Drug Information
Drug (ID: DG00088) and It's Reported Resistant Information
Name |
Irinotecan
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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)
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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]
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Target | DNA topoisomerase I (TOP1) | TOP1_HUMAN | [1] | ||
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Formula |
C33H38N4O6
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IsoSMILES |
CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)[C@@]4(CC)O)C2=NC5=C1C=C(C=C5)OC(=O)N6CCC(CC6)N7CCCCC7
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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
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InChIKey |
UWKQSNNFCGGAFS-XIFFEERXSA-N
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PubChem CID | |||||
ChEBI ID | |||||
TTD Drug ID | |||||
VARIDT ID | |||||
DrugBank ID |
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
Brain cancer [ICD-11: 2A00]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Drug Inactivation by Structure Modification (DISM) | ||||
Key Molecule: Glutathione S-transferase P (GSTP1) | [2] | |||
Molecule Alteration | Expression | Up-regulation |
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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) | ||||
Key Molecule: Multidrug resistance protein 1 (ABCB1) | [2] | |||
Molecule Alteration | Expression | Up-regulation |
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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) | ||||
Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) | [2] | |||
Molecule Alteration | Expression | Up-regulation |
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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]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Epigenetic Alteration of DNA, RNA or Protein (EADR) | ||||
Key Molecule: TP53 target 1 (TP53TG1) | [1] | |||
Molecule Alteration | Expression | Down-regulation |
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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) | ||||
Key Molecule: Y-box-binding protein 1 (YBX1) | [1] | |||
Molecule Alteration | Expression | Up-regulation |
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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]
Drug Resistance Data Categorized by Their Corresponding Mechanisms | ||||
Drug Inactivation by Structure Modification (DISM) | ||||
Key Molecule: Cocaine esterase (CES2) | [4] | |||
Molecule Alteration | Expression | Down-regulation |
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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) | ||||
Key Molecule: hsa-miR-17-5p | [3] | |||
Molecule Alteration | Expression | Up-regulation |
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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) | ||||
Key Molecule: Phosphatase and tensin homolog (PTEN) | [3] | |||
Molecule Alteration | Expression | Down-regulation |
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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) | ||||
Key Molecule: hsa-mir-451 | [5] | |||
Molecule Alteration | Expression | Up-regulation |
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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) | ||||
Key Molecule: Prostaglandin G/H synthase 2 (PTGS2) | [5] | |||
Molecule Alteration | Expression | Down-regulation |
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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
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