ESTRAMUSTINE PHOSPHATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C23H32Cl2NO6P
Molecular Weight	520.383
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CC[C@H](OP(O)(O)=O)[C@@]1(C)CC[C@]3([H])C4=C(CC[C@@]23[H])C=C(OC(=O)N(CCCl)CCCl)C=C4

InChI

InChIKey=ADFOJJHRTBFFOF-RBRWEJTLSA-N

InChI=1S/C23H32Cl2NO6P/c1-23-9-8-18-17-5-3-16(31-22(27)26(12-10-24)13-11-25)14-15(17)2-4-19(18)20(23)6-7-21(23)32-33(28,29)30/h3,5,14,18-21H,2,4,6-13H2,1H3,(H2,28,29,30)/t18-,19-,20+,21+,23+/m1/s1

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB01196
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018045s023lbl.pdf

Estramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nitrogen mustard. In vivo, the nitrogen-mustard moiety becomes active and participates in alkylation of DNA or other cellular components. This causes DNA damage in rapidly dividing cancerous cells leading to cell death and ideally, tumor shrinkage. Also, due to the drugs estrogen component, it can bind more selectively to active estrogen receptors. Used for the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
endothelial cell proliferation 7 Target ID: GO:0001935 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17851838	Inhibitor 8297	4.5 µM [IC50]
Estrogen receptor beta 110 Target ID: CHEMBL242 Sources: http://www.drugbank.ca/drugs/DB01196	Modulator 828
Estrogen receptor alpha 127 Target ID: CHEMBL206 Sources: http://www.drugbank.ca/drugs/DB01196	Agonist 2678
Microtubule-associated protein 1A 5 Target ID: P78559 Gene ID: 4130.0 Gene Symbol: MAP1A Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/1647395	Antagonist 2778
Microtubule-associated protein 2 5 Target ID: CHEMBL2390810 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1599956	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Carcinoma of the prostate 5 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018045s023lbl.pdf	Palliative		Approved 8429	Emcyt Approved Use EMCYT Capsules are indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Launch Date 1991

C_max

Value	Dose	Co-administered	Analyte	Population
362 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/6714283	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:		ESTRAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
2.88 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/6714283	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:		ESTRAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FED
972 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16568471	280 mg 3 times / day multiple, oral dose: 280 mg route of administration: Oral experiment type: MULTIPLE co-administered:		ESTRAMUSTINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
13.6 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/6714283	140 mg single, oral dose: 140 mg route of administration: Oral experiment type: SINGLE co-administered:		ESTRAMUSTINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
50% EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7736407			ESTRAMUSTINE plasma	Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
3000 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 3000 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3000 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118	unhealthy, 66 n = 4 Health Status: unhealthy Condition: Prostate cancer Age Group: 66 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118	DLT: Malaise and fatigue, Hypotension... Dose limiting toxicities: Malaise and fatigue (grade 3, 75%) Hypotension (grade 3, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118
2500 mg/m2 1 times / week multiple, intravenous MTD Dose: 2500 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2500 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1119, 1124	unhealthy, 66 n = 6 Health Status: unhealthy Condition: Prostate cancer Age Group: 66 Sex: M Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1119, 1124	DLT: Malaise and fatigue... Dose limiting toxicities: Malaise and fatigue (grade 3, 40%) Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1119, 1124

AEs

AE	Significance	Dose	Population
Hypotension	grade 3, 25% DLT	3000 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 3000 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3000 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118	unhealthy, 66 n = 4 Health Status: unhealthy Condition: Prostate cancer Age Group: 66 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118
Malaise and fatigue	grade 3, 75% DLT	3000 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 3000 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3000 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118	unhealthy, 66 n = 4 Health Status: unhealthy Condition: Prostate cancer Age Group: 66 Sex: M Population Size: 4 Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1118
Malaise and fatigue	grade 3, 40% DLT	2500 mg/m2 1 times / week multiple, intravenous MTD Dose: 2500 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 2500 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1119, 1124	unhealthy, 66 n = 6 Health Status: unhealthy Condition: Prostate cancer Age Group: 66 Sex: M Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/11844837 Page: p.1119, 1124

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/7736407/\|https://pubmed.ncbi.nlm.nih.gov/7908988/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4868	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4868
ChemicalBook	CB9127416	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9127416
MolPort	MolPort-006-114-857	https://www.molport.com/shop/molecule-link/MolPort-006-114-857
ZINC	ZINC000004099032	http://zinc15.docking.org/substances/ZINC000004099032
eMolecules	30151822	https://www.emolecules.com/cgi-bin/more?vid=30151822

PubMed

Title	Date	PubMed
Treatment options in hormone-refractory prostate cancer: current and future approaches.	2001	11772129
Oral combination of cyclophosphamide, uracil plus tegafur and estramustine for hormone-refractory prostate cancer.	2001	11150908
Can chemotherapy alter the course of prostate cancer?	2001 Aug	11561989
Treatment of hormone refractory prostate cancer.	2001 Aug	11561988
Estramustine-related hypocalcemia in patients with prostate carcinoma and osteoblastic metastases.	2001 Jul	11445494
[A male case of primary bilateral breast cancers during estrogen therapy for prostate cancer].	2001 Nov	11766369
[Clinical efficacy of leuprolide acetate and combined treatment with estramustine for advanced prostate cancer].	2001 Nov	11766367
The treatment challenge of hormone-refractory prostate cancer.	2001 Nov-Dec	11807418
Controversies in chemotherapy of prostate cancer.	2002	11842757
[Therapy for hormone-refractory prostate cancer].	2002 Dec	12599583
[Chemotherapy for prostate cancers].	2002 Dec	12599572
Fatal respiratory failure associated with treatment of prostate cancer using docetaxel and estramustine.	2002 Dec	12475686
EMP combination chemotherapy and low-dose monotherapy in advanced prostate cancer.	2002 Feb	12113067
Higher doses of mitoxantrone among men with hormone-refractory prostate carcinoma: a Cancer and Leukemia Group B study.	2002 Feb 1	11857298
The flare in alkaline phosphatase activity post-orchidectomy predicts which patient may benefit from early chemotherapy in metastatic prostate cancer.	2002 Feb 1	11816020
Phase I clinical and pharmacologic trial of intravenous estramustine phosphate.	2002 Feb 15	11844837
Docetaxel in the integrated management of prostate cancer. Current applications and future promise.	2002 Jun	12108899
Effects of docetaxel on pain due to metastatic androgen-independent prostate cancer.	2002 Jun	12084194
High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone.	2002 Jun 5	12087455
Estramustine phosphate enhances the effects of hyperthermia and induces the small heat shock protein HSP27 in the human prostate carcinoma cell line PC-3.	2002 May	12086019
Weekly epirubicin in patients with hormone-resistant prostate cancer.	2002 Sep 23	12232753
Role of chemotherapy in hormone-refractory prostate cancer. Old issues, recent advances and new perspectives.	2003	12566808
Docetaxel (taxotere) in the treatment of prostate cancer.	2003 Jun	12820771
Randomized, multicenter, phase II trial of two multicomponent regimens in androgen-independent prostate cancer.	2003 Mar 1	12610188
Characterization of the MRP4- and MRP5-mediated transport of cyclic nucleotides from intact cells.	2003 May 16	12637526
Neoadjuvant therapy before radical prostatectomy in high-risk localized prostate cancer: defining appropriate endpoints.	2003 May-Jun	12810211
High-risk localized prostate cancer: primary surgery and adjuvant therapy.	2003 May-Jun	12810210

Patents

Sample Use Guides

In Vivo Use Guide

The recommended daily dose is 14 mg per kg of body weight (ie, one 140 mg capsule for each 10 kg or 22 lb of body weight), given in 3 or 4 divided doses. Most patients in studies in the United States have been treated at a dosage range of 10 to 16 mg per kg per day.

Route of Administration: Oral

In Vitro Use Guide

Estramustine inhibited human endothelial cell proliferation with an IC50 of 4.5 uM and was active at 10-33% of the maximum tolerated dose (MTD) from clinical schedules

Name

Type

Language

ESTRAMUSTINE PHOSPHATE

Common Name

English

ESTRAMUSTINE 17-(DIHYDROGEN PHOSPHATE) [MI]

Common Name

English

LS 299

Common Name

English

ESTRAMUSTINE 17-(DIHYDROGEN PHOSPHATE)

Common Name

English

LS-299

Common Name

English

ESTRADIOL, 3-(BIS(2-CHLOROETHYL)CARBAMATE) DIHYDROGEN PHOSPHATE

Common Name

English

ESTRACYT

Brand Name

English

NSC-89199

Code

English

Estramustine phosphate [WHO-DD]

Common Name

English

Code System Code Type Description

EPA CompTox

DTXSID7048667