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 229 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 994

Conditions

Condition	Modality	Targets	Highest Phase	Product
Brain cancer 10 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf	Primary		Approved 8003	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 8003	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 1461		inhibitor 1701

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1768	inhibitor 3041 Sources: https://cancerres.aacrjournals.org/content/canres/53/21/5121.full.pdf	likely
CYP2D6 1735	inhibitor 3041 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
APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis.	2001 Apr	11550092
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
Chemotherapy for the treatment of oligodendroglial tumors.	2001 Aug	11550134
Melanoma-associated retinopathy: does autoimmunity prolong survival?	2001 Aug	11545422
PCV for oligodendroglial tumors: in search of prognostic factors for response and survival.	2001 Aug	11513339
Thyroid dysfunction as a late effect in childhood medulloblastoma: a comparison of hyperfractionated versus conventionally fractionated craniospinal radiotherapy.	2001 Aug 1	11483340
Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.	2001 Aug-Oct	12049483
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
Multiple myeloma in elderly patients: presenting features and outcome.	2001 Jan	11168502
Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.	2001 Jul	11561871
Protection of hematopoietic cells from O(6)-alkylation damage by O(6)-methylguanine DNA methyltransferase gene transfer: studies with different O(6)-alkylating agents and retroviral backbones.	2001 Jul	11553261
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
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
Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy.	2001 May 1	11331324
Lipid association improves the therapeutic index of lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] to suppress 36B-10 tumor growth in rats.	2001 May 1	11325837
Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a national cooperative cancer treatment group.	2001 Oct	11586105
Medical Research Council adjuvant trial in high-grade gliomas.	2001 Oct 1	11579124
Nitric oxide and free stable nitroxyl radicals in the mechanism of biological action of the spin-labeled compounds.	2001 Sep	11516220
[Role of adjuvant chemotherapy in the treatment of medulloblastoma in children].	2002	12455354
11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop.	2002 Apr	11921271
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
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
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
Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase.	2002 Mar 15	11912174
[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
Feasibility and toxicity of CCNU therapy in elderly patients with glioblastoma multiforme.	2003 Feb	12569300
Survival with dacarbazine and fotemustine in newly diagnosed glioblastoma multiforme.	2003 Feb 24	12592361
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
Glioma treatment, radionecrosis, and growth factors. In regard to Levin et al., IJROBP 2002;53:58-66.	2003 Mar 1	12573773
Interobserver variability in the radiological assessment of response to chemotherapy in glioma.	2003 Mar 11	12629241
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

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