FOTEMUSTINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C9H19ClN3O5P
Molecular Weight	315.691
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O

InChI

InChIKey=YAKWPXVTIGTRJH-UHFFFAOYSA-N

InChI=1S/C9H19ClN3O5P/c1-4-17-19(16,18-5-2)8(3)11-9(14)13(12-15)7-6-10/h8H,4-7H2,1-3H3,(H,11,14)

HIDE SMILES / InChI

Molecular Formula	C9H19ClN3O5P
Molecular Weight	315.691
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15020614
Curator's Comment: The description was created based on several sources, including https://www.drugs.com/international/fotemustine.html | https://www.ncbi.nlm.nih.gov/pubmed/24213227 | https://clinicaltrials.gov/ct2/show/NCT01960192 | https://www.ncbi.nlm.nih.gov/pubmed/26951379 | https://www.ncbi.nlm.nih.gov/pubmed/25702193

Fotemustine is a novel chloroethylnitrosourea alkylating agent approved for use in the treatment of metastasizing melanoma and Recurrent Malignant Gliomas. The antitumor activity of fotemustine is related to its ability to alkylate DNA. It's in vitro or in vivo pharmacological activity is similar or greater than that of other nitrosoureas. Significant activity has been found in mice xenograft models of human primary cerebral tumors after fotemustine intraperitoneal administration. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia, and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24213227	Crosslinking Agent 81

Conditions

Condition	Modality	Highest Phase	Product
Malignant melanoma 22 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15020614	Primary	Approved 8429	Muphoran Approved Use Unknown
Recurrent malignant glioma 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24213227	Primary	Approved 8429	Muphoran Approved Use Unknown
Primary CNS lymphoma 1 Sources: https://clinicaltrials.gov/ct2/show/NCT01960192	Primary	Phase IV 63	Muphoran Approved Use Unknown

PubMed

Title	Date	PubMed
Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy.	2002 Aug 1	12209758
Survival with dacarbazine and fotemustine in newly diagnosed glioblastoma multiforme.	2003 Feb 24	12592361
Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme.	2003 Jul	12853885
Cytotoxicity, DNA damage, and apoptosis induced by new fotemustine analogs on human melanoma cells in relation to O6-methylguanine DNA-methyltransferase expression.	2003 Nov	12970393
Isolated limb infusion with fotemustine after dacarbazine chemosensitisation for inoperable loco-regional melanoma recurrence.	2004 Dec	15522559
Artesunate in the treatment of metastatic uveal melanoma--first experiences.	2005 Dec	16273263
Organ- and treatment-specific local response rates to systemic and local treatment modalities in stage IV melanoma.	2005 Nov	16225601
O(6)-methylguanine DNA-methyltransferase (MGMT) overexpression in melanoma cells induces resistance to nitrosoureas and temozolomide but sensitizes to mitomycin C.	2006 Mar 1	16039682
Resection in the popliteal fossa for metastatic melanoma.	2007 Jan 19	17239242
Can high-dose fotemustine reverse MGMT resistance in glioblastoma multiforme?	2010 Nov	20556481
Human three prime exonuclease TREX1 is induced by genotoxic stress and involved in protection of glioma and melanoma cells to anticancer drugs.	2013 Aug	23578789

Patents

Sample Use Guides

In Vivo Use Guide

Fotemustine was administered weekly for 3 consecutive weeks (days 1, 8, and 15) at 100 mg/m2 as a 60-minute infusion, followed by a 5-week rest period

Route of Administration: Intravenous

In Vitro Use Guide

The BRAFV600E A375, Malme-3M, A2058 and RPMI7951 and wild-type SK-Mel537, SK-Mel505, RPMI18332 and SK-Mel187 melanoma cell lines were used for activity evaluation. Cells were treated with the chemotherapeutic (Fotemustine, FM) and the number of cell divisions following 120h incubation was determined using flow cytometry of CFSE stained cells. The cellular division rate was determined using carboxyfluorescein diacetate succinimidyl ester (CFSE) stained cells [39]. One day after labeling the control sample (0h) was harvested and analyzed by flow cytometry (FACS Canto II). On this day cells were treated or not with vemurafenib, TMZ, FM or combinations of the drugs, and 120h later samples were harvested and subjected to flow cytometry analysis. Using the mean 0h fluorescence signal, a standard curve was plotted to determine the number of cell divisions after 120h incubation in treated and untreated cells.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:42:20 UTC 2023` Edited by `admin` on `Sat Dec 16 16:42:20 UTC 2023`
Record UNII	GQ7JL9P5I2
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

FOTEMUSTINE

Official Name

English

MUSTOPHORANE

Brand Name

English

FOTEMUSTINE [MART.]

Common Name

English

S10036

Code

English

MUPHORAN

Brand Name

English

PHOSPHONIC ACID, P-(1-((((2-CHLOROETHYL)NITROSOAMINO)CARBONYL)AMINO)ETHYL)-, DIETHYL ESTER

Systematic Name

English

S-10036

Code

English

(±)-DIETHYL (1-(3-(2-CHLOROETHYL)-3-NITROSOUREIDO)ETHYL)PHOSPHONATE

Systematic Name

English

PHOSPHONIC ACID, (1-((((2-CHLOROETHYL)NITROSOAMINO)CARBONYL)AMINO)ETHYL)-, DIETHYL ESTER

Common Name

English

FOTEMUSTINE [MI]

Common Name

English

FOTEMUSTINE [HSDB]

Common Name

English

fotemustine [INN]

Common Name

English

Fotemustine [WHO-DD]

Common Name

English

Classification Tree Code System Code

WHO-ATC

L01AD05