Identification

Name
Lomustine
Accession Number
DB01206  (APRD00292)
Type
Small Molecule
Groups
Approved, Investigational
Description

An alkylating agent of value against both hematologic malignancies and solid tumors. [PubChem]

Structure
Thumb
Synonyms
  • 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea
  • 1-(2-Chloroethyl)-3-cyclohexylnitrosourea
  • Belustine
  • Cecenu
  • Chloroethylcyclohexylnitrosourea
  • CINU
  • Cyclohexyl chloroethyl nitrosourea
  • Lomustina
  • Lomustinum
  • N-(2-Chloroethyl)-n'-cyclohexyl-N-nitrosourea
External IDs
NSC-79037
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CeenuCapsule, gelatin coated100 mg/1OralE.R. Squibb & Sons, L.L.C.2008-12-152014-06-30Us
CeenuCapsule100 mgOralBristol Myers Squibb1976-12-31Not applicableCanada
CeenuCapsule, gelatin coated10 mg/1OralE.R. Squibb & Sons, L.L.C.2008-12-152016-04-15Us
CeenuCapsule10 mgOralBristol Myers Squibb1976-12-31Not applicableCanada
CeenuCapsule, gelatin coated40 mg/1OralE.R. Squibb & Sons, L.L.C.2008-12-152016-04-15Us
CeenuCapsule40 mgOralBristol Myers Squibb1976-12-31Not applicableCanada
GleostineCapsule, gelatin coated100 mg/1OralNextSource Biotechnology, LLC2014-08-18Not applicableUs
GleostineCapsule, gelatin coated10 mg/1OralNextSource Biotechnology, LLC2014-08-18Not applicableUs
GleostineCapsule, gelatin coated40 mg/1OralNextSource Biotechnology, LLC2014-08-18Not applicableUs
LomustineCapsule, gelatin coated100 mg/1OralNext Source Biotechnology, Llc2014-07-292016-01-14Us
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
CeenuLomustine (10 mg/1) + Lomustine (40 mg/1) + Lomustine (100 mg/1)KitBristol-Myers Squibb2009-05-212009-05-21Us
CeenuLomustine (10 mg/1) + Lomustine (40 mg/1) + Lomustine (100 mg/1)KitBristol-Myers Squibb2009-05-212009-05-21Us
CeenuLomustine (10 mg/1) + Lomustine (40 mg/1) + Lomustine (100 mg/1)KitBristol-Myers Squibb2009-05-212009-05-21Us
International/Other Brands
Belustine / CCNU / Cecenu / CeeNU
Categories
UNII
7BRF0Z81KG
CAS number
13010-47-4
Weight
Average: 233.695
Monoisotopic: 233.093104478
Chemical Formula
C9H16ClN3O2
InChI Key
GQYIWUVLTXOXAJ-UHFFFAOYSA-N
InChI
InChI=1S/C9H16ClN3O2/c10-6-7-13(12-15)9(14)11-8-4-2-1-3-5-8/h8H,1-7H2,(H,11,14)
IUPAC Name
3-(2-chloroethyl)-1-cyclohexyl-3-nitrosourea
SMILES
ClCCN(N=O)C(=O)NC1CCCCC1

Pharmacology

Indication

For the treatment of primary and metastatic brain tumors as a component of combination chemotherapy in addition to appropriate surgical and/or radiotherapeutic procedures. Also used in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin's disease.

Associated Conditions
Pharmacodynamics

Lomustine is an alkylating agent of the nitrosourea type. Lomustine and its metabolites interferes with the function of DNA and RNA. It is cell cycle–phase nonspecific. Cancers form when some cells within the body multiply uncontrollably and abnormally. These cells then spread and destroy nearby tissues. Lomustine acts by slowing this process down. It kills cancer cells by damaging the DNA (the genetic material inside the cells) and stops them from dividing.

Mechanism of action

Lomustine is a highly lipophilic nitrosourea compound which undergoes hydrolysis in vivo to form reactive metabolites. These metabolites cause alkylation and cross-linking of DNA (at the O6 position of guanine-containing bases) and RNA, thus inducing cytotoxicity. Other biologic effects include inhibition of DNA synthesis and some cell cycle phase specificity. Nitrosureas generally lack cross-resistance with other alkylating agents. As lomustine is a nitrosurea, it may also inhibit several key processes such as carbamoylation and modification of cellular proteins.

TargetActionsOrganism
ADNA
cross-linking/alkylation
Human
UStathmin-4
antagonist
Human
Absorption

Well and rapidly absorbed from the gastrointestinal tract.

Volume of distribution
Not Available
Protein binding

50%

Metabolism

Hepatic. Rapid and complete, with active metabolites.

Route of elimination

Following oral administration of radioactive CeeNU at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours.

Half life

Approximately 94 minutes, however the metabolites have a serum half-life of 16 to 48 hours.

Clearance
Not Available
Toxicity

Oral, rat: LD50 = 70 mg/kg. Pulmonary toxicity has been reported at cumulative doses usually greater than 1,100 mg/m2. There is one report of pulmonary toxicity at a cumulative dose of only 600 mg. The onset of toxicity has varied from 6 months after initiation of therapy, to as late as 15 years after.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Lomustine can be increased when it is combined with Abiraterone.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Lomustine.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Lomustine.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Lomustine.
AlclometasoneThe risk or severity of adverse effects can be increased when Lomustine is combined with Alclometasone.
AldesleukinThe risk or severity of adverse effects can be increased when Lomustine is combined with Aldesleukin.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Lomustine.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Lomustine.
AmcinonideThe risk or severity of adverse effects can be increased when Lomustine is combined with Amcinonide.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Lomustine.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015337
KEGG Drug
D00363
KEGG Compound
C07079
PubChem Compound
3950
PubChem Substance
46506562
ChemSpider
3813
ChEBI
6520
ChEMBL
CHEMBL514
Therapeutic Targets Database
DAP000991
PharmGKB
PA164749407
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Lomustine
ATC Codes
L01AD02 — Lomustine
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
MSDS
Download (56.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentGliomas1
1CompletedTreatmentBone Marrow Suppression / Brain and Central Nervous System Tumors / Drug/Agent Toxicity by Tissue/Organ1
1CompletedTreatmentMelanoma / Neoplasms, Brain1
1CompletedTreatmentNeoplasms, Brain / Recurrent Glioblastoma1
1CompletedTreatmentNeoplasms, Brain / Tumors, Central Nervous System1
1CompletedTreatmentRecurrent Glioblastoma Multiforme / Recurrent Glioblastoma Multiforme (rGBM)1
1TerminatedTreatmentLeptomeningeal Metastasis From Malignant Melanoma1
1TerminatedTreatmentMalignant Glioma (WHO Grade III or IV)1
1, 2Active Not RecruitingTreatmentMedulloblastomas1
1, 2Active Not RecruitingTreatmentRelapsed/Recurrent GBM (Phase 2) / Solid Tumors (Phase 1)1
1, 2TerminatedTreatmentGlioblastomas1
2Active Not RecruitingTreatmentGlioblastoma Multiforme (GBM)2
2Active Not RecruitingTreatmentGlioblastomas1
2Active Not RecruitingTreatmentNeoplasms, Brain / Tumors, Central Nervous System1
2CompletedTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas1
2CompletedTreatmentAnaplastic Glioma of Brain / Brain Cancer / Glioblastoma Multiforme (GBM)1
2CompletedTreatmentBrain Cancer / Glioblastomas1
2CompletedTreatmentBrain and Central Nervous System Tumors2
2CompletedTreatmentGlioblastomas1
2CompletedTreatmentIntraocular Melanoma / Melanoma (Skin)1
2CompletedTreatmentLung Cancers1
2CompletedTreatmentMalignant Lymphomas3
2RecruitingTreatmentAIDS-Related Diffuse Large Cell Lymphoma / AIDS-Related Diffuse Mixed Cell Lymphoma / AIDS-Related Diffuse Small Cleaved Cell Lymphoma / AIDS-related Immunoblastic Large Cell Lymphoma / AIDS-Related Lymphoblastic Lymphoma / AIDS-related Peripheral/Systemic Lymphoma / AIDS-related Small Noncleaved Cell Lymphoma / Stage III AIDS-related Lymphoma / Stage IV AIDS-related Lymphoma1
2RecruitingTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas / Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System1
2RecruitingTreatmentGlioblastoma Multiforme (GBM)1
2RecruitingTreatmentHigh Grade Recurrent Glioma and Newly Diagnosed Glioblastoma1
2RecruitingTreatmentMalignant Gliomas1
2RecruitingTreatmentMedulloblastomas / Untreated Childhood Medulloblastoma1
2TerminatedTreatmentMalignant Lymphomas1
2TerminatedTreatmentMedulloblastomas / Neoplasms, Brain / Primitive Neuroectodermal Tumor / Tumors, Central Nervous System1
2Unknown StatusTreatmentBrain and Central Nervous System Tumors2
2Unknown StatusTreatmentPrimary Non Hodgkin Lymphoma of the Central Nervous System1
2Unknown StatusTreatmentRecurrent Glioblastoma Multiforme1
2WithdrawnTreatmentMalignant Lymphomas1
2WithdrawnTreatmentMelanoma / Neoplasms, Brain1
2, 3CompletedTreatmentBrain and Central Nervous System Tumors1
2, 3RecruitingTreatmentAnaplastic Astrocytoma (AA) / Glioblastoma Multiforme (GBM)1
2, 3RecruitingTreatmentGBM / Glioblastoma Multiforme (GBM) / Glioblastoma, Adult / Glioblastomas / Recurrent Brain Tumors1
2, 3RecruitingTreatmentNeoplasms, Brain1
3Active Not RecruitingTreatmentCognition Disorders / Disability Evaluation / Glioblastoma Multiforme (GBM)1
3CompletedTreatmentBrain and Central Nervous System Tumors4
3CompletedTreatmentGlioblastomas3
3CompletedTreatmentLeukemia Acute Myeloid Leukemia (AML)1
3CompletedTreatmentNeoplasms, Brain / Tumors, Central Nervous System2
3CompletedTreatmentNeoplasms, Brain / Tumors, Central Nervous System / Untreated Childhood Medulloblastoma1
3RecruitingTreatmentAnaplastic Astrocytoma (AA) / Recurrent Anaplastic Astrocytoma1
3RecruitingTreatmentBrain and Central Nervous System Tumors1
3TerminatedTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas1
3Unknown StatusTreatmentBrain and Central Nervous System Tumors3
3Unknown StatusTreatmentMultiple Myeloma and Plasma Cell Neoplasm1
Not AvailableActive Not RecruitingTreatmentBrain and Central Nervous System Tumors1
Not AvailableActive Not RecruitingTreatmentMalignant Lymphomas1
Not AvailableCompletedTreatmentBrain and Central Nervous System Tumors1
Not AvailableNot Yet RecruitingTreatmentRecurrent High-grade Glioma1
Not AvailableRecruitingDiagnosticRecurrent Glioblastoma1
Not AvailableRecruitingTreatmentMedulloblastomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Bristol-Myers Squibb Co.
  • Group Health Cooperative
  • Mead Johnson and Co.
Dosage forms
FormRouteStrength
CapsuleOral10 mg
CapsuleOral100 mg
CapsuleOral40 mg
Capsule, gelatin coatedOral10 mg/1
Capsule, gelatin coatedOral100 mg/1
Capsule, gelatin coatedOral40 mg/1
Kit
Prices
Unit descriptionCostUnit
Ceenu 100 mg capsule60.61USD capsule
Ceenu 40 mg capsule31.88USD capsule
CeeNU 300 mg capsule31.69USD capsule
Ceenu dose pack30.47USD each
Ceenu 10 mg capsule10.77USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)88-90 °CPhysProp
water solubility111 mg/LNot Available
logP2.83HANSCH,C & LEO,AJ (1985)
Predicted Properties
PropertyValueSource
Water Solubility0.755 mg/mLALOGPS
logP2.62ALOGPS
logP2.16ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)13.3ChemAxon
pKa (Strongest Basic)-5.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area61.77 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity58.65 m3·mol-1ChemAxon
Polarizability23.61 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9962
Blood Brain Barrier+0.9383
Caco-2 permeable-0.5443
P-glycoprotein substrateNon-substrate0.6803
P-glycoprotein inhibitor INon-inhibitor0.837
P-glycoprotein inhibitor IINon-inhibitor0.8642
Renal organic cation transporterNon-inhibitor0.7664
CYP450 2C9 substrateNon-substrate0.763
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.651
CYP450 1A2 substrateNon-inhibitor0.8127
CYP450 2C9 inhibitorNon-inhibitor0.829
CYP450 2D6 inhibitorNon-inhibitor0.9159
CYP450 2C19 inhibitorNon-inhibitor0.7446
CYP450 3A4 inhibitorNon-inhibitor0.8499
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.789
Ames testAMES toxic0.9309
CarcinogenicityCarcinogens 0.5074
BiodegradationNot ready biodegradable0.7517
Rat acute toxicity3.5549 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8183
hERG inhibition (predictor II)Non-inhibitor0.8735
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as nitrosoureas. These are compounds containing a nitro group and an urea group N-N linked together, with the general structure R1N(R2)C(=O)N(R3)N=O.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Organic carbonic acids and derivatives
Sub Class
Ureas
Direct Parent
Nitrosoureas
Alternative Parents
Semicarbazides / Nitrosamides / Organopnictogen compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds / Alkyl chlorides
Substituents
Nitrosourea / Semicarbazide / Nitrosamide / Organic n-nitroso compound / Organic nitroso compound / Organic oxygen compound / Organopnictogen compound / Organic oxide / Hydrocarbon derivative / Alkyl chloride
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
organochlorine compound, N-nitrosoureas (CHEBI:6520)

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Yes
Actions
Cross-linking/alkylation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Larkin JM, Hughes SA, Beirne DA, Patel PM, Gibbens IM, Bate SC, Thomas K, Eisen TG, Gore ME: A phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. Br J Cancer. 2007 Jan 15;96(1):44-8. Epub 2006 Dec 5. [PubMed:17146474]
  4. Spiro T, Liu L, Gerson S: New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. Forum (Genova). 2000 Jul-Sep;10(3):274-85. [PubMed:11007934]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Tubulin binding
Specific Function
Exhibits microtubule-destabilizing activity.
Gene Name
STMN4
Uniprot ID
Q9H169
Uniprot Name
Stathmin-4
Molecular Weight
22071.02 Da
References
  1. Liang XJ, Choi Y, Sackett DL, Park JK: Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells. Cancer Res. 2008 Jul 1;68(13):5267-72. doi: 10.1158/0008-5472.CAN-07-6482. [PubMed:18593927]
  2. Wu WW, Wang G, Liang XJ, Park JK, Shen RF: Covalent modification of stathmin by CCNU determined by FTMS analysis of modified proteins and tryptic peptides. Biochem Biophys Res Commun. 2008 Feb 29;367(1):7-13. Epub 2007 Dec 26. [PubMed:18162179]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Zhou-Pan XR, Seree E, Zhou XJ, Placidi M, Maurel P, Barra Y, Rahmani R: Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions. Cancer Res. 1993 Nov 1;53(21):5121-6. [PubMed:8221648]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Drug created on June 13, 2005 07:24 / Updated on September 21, 2018 20:42