Toremifene

Toremifene
Clinical data
Pronunciation/ˈtɔːrəmɪfiːn/
Trade namesFareston, others
Other names(Z)-Toremifene; 4-Chlorotamoxifen; 4-CT; Acapodene; CCRIS-8745; FC-1157; FC-1157a; GTx-006; NK-622; NSC-613680
AHFS/Drugs.comMonograph
MedlinePlusa608003
License data
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator
ATC code
Pharmacokinetic data
BioavailabilityGood/~100%[1][2]
Protein binding99.7%[1]
MetabolismLiver (CYP3A4)[5][2]
MetabolitesN-Desmethyltoremifene; 4-Hydroxytoremifene; Ospemifene[3][4]
Elimination half-lifeToremifene: 3–7 days[1]
Metabolites: 4–21 days[2][4][1]
ExcretionFeces: 70% (as metabolites)[2]
Identifiers
  • 2-[4-[(1Z)-4-Chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy]-N,N-dimethylethanamine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.125.139 Edit this at Wikidata
Chemical and physical data
FormulaC26H28ClNO
Molar mass405.97 g·mol−1
3D model (JSmol)
  • ClCCC(/c1ccccc1)=C(/c2ccc(OCCN(C)C)cc2)c3ccccc3
  • InChI=1S/C26H28ClNO/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16H,17-20H2,1-2H3/b26-25- checkY
  • Key:XFCLJVABOIYOMF-QPLCGJKRSA-N checkY
  (verify)

Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women.[4][6][3] It is taken by mouth.[4]

Side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding.[5][7] It can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer.[5] High blood calcium levels can occur in women with bone metastases.[5]

The medication is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[5][7] It has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts.[6][8][9][5] It is a triphenylethylene derivative and is closely related to tamoxifen.[10]

Toremifene was introduced for medical use in 1997.[11][12] It was the first antiestrogen to be introduced since tamoxifen in 1978.[13] It is available as a generic medication in the United States.[14]

Medical uses

Toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors.[4][6] This is its only approved use in the United States.[4] It shows equivalent effectiveness to tamoxifen for this indication.[6][15] Toremifene has been found to be effective in the treatment of breast pain and may be a more effective medication than tamoxifen for this indication.[16] It also has superior effects on bone mineral density and lipid profile, including levels of cholesterol and triglycerides, compared to tamoxifen.[15] Toremifene has been reported to significantly improve symptoms of gynecomastia in men.[17]

Available forms

Toremifene is provided in the form of 60 mg oral tablets.[18][19]

Side effects

The side effects of toremifene are similar to those of tamoxifen.[5] The most common side effect is hot flashes.[5] Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding.[5][7] In women with bone metastases, hypercalcemia may occur.[5] Toremifene has a small risk of thromboembolic events.[5] Cataracts, vision changes, and elevation of liver enzymes have been reported.[5][7] The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias.[5] The risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing QT prolongation, and in those taking other QT-prolonging drugs.[5] Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer.[5]

Toremifene appears to be safer than tamoxifen.[15] It has a lower risk of venous thromboembolism (VTE) (e.g., pulmonary embolism), stroke, and cataracts.[15] The lower risk of VTE may be related to the fact tamoxifen decreases levels of the antithrombin III to a significantly greater extent than either 60 or 200 mg/day toremifene.[15]

Interactions

Toremifene is a substrate of CYP3A4, a cytochrome P450 enzyme, and hence drugs that induce or inhibit this enzyme can respectively decrease or increase levels of toremifene in the body.[5]

Pharmacology

Pharmacodynamics

Toremifene is a selective estrogen receptor modulator (SERM).[5][7][20] That is, it is a selective mixed agonist–antagonist of the estrogen receptors (ERs), with estrogenic actions in some tissues and antiestrogenic actions in other tissues.[5][7] The medication has estrogenic effects in bone, partial estrogenic effects in the uterus and liver, and antiestrogenic effects in the breasts.[6][8][9][5]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
Medication Breast Bone Liver Uterus Vagina Brain
Lipids Coagulation SHBGTooltip Sex hormone-binding globulin IGF-1Tooltip Insulin-like growth factor 1 Hot flashes Gonadotropins
Estradiol + + + + + + + + + +
"Ideal SERM" – + + ± ± ± – + + ±
Bazedoxifene – + + + + ? – ± – ?
Clomifene – + + ? + + – ? – ±
Lasofoxifene – + + + ? ? ± ± – ?
Ospemifene – + + + + + ± ± – ±
Raloxifene – + + + + + ± – – ±
Tamoxifen – + + + + + + – – ±
Toremifene – + + + + + + – – ±
Effect: + = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.

The affinity of toremifene for the ER is similar to that of tamoxifen.[6][21][22] In studies using rat ER, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the ER.[23][24][25][26][27][22] The affinities (Ki) of toremifene at the human ERs have been reported as 20.3 ± 0.1 nM for the ERα and 15.4 ± 3.1 nM for the ERβ.[20] In other rat ER studies, toremifene had 3–9% of the affinity of estradiol for the ER while its metabolites N-desmethyltoremifene and 4-hydroxytoremifene had 3–5% and 64–158% of the affinity of estradiol for the ER, respectively.[28][29][30] The affinity of another metabolite, 4-hydroxy-N-desmethyltoremifene, was not assessed.[29] 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic potency than toremifene in vitro in one study,[29] but not in another.[28] 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenic in vitro.[28] The metabolites of toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication.[1][29][28] On the other hand, some authorities consider toremifene not to be a prodrug.[31]

Toremifene is very similar to tamoxifen and shares most of its properties.[6][8][9][5] There are some indications that toremifene may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity.[6][3] However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited.[6][3] Toremifene is thought to have about one-third of the potency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.[32]

Toremifene has been found to have antigonadotropic effects in postmenopausal women,[33] progonadotropic effects in men,[34] to increase sex hormone-binding globulin levels,[33] and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men.[35]

In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the estrogen-related receptor γ (ERRγ).[36]

Pharmacokinetics

Absorption

The bioavailability of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%.[1][2] Levels of toremifene at steady state with a dosage of 60 mg/day are 800 to 879 ng/mL.[1] Levels of N-desmethyltoremifene at steady state with toremifene were 3,058 ng/mL at 60 mg/day, 5,942 ng/mL at 200 mg/day, and 11,913 ng/mL at 400 mg/day.[1] Levels of 4-hydroxytoremifene at steady state with toremifene were 438 ng/mL at 200 mg/day and 889 ng/mL at 400 mg/day.[1] Concentrations of toremifene increase linearly across a dose range of 10 to 680 mg.[37][38]

Distribution

Toremifene is 99.7% bound to plasma proteins, with 92% bound specifically to albumin, about 6% to β1 globulin fraction, and about 2% to a fraction between albumin and α1 globulins.[37][1] The apparent volume of distribution of toremifene ranged from 457 to 958 L.[37]

Metabolism

Toremifene is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation.[2] The metabolites of toremifene include N-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-N-desmethyltoremifene, among others.[1][29][2][39] Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene.[1][4]

Elimination

The elimination half-life of toremifene is 3 to 7 days in healthy individuals.[1] In people with impaired liver function, the half-life is 11 days.[1] The elimination half-lives of the metabolites of toremifene are 5 to 21 days for N-desmethyltoremifene, 5 days for 4-hydroxytoremifene, and 4 days for ospemifene.[1][2][4] The long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding.[1][5] Toremifene is eliminated 70% in the feces, as metabolites.[2]

Chemistry

See also: List of selective estrogen receptor modulators and Triphenylethylene

Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen.[10] It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene).[40][41]

History

Toremifene was introduced in the United States in 1997.[11][12] It was the first antiestrogen to be introduced in this country since tamoxifen in 1978.[13]

Society and culture

Generic names

Toremifene is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while toremifene citrate is its USANTooltip United States Adopted Name and JANTooltip Japanese Accepted Name and torémifène is its DCFTooltip Dénomination Commune Française.[42][43][44][45]

Brand names

Toremifene is marketed almost exclusively under the brand name Fareston.[43][45]

Availability

Toremifene is marketed widely throughout the world and is available in the United States, the United Kingdom, Ireland, many other European countries, South Africa, Australia, New Zealand, and elsewhere throughout the world.[43][45]

Research

Toremifene was also evaluated for prevention of prostate cancer and had the tentative brand name Acapodene.[46]

In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008[47]

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,[48] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.[49]

Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.[50]

Toremifene may be useful in the prevention of bicalutamide-induced gynecomastia.[15]

Phase III Trial Results

A double-blind, placebo-controlled, randomized, 3 year clinical trial of toremifene was conducted using a sample of 1,260 men. Subjects had a median age of 64 years and were diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN), which is considered premalignant, though Thompson and Leach feel a low grade PIN could also be deemed premalignant.[51]

The sponsor, GTx, who designed and managed the study, found 34.7% of the placebo and 32.3% of the toremifene groups had cancer events. No distinction was found in Gleason scores of either group.[52]

Previous murine studies using transgenic adenocarcinoma of mouse prostate (TRAMP) mice showed toremifene prevented palpable tumors in 60% of the animals. This study used toremifene as an early prophylactic, which differentiates it from the phase III human studies.[53]

References

  1. ^ a b c d e f g h i j k l m n o p Taras TL, Wurz GT, Linares GR, DeGregorio MW (November 2000). "Clinical pharmacokinetics of toremifene". Clin Pharmacokinet. 39 (5): 327–34. doi:10.2165/00003088-200039050-00002. PMID 11108432. S2CID 26647296.
  2. ^ a b c d e f g h i DeVita Jr VT, Lawrence TS, Rosenberg SA (7 January 2015). DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1126–. ISBN 978-1-4698-9455-3.
  3. ^ a b c d Chabner BA, Longo DL (7 December 2011). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 659–. ISBN 978-1-4511-4820-6.
  4. ^ a b c d e f g h "FARESTON (toremifene citrate) 60 mg Tablets oral administration" (PDF). GTx, Inc. U.S. Food and Drug Administration. March 2011.
  5. ^ a b c d e f g h i j k l m n o p q r s t u Rosenthal L, Burchum J (17 February 2017). Lehne's Pharmacotherapeutics for Advanced Practice Providers - E-Book. Elsevier Health Sciences. pp. 931–. ISBN 978-0-323-44779-9.
  6. ^ a b c d e f g h i Miller WR, Ingle JN (8 March 2002). Endocrine Therapy in Breast Cancer. CRC Press. pp. 55–57. ISBN 978-0-203-90983-6.
  7. ^ a b c d e f Schiff D, Arrillaga I, Wen PY (16 September 2017). Cancer Neurology in Clinical Practice: Neurological Complications of Cancer and its Treatment. Humana Press. pp. 296–. ISBN 978-3-319-57901-6.
  8. ^ a b c Morrow M, Jordan VC (2003). Managing Breast Cancer Risk. PMPH-USA. pp. 192–. ISBN 978-1-55009-260-8.
  9. ^ a b c Selective Estrogen Receptor Modulators—Advances in Research and Application: 2013 Edition: ScholarlyBrief. ScholarlyEditions. 1 May 2013. pp. 51–. ISBN 978-1-4901-0447-8.
  10. ^ a b Cano A, Calaf i Alsina J, Duenas-Diez JL (22 September 2006). Selective Estrogen Receptor Modulators: A New Brand of Multitarget Drugs. Springer Science & Business Media. pp. 52–. ISBN 978-3-540-34742-2.
  11. ^ a b Silva OE, Zurrida S (2005). Breast Cancer: A Practical Guide. Elsevier Health Sciences. pp. 355–. ISBN 0-7020-2744-8.
  12. ^ a b Bidlack WR, Omaye ST, Meskin MS, Topham DK (16 March 2000). Phytochemicals as Bioactive Agents. CRC Press. pp. 26–. ISBN 978-1-56676-788-0.
  13. ^ a b DiSaia PJ, Creasman WT, Mannel RS, McMeekin DS, Mutch DG (4 February 2017). Clinical Gynecologic Oncology E-Book. Elsevier Health Sciences. pp. 124–. ISBN 978-0-323-44316-6.
  14. ^ "Generic Fareston Availability - Drugs.com". Drugs.com. Retrieved 2019-04-19.
  15. ^ a b c d e f Sieber PR (December 2007). "Treatment of bicalutamide-induced breast events". Expert Rev Anticancer Ther. 7 (12): 1773–9. doi:10.1586/14737140.7.12.1773. PMID 18062751. S2CID 40410461.
  16. ^ Bland KI, Copeland EM, Klimberg VS, Gradishar WJ (29 June 2017). The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases. Elsevier Health Sciences. pp. 86–. ISBN 978-0-323-51187-2.
  17. ^ Tabbal M, Fuleihan GE (2010). "Future Therapies". Osteoporosis in Men. pp. 713–732. doi:10.1016/B978-0-12-374602-3.00057-2. ISBN 9780123746023.
  18. ^ Wirfs MJ (9 May 2019). The APRN and PA's Complete Guide to Prescribing Drug Therapy 2020. Springer Publishing Company. pp. 60–. ISBN 978-0-8261-7934-0.
  19. ^ Casciato DA (2012). "Chapter 4: Cancer Chemotherapeutic Agents". In Casciato DA, Territo MC (eds.). Manual of Clinical Oncology. Lippincott Williams & Wilkins. pp. 122–. ISBN 978-1-4511-1560-4.
  20. ^ a b Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA (March 2006). "Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy". Expert Opin Investig Drugs. 15 (3): 293–305. doi:10.1517/13543784.15.3.293. PMID 16503765. S2CID 29510508.
  21. ^ Workman P (6 December 2012). New Approaches in Cancer Pharmacology: Drug Design and Development. Springer Science & Business Media. pp. 104–. ISBN 978-3-642-77874-2.
  22. ^ a b Kallio S, Kangas L, Blanco G, Johansson R, Karjalainen A, Perilä M, Pippo I, Sundquist H, Södervall M, Toivola R (1986). "A new triphenylethylene compound, Fc-1157a. I. Hormonal effects". Cancer Chemother Pharmacol. 17 (2): 103–8. doi:10.1007/BF00306736. PMID 2941176. S2CID 13238715.
  23. ^ Wittliff JL, Kerr II JL, Andres SA (2005). "Estrogens IV: Estrogen-Like Pharmaceuticals". In Wexler P (ed.). Encyclopedia of Toxicology, 2nd Edition. Vol. Dib–L. Elsevier. pp. 254–258. ISBN 9780080548005.
  24. ^ Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan DM (March 2000). "The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands". Toxicol Sci. 54 (1): 138–53. doi:10.1093/toxsci/54.1.138. PMID 10746941.
  25. ^ Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM (March 2001). "Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens". Chem Res Toxicol. 14 (3): 280–94. doi:10.1021/tx000208y. PMID 11258977.
  26. ^ Chander SK, Sahota SS, Evans TR, Luqmani YA (December 1993). "The biological evaluation of novel antioestrogens for the treatment of breast cancer". Crit Rev Oncol Hematol. 15 (3): 243–69. doi:10.1016/1040-8428(93)90044-5. PMID 8142059.
  27. ^ Kavlock RJ, Daston GP (6 December 2012). Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects: Mechanistics Understanding of Human Development Toxicants. Springer Science & Business Media. pp. 437–. ISBN 978-3-642-60447-8.
  28. ^ a b c d Kangas L (1990). "Biochemical and pharmacological effects of toremifene metabolites". Cancer Chemother Pharmacol. 27 (1): 8–12. doi:10.1007/BF00689269. PMID 2147128. S2CID 11502291.
  29. ^ a b c d e Robinson SP, Parker CJ, Jordan VC (August 1990). "Preclinical studies with toremifene as an antitumor agent". Breast Cancer Res Treat. 16 (Suppl): S9–17. doi:10.1007/BF01807139. PMID 2149286. S2CID 19989845.
  30. ^ Osborne CK (6 December 2012). Endocrine Therapies in Breast and Prostate Cancer. Springer Science & Business Media. pp. 104–. ISBN 978-1-4613-1731-9.
  31. ^ Vogel CL, Johnston MA, Capers C, Braccia D (February 2014). "Toremifene for breast cancer: a review of 20 years of data". Clin Breast Cancer. 14 (1): 1–9. doi:10.1016/j.clbc.2013.10.014. PMID 24439786.
  32. ^ MacGregor JI, Jordan VC (June 1998). "Basic guide to the mechanisms of antiestrogen action". Pharmacol. Rev. 50 (2): 151–96. PMID 9647865.
  33. ^ a b Ellmén J, Hakulinen P, Partanen A, Hayes DF (November 2003). "Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients" (PDF). Breast Cancer Res. Treat. 82 (2): 103–11. doi:10.1023/B:BREA.0000003957.54851.11. hdl:2027.42/44217. PMID 14692654. S2CID 207694212.
  34. ^ Tsourdi E, Kourtis A, Farmakiotis D, Katsikis I, Salmas M, Panidis D (April 2009). "The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia". Fertil. Steril. 91 (4 Suppl): 1427–30. doi:10.1016/j.fertnstert.2008.06.002. PMID 18692782.
  35. ^ Roelfsema F, Yang RJ, Takahashi PY, Erickson D, Bowers CY, Veldhuis JD (February 2018). "Effects of Toremifene, a Selective Estrogen Receptor Modulator, on Spontaneous and Stimulated GH Secretion, IGF-I, and IGF-Binding Proteins in Healthy Elderly Subjects". Journal of the Endocrine Society. 2 (2): 154–165. doi:10.1210/js.2017-00457. PMC 5789038. PMID 29383334.
  36. ^ Ariazi EA, Jordan VC (2006). "Estrogen-related receptors as emerging targets in cancer and metabolic disorders". Curr Top Med Chem. 6 (3): 203–15. doi:10.2174/1568026610606030203. PMID 16515477.
  37. ^ a b c Gennari L, Merlotti D, Stolakis K, Nuti R (April 2012). "Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis". Expert Opin Drug Metab Toxicol. 8 (4): 505–13. doi:10.1517/17425255.2012.665873. PMID 22356442. S2CID 19547631.
  38. ^ Anttila M, Valavaara R, Kivinen S, Mäenpää J (June 1990). "Pharmacokinetics of toremifene". J Steroid Biochem. 36 (3): 249–52. doi:10.1016/0022-4731(90)90019-o. PMID 2142247.
  39. ^ Brenner GM, Stevens C (28 September 2017). Brenner and Stevens' Pharmacology E-Book. Elsevier Health Sciences. pp. 394–. ISBN 978-0-323-39172-6.
  40. ^ Weber GF (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 304–. ISBN 978-3-319-13278-5.
  41. ^ Maximov PY, McDaniel RE, Jordan VC (23 July 2013). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 170–. ISBN 978-3-0348-0664-0.
  42. ^ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1222–. ISBN 978-1-4757-2085-3.
  43. ^ a b c Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 1048–. ISBN 978-3-88763-075-1.
  44. ^ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 277–. ISBN 978-94-011-4439-1.
  45. ^ a b c "Toremifene - Drugs.com". Drugs.com. Retrieved 2018-02-08.
  46. ^ Price N, Sartor O, Hutson T, Mariani S (2005). "Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer". Clin Prostate Cancer. 3 (4): 211–4. doi:10.1016/s1540-0352(11)70089-0. PMID 15882476.
  47. ^ "GTx's Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review" (Press release). GTx Inc. 2007-07-12. Retrieved 2006-07-14.
  48. ^ "GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA" (Press release).
  49. ^ "GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study". 2 Mar 2011.
  50. ^ "Toremifene - AdisInsight". adisinsight.springer.com. Retrieved 2018-02-08.
  51. ^ Thompson Jr, I. M., and Leach, R., Prostate cancer and prostatic intraepithelial neoplasia: true, true, and unrelated? J Clin Oncol, 2013;31:515-6. https://ascopubs.org/doi/full/10.1200/JCO.2012.46.6151=[permanent dead link‍] Retrieved 31 July 2019
  52. ^ Taneja, S. S., Morton, R., Barnette, G., Sieber, P., Hancock, M. L., and Steiner, M., Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene J Clin Oncol, 2013;31:523-9. https://ascopubs.org/doi/abs/10.1200/JCO.2012.41.7634=[permanent dead link‍] Retrieved 31 July 2019
  53. ^ Raghow, S., Hooshdaran, M. Z., Katiyar, S., and Steiner, M. S., Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. Cancer Research 2002;62:1370-6. http://cancerres.aacrjournals.org/content/62/5/1370= Retrieved 31 July 2019

Further reading