Drug (ID: DG00088) and It's Reported Resistant Information
Name
Irinotecan
Synonyms
Biotecan; Camptosar; Irinotecanum; IRINOTECAN HYDROCHLORIDE Trihydrate; Irinotecan Hcl; Irinotecan hydrochloride; CP0; Biotecan (TN); Campto (TN); Camptosar (TN); Irinotecan (INN); Irinotecan [INN:BAN]; Irinotecanum [INN-Latin]; IRINOTECAN, CPT-11; Camptosar, Campto, CPT-11, Irinotecan; (+)-Irinotecan; (4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3',4':6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL 1,4'-BIPIPERIDINE-1'-CARBOXYLATE; (4S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-4,12-dihydro-1H-pyrano[3,4-f]quinolino[2,3-a]indolizin-9-yl 4-piperidylpiperidinecarboxylate; Irinotecan (TOPO1 inhibitor); Onivyde
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Indication
In total 1 Indication(s)
Colorectal cancer [ICD-11: 2B91]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Brain cancer [ICD-11: 2A00]
[2]
Colorectal cancer [ICD-11: 2B91]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[1]
Target DNA topoisomerase I (TOP1) TOP1_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C33H38N4O6
IsoSMILES
CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)[C@@]4(CC)O)C2=NC5=C1C=C(C=C5)OC(=O)N6CCC(CC6)N7CCCCC7
InChI
1S/C33H38N4O6/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3/t33-/m0/s1
InChIKey
UWKQSNNFCGGAFS-XIFFEERXSA-N
PubChem CID
60838
ChEBI ID
CHEBI:80630
TTD Drug ID
D07HOB
VARIDT ID
DR00112
DrugBank ID
DB00762
Type(s) of Resistant Mechanism of This Drug
  DISM: Drug Inactivation by Structure Modification
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  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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Brain cancer [ICD-11: 2A00]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Glutathione S-transferase P (GSTP1) [2]
Molecule Alteration Expression
Up-regulation
Resistant Disease Malignant glioma [ICD-11: 2A00.2]
Experimental Note Identified from the Human Clinical Data
In Vitro Model Malignant gliomas tissue N.A.
Experiment for
Molecule Alteration
Immunohistochemistry assay
Experiment for
Drug Resistance
EDR assay
Mechanism Description In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]
Molecule Alteration Expression
Up-regulation
Resistant Disease Malignant glioma [ICD-11: 2A00.2]
Experimental Note Identified from the Human Clinical Data
In Vitro Model Malignant gliomas tissue N.A.
Experiment for
Molecule Alteration
Immunohistochemistry assay
Experiment for
Drug Resistance
EDR assay
Mechanism Description In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [2]
Molecule Alteration Expression
Up-regulation
Resistant Disease Malignant glioma [ICD-11: 2A00.2]
Experimental Note Identified from the Human Clinical Data
In Vitro Model Malignant gliomas tissue N.A.
Experiment for
Molecule Alteration
Immunohistochemistry assay
Experiment for
Drug Resistance
EDR assay
Mechanism Description In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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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: TP53 target 1 (TP53TG1) [1]
Molecule Alteration Expression
Down-regulation
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
qPCR
Experiment for
Drug Resistance
MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1) [1]
Molecule Alteration Expression
Up-regulation
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation p53 signaling pathway Inhibition hsa04115
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
GCIY cells Gastric Homo sapiens (Human) CVCL_1228
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
MkN-7 cells Gastric Homo sapiens (Human) CVCL_1417
SNU-1 cells Gastric Homo sapiens (Human) CVCL_0099
TGBC11TkB cells Gastric Homo sapiens (Human) CVCL_1768
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
Western blot analysis
Experiment for
Drug Resistance
MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Colorectal cancer [ICD-11: 2B91]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cocaine esterase (CES2) [4]
Molecule Alteration Expression
Down-regulation
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Experimental Note Identified from the Human Clinical Data
In Vitro Model CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
IPS cells Colon Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration
qPCR
Experiment for
Drug Resistance
Transcellular transport study assay
Mechanism Description The extraction ratio of metabolism of irinotecan (a CES2 substrate) to SN-38 in hiPSC-IECs was 3.52 +/- 0.15 (%) and decreased to 2.42 +/- 0.17 (%) in the presence of 100 uM telmisartan (a CES2 inhibitor). The extraction ratio in Caco-2 cells was 3.96 +/- 0.55 (%) and also decreased to 2.30 +/- 0.30 (%) in the presence of 100 uM telmisartan.
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-miR-17-5p [3]
Molecule Alteration Expression
Up-regulation
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
PTEN/AKT/PI3K signaling pathway Activation hsa05235
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
qRT-PCR
Experiment for
Drug Resistance
MTT assay; Flow cytometry assay
Mechanism Description The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN) [3]
Molecule Alteration Expression
Down-regulation
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
PTEN/AKT/PI3K signaling pathway Activation hsa05235
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
Experiment for
Molecule Alteration
Western blot analysis
Experiment for
Drug Resistance
MTT assay; Flow cytometry assay
Mechanism Description The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-451 [5]
Molecule Alteration Expression
Up-regulation
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Sphere tumorogenicity Inhibition hsa04140
Wnt signaling pathway Inhibition hsa04310
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
LOVO cells Colon Homo sapiens (Human) CVCL_0399
RkO cells Colon Homo sapiens (Human) CVCL_0504
LS513 cells Colon Homo sapiens (Human) CVCL_1386
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
qRT-PCR
Experiment for
Drug Resistance
MTS assay
Mechanism Description COX-2 allows Wnt activation, which is essential for CSC growth, the decrease of colorectal CSC formation and growth could result from miR-451-mediated downregulation of cyclooxygenase-2 (COX-2) and Wnt pathway.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Prostaglandin G/H synthase 2 (PTGS2) [5]
Molecule Alteration Expression
Down-regulation
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Sphere tumorogenicity Inhibition hsa04140
Wnt signaling pathway Inhibition hsa04310
In Vitro Model HT29 Cells Colon Homo sapiens (Human) CVCL_A8EZ
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
SW620 cells Colon Homo sapiens (Human) CVCL_0547
LOVO cells Colon Homo sapiens (Human) CVCL_0399
RkO cells Colon Homo sapiens (Human) CVCL_0504
LS513 cells Colon Homo sapiens (Human) CVCL_1386
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration
Western blotting analysis
Experiment for
Drug Resistance
MTS assay
Mechanism Description COX-2 allows Wnt activation, which is essential for CSC growth, the decrease of colorectal CSC formation and growth could result from miR-451-mediated downregulation of cyclooxygenase-2 (COX-2) and Wnt pathway.
References
Ref 1 Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7535-E7544. doi: 10.1073/pnas.1608585113. Epub 2016 Nov 7.
Ref 2 In vitro drug response and molecular markers associated with drug resistance in malignant gliomas .Clin Cancer Res. 2006 Aug 1;12(15):4523-32. doi: 10.1158/1078-0432.CCR-05-1830. 10.1158/1078-0432.CCR-05-1830
Ref 3 MicroRNA-17-5p promotes chemotherapeutic drug resistance and tumour metastasis of colorectal cancer by repressing PTEN expression. Oncotarget. 2014 May 30;5(10):2974-87. doi: 10.18632/oncotarget.1614.
Ref 4 Application of Intestinal Epithelial Cells Differentiated from Human Induced Pluripotent Stem Cells for Studies of Prodrug Hydrolysis and Drug Absorption in the Small Intestine. Drug Metab Dispos. 2018 Nov;46(11):1497-1506. doi: 10.1124/dmd.118.083246. Epub 2018 Aug 22.
Ref 5 MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells. 2011 Nov;29(11):1661-71. doi: 10.1002/stem.741.

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