Estramustine phosphate

Source: Wikipedia, the free encyclopedia.
Not to be confused with Estramustine.
Estramustine phosphate
Clinical data
Trade namesEmcyt, Estracyt
Other namesEMP; Leo 299; NSC-89199; Ro 21-8837/001; Estradiol normustine phosphate; Estradiol 3-normustine 17β-phosphate; Estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate)
AHFS/Drugs.comMonograph
MedlinePlusa608046
License data
Pregnancy
category
  • AU: D
Chemotherapeutic agent; Estrogen; Estrogen ester
ATC code
Legal status
Legal status
feces (2.9–4.8%)[1][6]
Identifiers
  • [(8R,9S,13S,14S,17S)-13-methyl-17-phosphonooxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] N,N-bis(2-chloroethyl)carbamate
JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2OP(=O)(O)O)CCC4=C3C=CC(=C4)OC(=O)N(CCCl)CCCl
  • 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
  • Key:ADFOJJHRTBFFOF-RBRWEJTLSA-N

Estramustine phosphate (EMP), also known as estradiol normustine phosphate and sold under the brand names Emcyt and Estracyt, is a dual

injection into a vein.[7][8][3][1][5][12]

antigonadotropic and functional antiandrogenic effects.[4][1][3][14]

EMP was introduced for medical use in the early 1970s.[3] It is available in the United States, Canada, the United Kingdom, other European countries, and elsewhere in the world.[15][16]

Medical uses

EMP is indicated, in the

high-dose estrogen therapy.[18]

Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer.[4] This is especially true in Western countries today.[4] As a result, and also due to the scarce side effects of gonadotropin-releasing hormone modulators (GnRH modulators) like leuprorelin, EMP was almost abandoned.[3] However, encouraging clinical research findings resulted in renewed interest of EMP for the treatment of prostate cancer.[3]

EMP has been used at doses of 140 to 1,400 mg/day orally in the treatment of prostate cancer.[19] However, oral EMP is most commonly used at a dose of 560 to 640 mg/day (280–320 mg twice daily).[1] The recommended dosage of oral EMP in the Food and Drug Administration (FDA) label for Emcyt is 14 mg per kg of body weight (i.e., one 140 mg oral capsule for each 10 kg or 22 lbs of body weight) given in 3 or 4 divided doses per day.[7] The label states that most patients in studies of oral EMP in the United States have received 10 to 16 mg per kg per day.[7] This would be about 900 to 1,440 mg/day for a 90-kg or 200-lb man.[7] Lower doses of oral EMP, such as 280 mg/day, have been found to have comparable effectiveness as higher doses but with improved tolerability and reduced toxicity.[4] Doses of 140 mg/day have been described as a very low dosage.[20] EMP has been used at doses of 240 to 450 mg/day intravenously.[1]

EMP and other estrogens such as polyestradiol phosphate and ethinylestradiol are far less costly than newer therapies such as GnRH modulators, abiraterone acetate, and enzalutamide.[4][21][22] In addition, estrogens may offer significant benefits over other means of androgen deprivation therapy, for instance in terms of bone loss and fractures, hot flashes, cognition, and metabolic status.[4][22]

EMP has been used to prevent the

GnRH agonist therapy in men with prostate cancer.[23]

Estrogen dosages for prostate cancer
Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–3 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 100–480 mg 1–3x/day
Chlorotrianisene 12–48 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
SC injection
 Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection
 Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Available forms

EMP is or has been available in the form of both capsules (140 mg, 280 mg) for oral administration and aqueous solutions (300 mg) for intravenous injection.[19][24][25][7]

Contraindications

EMP is

fluid retention.[17]

Side effects

The

irradiation of the breasts can be used to decrease the incidence and severity of gynecomastia with estrogens.[13]

Severe adverse effects of EMP are

molecular-weight heparin, and vitamin K antagonists can be useful for decreasing the risk of thromboembolism with EMP and other estrogens like diethylstilbestrol and ethinylestradiol.[9][30][4]

Adverse

myelosuppression (bone marrow suppression), gastrointestinal toxicity, or other more marked toxicity associated with such agents.[5][1][31] In contrast to most other cytostatic agents, which often cause myelosuppression, leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count), EMP actually produces leukocytosis (increased white blood cell count) as a side effect.[32][33]

In a small low-dose study using 280 mg/day oral EMP for 150 days, tolerability was significantly improved, with gastrointestinal

elevated liver enzymes were observed.[3] These findings suggest that lower doses of oral EMP may be a safer option than higher doses for the treatment of prostate cancer.[4] However, a subsequent 2004 meta-analysis of 23 studies of thromboembolic events with EMP found substantial incidence of thromboembolic events regardless of dosage and no association of EMP dose with risk of these complications.[28]

Side effects of estramustine phosphate (EMC)
System organ class
 Very common (≥10%) Common (1–10%) Frequency unknownc
lymphatic system disorders
 Anemia; Leukopenia Thrombocytopenia
Immune system disorders
 Hypersensitivity
nutrition disorders
Fluid retention
Psychiatric disorders
 Confusional state; Depression
Nervous system disorders
 Lethargy; Headache
Cardiac disorders
Congestive heart failure
 Myocardial infarction
Myocardial ischemia
Vascular disorders
 Embolism Hypertension
Gastrointestinal disorders
 Nauseab; Vomitingb; Diarrheab
Hepatobiliary disorders
Abnormal hepatic function
Skin and subcutaneous tissue disorders
Allergic dermatitis
connective tissue disorders
 Muscle weakness
breast disorders
 Gynecomastia Erectile dysfunction
General disorders and administration site conditions
IVTooltip intravenous solution
)
Footnotes: a = Could not be estimated from available data. b = Especially during the first 2 weeks of therapy. c = Angioedema (
larynx edema) can occur. Often occurs in combination with ACE inhibitors
. EMP should be immediately discontinued if angioedema occurs. Sources: See template.
Side effects of estramustine phosphate (FDA)
Side effect Estramustine phosphate (oral
11.5–15.9 mg/kg/day) (n = 93) (%)		 Diethylstilbestrol (oral
3.0 mg/day) (n = 93) (%)
respiratory
Cardiac arrest 0 2
Cerebrovascular accident
(stroke)		 2 0
Myocardial infarction (heart attack) 3 1
Thrombophlebitis 3 7
Pulmonary embolism 2 5
Congestive heart failure
 3 2
swelling
)		 19 17
Dyspnea
(shortness of breath)		 11 3
Leg cramps
 8 11
Upper respiratory discharge
 1 1
Hoarseness
 1 0
Gastrointestinal
Nausea 15 8
Diarrhea 12 11
Minor
gastrointestinal upset
 11 6
Anorexia (appetite loss) 4 3
Flatulence 2 0
Vomiting 1 1
Gastrointestinal bleeding 1 0
Burning throat
 1 0
Thirst 1 0
Integumentary
Rash 1 4
Pruritus
(itching)		 2 2
Dry skin
 2 0
Pigment changes
 0 3
Easy bruising
 3 0
Flushing 1 0
Night sweats
 0 1
Peeling of fingertip skin
 1 0
Thinning hair
 1 1
Breast changes
Breast tenderness
 66 64
Breast enlargement (gynecomastia or male breast development)
  Mild 60 54
  Moderate 10 16
  Marked 0 5
Miscellaneous
Lethargy alone 4 3
Depression 0 2
Emotional lability 2 0
Insomnia 3 0
Headache 1 1
Anxiety 1 0
Chest pain 1 1
Hot flashes 0 1
Eye pain 0 1
Lacrimation
(eye tears)		 1 1
Tinnitus 0 1
Laboratory abnormalities
Hematologic (blood
)
Leukopenia (low white blood cells) 4 2
Thrombopenia (low platelets
)		 1 2
Hepatic
(liver)
Bilirubin alone 1 5
Bilirubin and LDHTooltip lactate dehydrogenase 0 1
Bilirubin and ASTTooltip aspartate transaminase 2 1
Bilirubin, LDH, and SGOT 2 0
LDH and/or SGOT 31 28
Miscellaneous
Transient
hypercalcemia (high calcium
)		 0 1
Sources: [34]

Overdose

There has been no clinical experience with

hematological and hepatic parameters should continue to be monitored for at least 6 weeks.[7]

EMP has been used at high doses of as much as 1,260 mg/day by the

intravenous injection.[3][1]

Interactions

EMP has been reported to increase the

absorption and hence oral bioavailability of EMP.[3][1][17] There may be an increased risk of angioedema in those concurrently taking ACE inhibitors.[17]

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of estradiol
Estramustine, the major active cytostatic form of estramustine phosphate.
Estradiol, the major active estrogenic form of estramustine phosphate.

EMP, also known as estradiol normustine phosphate, is a combined

molecular weight than estradiol due to the presence of its C3 normustine and C17β phosphate esters.[35][15] Because EMP is a prodrug of estradiol, it may be considered to be a natural and bioidentical form of estrogen,[14] although it does have additional cytostatic activity via estramustine and estromustine.[1][3]

EMP acts by a dual

EC50Tooltip half-maximal effective concentration = 0.5–3.1 μM), although the clinical significance of this is unknown.[39][36][3][1]

Extremely high levels of estradiol and estrone occur during EMP therapy.

uterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans.[40][41]

The mechanism of action of the

cytostatic effects of EMP is complex and only partially understood.[1] EMP is considered to mainly be a mitotic inhibitor, inhibiting mechanisms involved in the mitosis phase of the cell cycle.[1][4] Specifically, it binds to microtubule-associated proteins and/or to tubulin and produces depolymerization of microtubules (Kd = 10–20 μM for estramustine), resulting in the arrest of cell division in the G2/M phase (specifically metaphase).[1][4][42] EMP was originally thought to mediate its cytostatic effects as a prodrug of normustine, a nitrogen mustard, and hence was thought to be an alkylating antineoplastic agent.[3][10][5][14] However, subsequent research has found that EMP is devoid of alkylating actions, and that the influence of EMP on microtubules is mediated by intact estramustine and estromustine, with normustine or estradiol alone having only minor or negligible effects.[1][3][43] As such, the unique properties of the estramustine and estromustine structures, containing a carbamate-ester bond, appear to be responsible for the cytostatic effects of EMP.[1] In addition to its antimitotic actions, EMP has also been found to produce other cytostatic effects, including induction of apoptosis, interference with DNA synthesis, nuclear matrix interaction, cell membrane alterations, induction of reactive oxygen species (free oxygen radicals), and possibly additional mechanisms.[1][4] EMP has been found to have a radiosensitizing effect in prostate cancer and glioma cells, improving sensitivity to radiation therapy as well.[1]

The cytostatic metabolites of EMP are accumulated in tissues in a selective manner, for instance in prostate cancer cells.[5][1][4] This may be due to the presence of a specific estramustine-binding protein (EMBP) (Kd = 10–35 nM for estramustine), also known as prostatin or prostatic secretion protein (PSP), which has been detected in prostate cancer, glioma, melanoma, and breast cancer cells.[1][4][44] Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells.[5][4][1]

EMP was originally developed as a dual ester prodrug of an estrogen and normustine as a nitrogen mustard alkylating antineoplastic agent which, due to the affinity of the estrogen

tumor cells.[4][14][2] Consequentially, it was thought that EMP would preferentially deliver the alkylating normustine moiety to these tissues, allowing for reduced cytostatic effects in healthy tissues and hence improved efficacy and tolerability.[4] However, subsequent research found that there is very limited and slow cleavage of the normustine ester and that EMP is devoid of alkylating activity.[4][1][3][31] In addition, it appears that estramustine and estromustine may be preferentially accumulated in estrogen target tissues not due to affinity for the estrogen receptors, but instead due to affinity for the distinct EMBP.[1][3]

Extremely high,

myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count).[citation needed
]

Antigonadotropic effects

EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days.[3] Similarly, a dosage of 70 mg/day EMP suppressed testosterone levels into the castrate range within 4 weeks.[3]

Pharmacokinetics

See also: Pharmacokinetics of estradiol
Estradiol and testosterone levels during therapy with 280 mg/day oral EMP in men with prostate cancer (n = 11).[3]
Pharmacokinetics of estromustine after a single dose of EMP in men with prostate cancer (n = 5)
Parameter IV 300 mg Oral 420 mg
Cmax 506 ± 61 ng/mL 362 ± 38 ng/mL
Tmax
 2.6 ± 0.4 hours 2.2 ± 0.2 hours
t1/2
 10.3 ± 0.95 hours 13.6 ± 3.09 hours
AUC0–32 4.82 ± 0.62 2.88 ± 0.34
Bioavailability 100.0% 43.7% ± 4.6%
Sources: [31]

Levels of EMP metabolites during continuous therapy with 560 mg/day oral EMP in men
Metabolite Plasma Ratio
Estramustine 20,000–23,000 pg/mL 1:9.6–9.8
Estromustine 191,000–267,000 pg/mL
Estradiol 4,900–9,000 pg/mL 1:9.4–11.8
Estrone 71,000–85,000 pg/mL
Sources: [31]

Upon

carbamidases, although the genes encoding the responsible enzymes have not been characterized.[1][47][48] The circulating levels of normustine formed from EMP are insignificant.[43][49] Release of nitrogen mustard gas from normustine via cleavage of the carboxylic acid group has not been demonstrated and does not seem to occur.[42][31]

The oral

absorption from the intestines, and this may interfere with its therapeutic effectiveness at low doses.[3][17]

Following a single oral dose of 420 mg EMP in men with prostate cancer, maximal levels of estromustine were 310 to 475 ng/mL (475,000 pg/mL) and occurred after 2 to 3 hours.[1] Estradiol levels with 280 mg/day oral EMP have been found to increase to very high concentrations within one week of therapy.[3] In one study, levels of estradiol were over 20,000 pg/mL after 10 days, were about 30,000 pg/mL after 30 days, and peaked at about 40,000 pg/mL at 50 days.[3] Another study found lower estradiol levels of 4,900 to 9,000 pg/mL during chronic therapy with 560 mg/day oral EMP.[31] An additional study found estradiol levels of about 17,000 pg/mL with 140 mg/day oral EMP and 38,000 pg/mL with 280 mg/day oral EMP.[citation needed] The circulating levels of estradiol and estrone during EMP therapy have been reported to exceed normal levels in men by more than 100- and 1,000-fold, respectively.[4][31] Levels of estramustine and estradiol in the circulation are markedly lower than those of estromustine and estrone, respectively, with a ratio of about 1:10 in both cases.[1][31] Nonetheless, estradiol levels during EMP therapy appear to be similar to those that occur in mid-to-late pregnancy, which range from 5,000 to 40,000 pg/mL.[50] No unchanged EMP is seen in the circulation with oral administration.[1]

The

tumor tissue, for instance prostate cancer and glioma tissue, with estramustine levels much higher in these tissues than in plasma (e.g., 6.3- and 15.9-fold, respectively).[1] Conversely, levels of estromustine in tumor versus plasma are similar (1.0- and 0.5-fold, respectively).[1] Estramustine and estromustine appear to accumulate in adipose tissue.[1]

The

elimination half-life of estromustine with oral EMP was 13.6 hours on average, with a range of 8.8 to 22.7 hours.[1] Conversely, the elimination half-life of estromustine with intravenous injection was 10.3 hours, with a range of 7.36 to 12.3 hours.[1] For comparison, the corresponding elimination half-lives of estrone were 16.5 and 14.7 hours for oral and intravenous administration, respectively.[1] Estramustine and estromustine are mainly excreted in bile and hence in feces.[1][31] They are not believed to be excreted in urine.[1]

Metabolism of oral estramustine phosphate in humans.[5][1][31][47][48]

Chemistry

See also: Estrogen ester, List of estrogen esters § Estradiol esters, and List of hormonal cytostatic antineoplastic agents

EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a

Antineoplastic agents related to EMP, although none of them were marketed, include alestramustine, atrimustine, cytestrol acetate, estradiol mustard, ICI-85966, and phenestrol.[35][15]

Due to its

intravenous administration.[7]

The molecular weight of EMP sodium is 564.3 g/mol, of EMP meglumine is 715.6 g/mol, of EMP is 520.4 g/mol, of estramustine is 440.4 g/mol, and of estradiol is 272.4 g/mol.[54] As a result of these differences in molecular weights, EMP contains about 52%, EMP sodium about 48%, and EMP meglumine about 38% of the amount of estradiol within their structures as does an equal-mass quantity of estradiol.[54]

Structural properties of selected estradiol esters
Estrogen Structure Ester(s) Relative
mol. weight		 Relative
E2 contentb		 log Pc
Position(s) Moiet(ies) Type Lengtha
Estradiol
– – – – 1.00 1.00 4.0
Estradiol acetate
C3
Ethanoic acid
 Straight-chain fatty acid 2 1.15 0.87 4.2
Estradiol benzoate
C3 Benzoic acid Aromatic fatty acid – (~4–5) 1.38 0.72 4.7
Estradiol dipropionate
C3, C17β
Propanoic acid
(×2)		 Straight-chain fatty acid 3 (×2) 1.41 0.71 4.9
Estradiol valerate
C17β
Pentanoic acid
 Straight-chain fatty acid 5 1.31 0.76 5.6–6.3
Estradiol benzoate butyrate
C3, C17β Benzoic acid, butyric acid Mixed fatty acid – (~6, 2) 1.64 0.61 6.3
Estradiol cypionate
C17β
Cyclopentylpropanoic acid
 Cyclic fatty acid – (~6) 1.46 0.69 6.9
Estradiol enanthate
C17β
Heptanoic acid
 Straight-chain fatty acid 7 1.41 0.71 6.7–7.3
Estradiol dienanthate
C3, C17β
Heptanoic acid
(×2)		 Straight-chain fatty acid 7 (×2) 1.82 0.55 8.1–10.4
Estradiol undecylate
C17β
Undecanoic acid
 Straight-chain fatty acid 11 1.62 0.62 9.2–9.8
Estradiol stearate
C17β
Octadecanoic acid
 Straight-chain fatty acid 18 1.98 0.51 12.2–12.4
Estradiol distearate
C3, C17β
Octadecanoic acid
(×2)		 Straight-chain fatty acid 18 (×2) 2.96 0.34 20.2
Estradiol sulfate
C3 Sulfuric acid Water-soluble conjugate – 1.29 0.77 0.3–3.8
Estradiol glucuronide
C17β Glucuronic acid Water-soluble conjugate – 1.65 0.61 2.1–2.7
Estramustine phosphated
C3, C17β Normustine, phosphoric acid Water-soluble conjugate – 1.91 0.52 2.9–5.0
Polyestradiol phosphatee
C3–C17β Phosphoric acid Water-soluble conjugate – 1.23f 0.81f 2.9g
Footnotes: a = Length of
hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units
). f = Relative molecular weight or estradiol content per repeat unit. g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

EMP was first

prostate gland, and this finding culminated in the medication being repurposed for the treatment of prostate cancer.[1][3] EMP was introduced for medical use in the treatment of this condition in the early 1970s, and was approved in the United States for this indication in 1981.[1][3][55] EMP was originally introduced for use by intravenous injection.[31] Subsequently, an oral formulation was introduced, and the intravenous preparation was almost abandoned in favor of the oral version.[31]

Society and culture

Generic names

EMP is provided as the

INNMTooltip International Nonproprietary Name is estramustine phosphate.[35] The name estramustine phosphate is a contraction of estradiol normustine phosphate.[35][16] EMP is also known by its former developmental code names Leo 299, Ro 21-8837, and Ro 21-8837/001.[35][15][16]

Brand names

EMP is most commonly marketed under the brand names Estracyt and Emcyt, but has also been sold under a number of other brand names, including Amsupros, Biasetyl, Cellmustin, Estramustin HEXAL, Estramustina Filaxis, Estranovag, Multosin, Multosin Injekt, Proesta, Prostamustin, and Suloprost.[15][16][24]

Availability

See also: List of estrogens available in the United States

EMP is marketed in the United States,[57] Canada, and Mexico under the brand name Emcyt, whereas the medication is marketed under the brand name Estracyt in the United Kingdom and elsewhere throughout Europe as well as in Argentina, Chile, and Hong Kong.[15] It has been discontinued in a number of countries, including Australia, Brazil, Ireland, and Norway.[58]

Research

EMP has been studied in the treatment of other cancers such as glioma and breast cancer.[1] It has been found to slightly improve quality of life in people with glioma during the first 3 months of therapy.[1]

References

  1. ^
    S2CID 1943973
    .
  2. ^
    S2CID 24616324
    .
  3. ^
    S2CID 43384150
    .
  4. ^
    ISBN 978-981-10-7012-9
    .
  5. ^
    S2CID 36725810
    .
  6. ^ a b c "Emcyt (estramustine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 8 February 2014.
  7. ^ a b c d e f g h i j k l "Emcyt estramustine phosphate sodium capsules" (PDF). FDA. Retrieved 14 March 2022.
  8. ^
    PMID 27684806
    .
  9. ^
    S2CID 33456591
    .
  10. ^
    S2CID 70507026
    .
  11. PMID 9050135
    .
  12. ^
    PMID 8595142
    .
  13. ^
    PMID 9274433
    .
  14. ^
    ISBN 978-3-642-60107-1
    .
  15. ^
    ISBN 978-3-88763-075-1
    .
  16. ^ a b c d e "Estramustine Uses, Side Effects & Warnings".
  17. ^ a b c d e f g h i j "Estracyt Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfizer Limited. 12 August 2013. Archived from the original on 22 February 2014. Retrieved 8 February 2014.
  18. ISBN 978-0-8493-5973-6
    .
  19. ^
    ISBN 978-0-387-49782-2
    .
  20. S2CID 7710924
    .
  21. PMID 14644018
    .
  22. ^
    PMID 10699602
    .
  23. PMID 7541359
    .
  24. ^
    ISBN 978-3-7692-2114-5
    .
  25. ISBN 978-0-7817-1750-2
    .
  26. S2CID 25425351
    .
  27. PMID 7500443
    .
  28. ^
    S2CID 21465413
    .
  29. PMID 17942366
    .
  30. PMID 25920994
    .
  31. ^
    PMID 6375076
    .
  32. ^
    PMID 86404
    .
  33. ^
    PMID 6349745
    .
  34. ^ "Emcyt estramustine phosphate sodium capsules" (PDF). FDA. Retrieved 14 March 2022.
  35. ^
    ISBN 978-1-4757-2085-3
    .
  36. ^
    PMID 10076535
    .
  37. ^
    PMID 2093302
    .
  38. ^
    PMID 7190620
    .
  39. S2CID 31084737
    .
  40. ^
    PMID 3092893
    .
  41. ^ Fredholm, B., Jensen, G., Lindskog, M., & Muntzing, J. (1974, January). Effects of estramustine phosphate (Estracyt) on growth of DMBA-induced mammary tumors in rats. In Acta Pharmacologica et Toxicologica (Vol. 35, pp. 28-28). 35 Norre Sogade, PO Box 2148, DK-1016 Copenhagen, Denmark: Munksgaard Int Publ Ltd.
  42. ^
    PMID 1545778
    .
  43. ^
    S2CID 25303747
    .
  44. PMID 2682681
    .
  45. ISBN 978-0-203-09289-7
    .
  46. S2CID 22105700
    .
  47. ^
    S2CID 38350076
    .
  48. ^
    S2CID 71166897
    .
  49. ISBN 978-90-481-9703-3
    .
  50. ^ "Estradiol" (PDF). Abbott Laboratories. November 2009.
  51. ISBN 978-0-12-411562-0
    .
  52. ISBN 978-1-4200-0209-6
    .
  53. ISBN 978-1-60590-705-5
    .
  54. ^ a b "Estramustine phosphate". PubChem. U.S. National Library of Medicine.
  55. ISBN 978-1-60327-829-4
    .
  56. ISBN 978-94-011-4439-1
    .
  57. ^ "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 29 January 2017.
  58. ^ Sweetman, S, ed. (12 February 2013). "Estramustine Sodium Phosphate". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 8 February 2014.

Further reading
Retrieved from "https://en.wikipedia.org/w/index.php?title=Estramustine_phosphate&oldid=1190948922"