LOMUSTINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C9H16ClN3O2
Molecular Weight	233.695
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

ClCCN(N=O)C(=O)NC1CCCCC1

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 247 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Crosslinking Agent 80
RNA 18 Target ID: CHEMBL2311222 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Binding Agent 1059

Conditions

Condition	Modality	Targets	Highest Phase	Product
Brain cancer 10 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Primary		Approved 8360	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 8360	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 1579		inhibitor 1837

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1909	inhibitor 3240 Sources: https://cancerres.aacrjournals.org/content/canres/53/21/5121.full.pdf	likely
CYP2D6 1875	inhibitor 3240 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
[Post-operative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of German prospective randomised trial HIT'91].	2001 Apr	11355586
Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU.	2001 Aug	11571537
Melanoma-associated retinopathy: does autoimmunity prolong survival?	2001 Aug	11545422
Adults with newly diagnosed high-grade gliomas.	2001 Dec	12057096
Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia.	2001 Feb 15	11181679
Bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone (BLEO-CCVPP) in patients with Hodgkin's disease who relapsed after radiotherapy alone: a long-term follow-up study of the Eastern Cooperative Oncology Group (E3481).	2001 Jan	11426558
Spin labelled nitrosoureas and triazenes and their non-labelled clinically used analogues--a comparative study on their physicochemical properties and antimelanomic effects.	2001 Jan 16	11165083
Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.	2001 Jul	11561871
Bleomycin, methotrexate, and CCNU in locally advanced or recurrent, inoperable, squamous-cell carcinoma of the vulva: an EORTC Gynaecological Cancer Cooperative Group Study. European Organization for Research and Treatment of Cancer.	2001 Jun	11371121
PCV chemotherapy for recurrent glioblastoma multiforme.	2001 Jun 26	11425963
[Therapeutic effect on glioblastoma of chemotherapy on the basis of brain irradiation].	2001 Mar	11783028
Death receptor-independent cytochrome c release and caspase activation mediate thymidine kinase plus ganciclovir-mediated cytotoxicity in LN-18 and LN-229 human malignant glioma cells.	2001 Mar	11313826
Medical Research Council adjuvant trial in high-grade gliomas.	2001 Oct 1	11579124
The effectiveness of the O(6)-alkylguanine-DNA alkyltransferase encoded by the ogt(ST) gene from S. typhimurium in protection against alkylating drugs, resistance to O(6)-benzylguanine and sensitisation to dibromoalkane genotoxicity.	2001 Oct 18	11525913
Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt.	2002 Aug 1	12151519
Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91.	2002 Feb 1	11821469
High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma.	2002 Feb 1	11802203
Treatment of intracranial metastatic esthesioneuroblastoma.	2002 Jan 1	11773199
Treatment of intracranial metastatic esthesioneuroblastoma.	2002 Jul 15	12124822
Evaluation of naphthal-NU, a 2-chloroethylnitrosourea derivative of naphthalimide, as a mixed-function anticancer agent.	2002 Mar	12071535
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
Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972.	2003 Apr	12649108
Dramatic response to chemotherapy in oligodendroglial gliomatosis cerebri.	2003 Jan 14	12525747
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
Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group.	2003 May 1	12712456
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 [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

Lomustine [WHO-DD]

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

NBK548631