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
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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]
Structure
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]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
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
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Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-17-92 [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Mantle cell lymphoma [ICD-11: 2A85.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model Jeko-1 cells Blood Homo sapiens (Human) CVCL_1865
Granta-519 cells Blood Homo sapiens (Human) CVCL_1818
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) Click to Show/Hide
Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2) [3]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Mantle cell lymphoma [ICD-11: 2A85.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell proliferation Activation hsa05200
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model Jeko-1 cells Blood Homo sapiens (Human) CVCL_1865
Granta-519 cells Blood Homo sapiens (Human) CVCL_1818
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]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-21 [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell colony Inhibition hsa05200
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) Click to Show/Hide
Key Molecule: Programmed cell death protein 4 (PDCD4) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell colony Inhibition hsa05200
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.

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