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Details

Stereochemistry ACHIRAL
Molecular Formula C26H26N2O7
Molecular Weight 478.4938
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of INDOTECAN

SMILES

COC1=C(OC)C=C2C(=O)N(CCCN3CCOCC3)C4=C(C(=O)C5=C4C=C6OCOC6=C5)C2=C1

InChI

InChIKey=FMFIFGLHVOZDEL-UHFFFAOYSA-N
InChI=1S/C26H26N2O7/c1-31-19-10-15-18(13-20(19)32-2)26(30)28(5-3-4-27-6-8-33-9-7-27)24-16-11-21-22(35-14-34-21)12-17(16)25(29)23(15)24/h10-13H,3-9,14H2,1-2H3

HIDE SMILES / InChI

Description
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT01051635 | https://clinicaltrials.gov/ct2/show/record/NCT01794104 | https://goo.gl/gpqwt8 | https://www.ncbi.nlm.nih.gov/pubmed/27097152 | https://www.ncbi.nlm.nih.gov/pubmed/20630766

Indotecan (LMP400) is a novel indenoisoquinoline derivative with specific topoisomerase I inhibition activity, developed by Division of Cancer Treatment and Diagnosis National Cancer Institute for cancer treatment. In preclinical studied Indotecan inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. Low doses of Indotecan decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. In vitro, Indotecan showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. Recently Indotecan has entered Phase I clinical trials for the treatment of cancer patients at the National Cancer Institute, and definite plans are being formulated to commence Phase II clinical trials.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1.61 μg/mL
60 mg/m² 1 times / day multiple, intravenous
dose: 60 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1.65 μg/mL
80 mg/m² 1 times / day multiple, intravenous
dose: 80 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1.93 μg/mL
135 mg/m² 1 times / day multiple, intravenous
dose: 135 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1.69 μg/mL
90 mg/m² 1 times / day multiple, intravenous
dose: 90 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
12.8 μg × h/mL
60 mg/m² 1 times / day multiple, intravenous
dose: 60 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
14.7 μg × h/mL
80 mg/m² 1 times / day multiple, intravenous
dose: 80 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
70.8 μg × h/mL
135 mg/m² 1 times / day multiple, intravenous
dose: 135 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
88.6 μg × h/mL
90 mg/m² 1 times / day multiple, intravenous
dose: 90 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
50 h
135 mg/m² 1 times / day multiple, intravenous
dose: 135 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
74 h
90 mg/m² 1 times / day multiple, intravenous
dose: 90 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
INDOTECAN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
135 mg/m2 1 times / week multiple, intravenous
Highest studied dose
Dose: 135 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 135 mg/m2, 1 times / week
Sources: Page: p.5
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.5
DLT: nausea, thrombocytopenia...
Dose limiting toxicities:
nausea (grade 3, 14.3%)
thrombocytopenia (grade 4, 14.3%)
Sources: Page: p.5
60 mg/m2 1 times / day multiple, intravenous
MTD
Dose: 60 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 60 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.5
Other AEs: myelosuppression...
Other AEs:
myelosuppression (grade 4, 16.7%)
Sources: Page: p.5
90 mg/m2 1 times / week multiple, intravenous
MTD
Dose: 90 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / week
Sources: Page: p.5
unhealthy, ADULT
n = 8
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 8
Sources: Page: p.5
80 mg/m2 1 times / day multiple, intravenous
Studied dose
Dose: 80 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 80 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.5
DLT: thrombocytopenia, neutropenia...
Dose limiting toxicities:
thrombocytopenia (grade 4, 66.7%)
neutropenia (grade 4, 33.3%)
fatigue (grade 3, 33.3%)
neutropenia (grade 3, 33.3%)
Sources: Page: p.5
AEs

AEs

AESignificanceDosePopulation
nausea grade 3, 14.3%
DLT
135 mg/m2 1 times / week multiple, intravenous
Highest studied dose
Dose: 135 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 135 mg/m2, 1 times / week
Sources: Page: p.5
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.5
thrombocytopenia grade 4, 14.3%
DLT
135 mg/m2 1 times / week multiple, intravenous
Highest studied dose
Dose: 135 mg/m2, 1 times / week
Route: intravenous
Route: multiple
Dose: 135 mg/m2, 1 times / week
Sources: Page: p.5
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources: Page: p.5
myelosuppression grade 4, 16.7%
60 mg/m2 1 times / day multiple, intravenous
MTD
Dose: 60 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 60 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.5
fatigue grade 3, 33.3%
DLT
80 mg/m2 1 times / day multiple, intravenous
Studied dose
Dose: 80 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 80 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.5
neutropenia grade 3, 33.3%
DLT, Disc. AE
80 mg/m2 1 times / day multiple, intravenous
Studied dose
Dose: 80 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 80 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.5
neutropenia grade 4, 33.3%
DLT
80 mg/m2 1 times / day multiple, intravenous
Studied dose
Dose: 80 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 80 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.5
thrombocytopenia grade 4, 66.7%
DLT, Disc. AE
80 mg/m2 1 times / day multiple, intravenous
Studied dose
Dose: 80 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 80 mg/m2, 1 times / day
Sources: Page: p.5
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.5
PubMed

PubMed

TitleDatePubMed
Alcohol-, diol-, and carbohydrate-substituted indenoisoquinolines as topoisomerase I inhibitors: investigating the relationships involving stereochemistry, hydrogen bonding, and biological activity.
2011 Jul 28
Patents

Sample Use Guides

Indotecan was administered intravenously through a central line over 1 h for the daily schedule (days 1–5, followed by 23 days without drug in 28-day cycles) and over 3 h for the weekly schedule (days 1, 8, and 15 in 28-day cycles). An MTD of 60 mg/m2/day was established for the daily regimen, compared to 90 mg/m2 for the weekly regimen.
Route of Administration: Intravenous
Human recombinant Top1 was purified from Baculovirus. 117-bp DNA oligonucleotide (Integrated DNA Technologies) encompassing the previous identified Top1 cleavage sites identified in the 161-bp fragment from pBluescript SK(−) phagemid DNA was employed. This 117-bp oligonucleotide contains a single 5′-cytosine overhang, which was 3′-end labeled by fill-in reaction with [•-32P]-dGTP in React 2 buffer (50 mM Tris-HCl, pH 8.0, 100 mM MgCl2, 50 mM NaCl) with 0.5 units of DNA polymerase I (Klenow fragment, New England BioLabs). Unincorporated 32P-dGTP was removed using mini Quick Spin DNA columns (Roche, Indianapolis, IN), and the eluate containing the 3′-end-labeled DNA substrate was collected. Approximately 2 nM of radiolabeled DNA substrate was incubated with recombinant Top1 in 20 μL of reaction buffer [10 mM Tris-HCl (pH 7.5), 50 mM KCl, 5 mM MgCl2, 0.1 mM EDTA, and 15 μg/mL BSA] at 25 °C for 20 min in the presence of various concentrations of compound 5 (Indotecan). The reactions were terminated by adding SDS (0.5% final concentration) followed by the addition of two volumes of loading dye (80% formamide, 10 mM sodium hydroxide, 1 mM sodium EDTA, 0.1% xylene cyanol, and 0.1% bromophenol blue).
Name Type Language
INDOTECAN
Common Name English
NSC-724998
Code English
5H-(1,3)DIOXOLO(4',5':5,6)INDENO(1,2-C)ISOQUINOLINE-5,12(6H)-DIONE, 2,3-DIMETHOXY-6-(3-(4-MORPHOLINYL)PROPYL)-
Systematic Name English
Classification Tree Code System Code
NCI_THESAURUS C2843
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
Code System Code Type Description
PUBCHEM
11533060
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
PRIMARY
EPA CompTox
DTXSID90238613
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
PRIMARY
NCI_THESAURUS
C95907
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
PRIMARY
FDA UNII
BTA69L5M8D
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
PRIMARY
CAS
915303-09-2
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
PRIMARY
NSC
724998
Created by admin on Fri Dec 15 17:14:56 GMT 2023 , Edited by admin on Fri Dec 15 17:14:56 GMT 2023
PRIMARY