LOMUSTINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C9H16ClN3O2
Molecular Weight	233.6955
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C1CCC(CC1)N=C(N(CCCl)N=O)O

InChI

InChIKey=GQYIWUVLTXOXAJ-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf
Curator's Comment:: description was created based on several sources, including: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f77526b-4c40-409c-82ea-d0f934d89cc2

Lomustine is used in the treatment of certain neoplastic diseases. Although it is generally agreed that lomustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. Common adverse reactions include delayed myelosupression, nausea, vomiting, stomatitis, and alopecia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 232 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Crosslinking Agent 76
RNA 17 Target ID: CHEMBL2311222 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Binding Agent 996

Conditions

Condition	Modality	Targets	Highest Phase	Product
Brain cancer 10 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Primary		Approved 8043	GLEOSTINE Approved Use CeeNU has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. Hodgkin’s disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy. Launch Date 2.07964799E11
Hodgkin's lymphoma 34 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Primary		Approved 8043	GLEOSTINE Approved Use CeeNU has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures. Hodgkin’s disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy. Launch Date 2.07964799E11

C_max

Value	Dose	Co-administered	Analyte	Population
8.6 μg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3966974	20 mg/kg single, oral dose: 20 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LOMUSTINE plasma	Mus musculus population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
2 ng/mL OTHER GOV https://www.medicines.org.uk/emc/product/1401/smpc	100 mg/m² single, oral dose: 100 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		LOMUSTINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
705 μg × min/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3966974	20 mg/kg single, oral dose: 20 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LOMUSTINE plasma	Mus musculus population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
50% REVIEW http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Lomustine_monograph.pdf			LOMUSTINE plasma	Homo sapiens

Doses

Dose	Population	Adverse events
400 mg/m2 single, oral Highest studied dose Dose: 400 mg/m2 Route: oral Route: single Dose: 400 mg/m2 Co-administed with:: etoposide, i.v(1 g/m2) ara-C, i.v(4g/m2) melphalan(140 mg/m2) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	unhealthy, 36 n = 2 Health Status: unhealthy Condition: Lymphoma Age Group: 36 Population Size: 2 Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	DLT: Gastrointestinal toxicity, Sinusoidal obstruction syndrome... Dose limiting toxicities: Gastrointestinal toxicity (grade 4, 50%) Sinusoidal obstruction syndrome (grade 4, 50%) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380
300 mg/m2 single, oral MTD Dose: 300 mg/m2 Route: oral Route: single Dose: 300 mg/m2 Co-administed with:: etoposide, i.v(1 g/m2) ara-C, i.v(4g/m2) melphalan(140 mg/m2) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	unhealthy, 36 n = 6 Health Status: unhealthy Condition: Lymphoma Age Group: 36 Population Size: 6 Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	DLT: Neurotoxicity... Dose limiting toxicities: Neurotoxicity (grade 4, 33.3%) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380
130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	Disc. AE: Myelosuppression, Pulmonary toxicity... AEs leading to discontinuation/dose reduction: Myelosuppression (grade 5) Pulmonary toxicity Pulmonary fibrosis Acute leukemia Myelodysplasia Hepatotoxicity Nephrotoxicity Fetal damage Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Gastrointestinal toxicity	grade 4, 50% DLT	400 mg/m2 single, oral Highest studied dose Dose: 400 mg/m2 Route: oral Route: single Dose: 400 mg/m2 Co-administed with:: etoposide, i.v(1 g/m2) ara-C, i.v(4g/m2) melphalan(140 mg/m2) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	unhealthy, 36 n = 2 Health Status: unhealthy Condition: Lymphoma Age Group: 36 Population Size: 2 Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380
Sinusoidal obstruction syndrome	grade 4, 50% DLT	400 mg/m2 single, oral Highest studied dose Dose: 400 mg/m2 Route: oral Route: single Dose: 400 mg/m2 Co-administed with:: etoposide, i.v(1 g/m2) ara-C, i.v(4g/m2) melphalan(140 mg/m2) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	unhealthy, 36 n = 2 Health Status: unhealthy Condition: Lymphoma Age Group: 36 Population Size: 2 Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380
Neurotoxicity	grade 4, 33.3% DLT	300 mg/m2 single, oral MTD Dose: 300 mg/m2 Route: oral Route: single Dose: 300 mg/m2 Co-administed with:: etoposide, i.v(1 g/m2) ara-C, i.v(4g/m2) melphalan(140 mg/m2) Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380	unhealthy, 36 n = 6 Health Status: unhealthy Condition: Lymphoma Age Group: 36 Population Size: 6 Sources: https://www.tctjournal.org/action/showPdf?pii=S1083-8791%2813%2900730-1 https://pubmed.ncbi.nlm.nih.gov/24887380
Acute leukemia	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Fetal damage	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Hepatotoxicity	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Myelodysplasia	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Nephrotoxicity	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Pulmonary fibrosis	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Pulmonary toxicity	Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1
Myelosuppression	grade 5 Disc. AE	130 mg/m2 1 times / 6 weeks multiple, oral Recommended Dose: 130 mg/m2, 1 times / 6 weeks Route: oral Route: multiple Dose: 130 mg/m2, 1 times / 6 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Brain tumors\|Hodgkin’s lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf Page: p.1

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1467		inhibitor 1702

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1772	inhibitor 3045 Sources: https://cancerres.aacrjournals.org/content/canres/53/21/5121.full.pdf	likely
CYP2D6 1738	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/8258200/	yes [Ki 7.7 uM]

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:6520	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:6520
ChemicalBook	CB5123021	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5123021
MolPort	MolPort-001-768-818	https://www.molport.com/shop/molecule-link/MolPort-001-768-818
Selleck Chemicals	Lomustine(CeeNU)	http://www.selleckchem.com/products/Lomustine(CeeNU).html
ZINC	ZINC000003831006	http://zinc15.docking.org/substances/ZINC000003831006
eMolecules	734270	https://www.emolecules.com/cgi-bin/more?vid=734270

PubMed

Title	Date	PubMed
Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.	2001 Aug-Oct	12049483
Adults with newly diagnosed high-grade gliomas.	2001 Dec	12057096
[Therapeutic effect on glioblastoma of chemotherapy on the basis of brain irradiation].	2001 Mar	11783028
PCV chemotherapy for oligodendroglioma: response analyzed on T2 weighted-MRI.	2001 Oct	11804282
A possible correlation between unscheduled DNA repair and cholesterolemia in Wistar rat, modulated by vitamin E.	2001 Oct-Dec	12561677
[Role of adjuvant chemotherapy in the treatment of medulloblastoma in children].	2002	12455354
Structure-based design of nitrosoureas containing tyrosine derivatives as potential antimelanoma agents.	2002 Apr	11960664
11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop.	2002 Apr	11921271
Intensified PCV-chemotherapy with optional stem cell support in recurrent malignant oligodendroglioma.	2002 Aug	12195453
Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil.	2002 Aug	12153595
Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt.	2002 Aug 1	12151519
Coeliac disease following high-dose chemotherapy.	2002 Dec	12512973
Recurrent malignant glioma in adults.	2002 Dec	12392640
Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study.	2002 Dec 1	12436452
Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma.	2002 Dec 1	12436444
An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease.	2002 Dec 15	12467067
High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma.	2002 Feb 1	11802203
Preradiation chemotherapy for pediatric patients with high-grade glioma.	2002 Jan 1	11815986
Treatment of intracranial metastatic esthesioneuroblastoma.	2002 Jul 15	12124822
Hematological toxicity and therapeutic efficacy of lomustine in 20 tumor-bearing cats: critical assessment of a practical dosing regimen.	2002 Jul-Aug	12118689
Long-term follow-up in managing anaplastic astrocytoma by multimodality approach with surgery followed by postoperative radiotherapy and PCV-chemotherapy: phase II trial.	2002 Jun	12040293
Evaluation of naphthal-NU, a 2-chloroethylnitrosourea derivative of naphthalimide, as a mixed-function anticancer agent.	2002 Mar	12071535
Study of three hepatobiliary agents in experimental animals.	2002 Mar-Apr	11990340
Concurrent modified PCV chemotherapy and radiotherapy in newly diagnosed grade IV astrocytoma.	2002 May	12125984
NO-mediated chemoresistance in C6 glioma cells.	2002 May	12076959
[Chemo-radiotherapy for malignant brain tumors].	2002 May	12040669
Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas.	2002 May 1	12007942
Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma.	2002 May 1	11980654
Acute diarrhea during adjuvant therapy for rectal cancer: a detailed analysis from a randomized intergroup trial.	2002 Oct 1	12243815
Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate.	2002 Sep	12241121
Radiotherapy alone for lymphocyte-predominant Hodgkin's disease.	2002 Sep-Oct	12416895
Low-dose continuous chemotherapy for metastatic melanoma: a phase II trial.	2003 Apr	12690305
Survival and prognostic factors of patients with unresectable glioblastoma multiforme.	2003 Apr	12679735
Recent developments in the molecular characterization and treatment of oligodendroglial tumors.	2003 Apr	12672285
Partially successful treatment of a patient with chronic lymphocytic leukemia and Hodgkin's disease: case report and literature review.	2003 Apr	12666139
Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: efficacy and associations with chromosomal abnormalities.	2003 Jan 15	12525516
Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.	2003 Jul 1	12829671
Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group.	2003 Jul 15	12860951
Phase I study of temozolamide (TMZ) combined with procarbazine (PCB) in patients with gliomas.	2003 Jul 21	12865911
Myeloid clonogenic assays for comparison of the in vitro toxicity of alkylating agents.	2003 Jun	12781205
High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy.	2003 Jun 15	12805333
Survival improvement in patients with glioblastoma multiforme during the last 20 years in a single tertiary-care center.	2003 Jun 24	12879737
Genetic alterations of human brain tumors as molecular prognostic factors.	2003 Mar	12722932
Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas.	2003 Mar	12631596
New chemotherapy agents in veterinary medicine.	2003 May	12852240
Combined modality therapy for poorly differentiated gliomas of the posterior fossa in children: a Children's Cancer Group report.	2003 May	12814254
Bleomycin, vincristine, lomustine and dacarbazine (BOLD) in combination with recombinant interferon alpha-2b for metastatic uveal melanoma.	2003 May	12736111
Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group.	2003 May 1	12712456
Conformal irradiation for pure and mixed oligodendroglioma: the experience of Centre Leon Berard Lyon.	2003 May 1	12694851
Role of mismatch repair in the induction of chromosomal aberrations and sister chromatid exchanges in cells treated with different chemotherapeutic agents.	2003 Sep	12827294

Patents

Sample Use Guides

In Vivo Use Guide

Recommended dose in adult and pediatric patients is 130 mg/m2 orally every 6 weeks.

Route of Administration: Oral

In Vitro Use Guide

Alkylation of the nuclear matrix by Lomustine was 1.27 pmoles drug/micrograms protein, whereas carbamoylation by Lomustine was 32.5 pmoles/micrograms.

Name

Type

Language

LOMUSTINE

Official Name

English

LOMUSTINE [USP MONOGRAPH]

Common Name

English

1-(2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA [IARC]

Common Name

English

1-(2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA

Systematic Name

English

LOMUSTINE [HSDB]

Common Name

English

LOMUSTINE [WHO-DD]

Common Name

English

LOMUSTINE [EP MONOGRAPH]

Common Name

English

CEENU

Brand Name

English

CCN-U

Code

English

LOMUSTINE [MART.]

Common Name

English

CCNU

Code

English

LOMUSTINE [VANDF]

Common Name

English

UREA, N-(2-CHLOROETHYL)-N'-CYCLOHEXYL-N-NITROSO-

Systematic Name

English

LOMUSTINE [USP-RS]

Common Name

English

LOMUSTINE [ORANGE BOOK]

Common Name

English

NSC-79037

Code

English

LOMUSTINE [USAN]

Common Name

English

LOMUSTINE [MI]

Common Name

English

LOMUSTINE [INN]

Common Name

English

Classification Tree Code System Code

LIVERTOX

566