ICD-11: 2C90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: Inhibition of miR-21 rescues PDCD4 and PTEN protein levels and improves chemosensitivity and therapeutic response.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: Inhibition of miR-21 rescues PDCD4 and PTEN protein levels and improves chemosensitivity and therapeutic response.

References

• Ref 1: Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan. J Med Chem. 2018 Jul 26;61(14):5900-5909. doi: 10.1021/acs.jmedchem.7b01891. Epub 2018 Jul 11.
• Ref 2: Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer .Int J Cancer. 2009 Dec 1;125(11):2721-7. doi: 10.1002/ijc.24654. 10.1002/ijc.24654
• Ref 3: The miRNA-17 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia. 2012 May;26(5):1064-72. doi: 10.1038/leu.2011.305. Epub 2011 Nov 25.