Toremifene

Toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors. This is its only approved use in the United States. It shows equivalent effectiveness to tamoxifen for this indication. 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.{{cite book| vauthors = Bland KI, Copeland EM, Klimberg VS, Gradishar WJ |title=The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases|url=https://books.google.com/books?id=hJwqDwAAQBAJ&pg=PA86|date=29 June 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-51187-2|pages=86–}} It also has superior effects on bone mineral density and lipid profile, including levels of cholesterol and triglycerides, compared to tamoxifen. Toremifene has been reported to significantly improve symptoms of gynecomastia in men.{{cite book| vauthors = Tabbal M, Fuleihan GE |title=Osteoporosis in Men |chapter=Future Therapies|year=2010|pages=713–732|doi=10.1016/B978-0-12-374602-3.00057-2|isbn=9780123746023}}

Toremifene is provided in the form of 60 mg oral tablets.{{cite book| vauthors = Wirfs MJ |title=The APRN and PA's Complete Guide to Prescribing Drug Therapy 2020|url=https://books.google.com/books?id=6DiPDwAAQBAJ&pg=PA60|date=9 May 2019|publisher=Springer Publishing Company|isbn=978-0-8261-7934-0|pages=60–}}{{cite book | vauthors = Casciato DA | chapter = Chapter 4: Cancer Chemotherapeutic Agents | veditors = Casciato DA, Territo MC |title=Manual of Clinical Oncology|chapter-url=https://books.google.com/books?id=4ggoPDgZx2YC&pg=PA122|year=2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-1560-4|pages=122–}}

The side effects of toremifene are similar to those of tamoxifen. The most common side effect is hot flashes. Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding.{{cite book| vauthors = Schiff D, Arrillaga I, Wen PY |title=Cancer Neurology in Clinical Practice: Neurological Complications of Cancer and its Treatment|url=https://books.google.com/books?id=wQI2DwAAQBAJ&pg=PA296|date=16 September 2017|publisher=Humana Press|isbn=978-3-319-57901-6|pages=296–}} In women with bone metastases, hypercalcemia may occur. Toremifene has a small risk of thromboembolic events. Cataracts, vision changes, and elevation of liver enzymes have been reported. The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias. 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. Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer.

Toremifene appears to be safer than tamoxifen. It has a lower risk of venous thromboembolism (VTE) (e.g., pulmonary embolism), stroke, and cataracts. 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.

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.

Toremifene is a selective estrogen receptor modulator (SERM).{{cite journal | vauthors = Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA | title = Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy | journal = Expert Opin Investig Drugs | volume = 15 | issue = 3 | pages = 293–305 | date = March 2006 | pmid = 16503765 | doi = 10.1517/13543784.15.3.293 | s2cid = 29510508 }} 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. The medication has estrogenic effects in bone, partial estrogenic effects in the uterus and liver, and antiestrogenic effects in the breasts.{{cite book| vauthors = Morrow M, Jordan VC |title=Managing Breast Cancer Risk|url=https://books.google.com/books?id=HXKibhaF5lMC&pg=PA192|year=2003|publisher=PMPH-USA|isbn=978-1-55009-260-8|pages=192–}}{{cite book|title=Selective Estrogen Receptor Modulators—Advances in Research and Application: 2013 Edition: ScholarlyBrief|url=https://books.google.com/books?id=AAzZGOf6rl0C&pg=PT51|date=1 May 2013|publisher=ScholarlyEditions|isbn=978-1-4901-0447-8|pages=51–}}{{cite book| vauthors = Rosenthal L, Burchum J |title=Lehne's Pharmacotherapeutics for Advanced Practice Providers - E-Book|url=https://books.google.com/books?id=gfYoDgAAQBAJ&pg=PA931|date=17 February 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-44779-9|pages=931–}}

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

The affinity of toremifene for the ER is similar to that of tamoxifen.{{cite book| vauthors = Workman P |title=New Approaches in Cancer Pharmacology: Drug Design and Development|url=https://books.google.com/books?id=ZLkJCAAAQBAJ&pg=PT104|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-77874-2|pages=104–}}{{cite journal | vauthors = Kallio S, Kangas L, Blanco G, Johansson R, Karjalainen A, Perilä M, Pippo I, Sundquist H, Södervall M, Toivola R | title = A new triphenylethylene compound, Fc-1157a. I. Hormonal effects | journal = Cancer Chemother Pharmacol | volume = 17 | issue = 2 | pages = 103–8 | date = 1986 | pmid = 2941176 | doi = 10.1007/BF00306736 | s2cid = 13238715 }} In studies using rat ER, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the ER.{{cite book | vauthors = Wittliff JL, Kerr II JL, Andres SA | year = 2005 | chapter = Estrogens IV: Estrogen-Like Pharmaceuticals | veditors = Wexler P | title = Encyclopedia of Toxicology, 2nd Edition | volume = Dib-L | pages = 254–258 | publisher = Elsevier | isbn = 9780080548005 | chapter-url = https://books.google.com/books?id=dEnbcGW44RYC&pg=PT3318}}{{cite journal | vauthors = Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan DM | title = The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands | journal = Toxicol Sci | volume = 54 | issue = 1 | pages = 138–53 | date = March 2000 | pmid = 10746941 | doi = 10.1093/toxsci/54.1.138 | doi-access = free }}{{cite journal | vauthors = Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, Hass BS, Xie Q, Dial SL, Moland CL, Sheehan DM | title = Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens | journal = Chem Res Toxicol | volume = 14 | issue = 3 | pages = 280–94 | date = March 2001 | pmid = 11258977 | doi = 10.1021/tx000208y }}{{cite journal | vauthors = Chander SK, Sahota SS, Evans TR, Luqmani YA | title = The biological evaluation of novel antioestrogens for the treatment of breast cancer | journal = Crit Rev Oncol Hematol | volume = 15 | issue = 3 | pages = 243–69 | date = December 1993 | pmid = 8142059 | doi = 10.1016/1040-8428(93)90044-5 }}{{cite book| vauthors = Kavlock RJ, Daston GP |title=Drug Toxicity in Embryonic Development II: Advances in Understanding Mechanisms of Birth Defects: Mechanistics Understanding of Human Development Toxicants|url=https://books.google.com/books?id=vcHsCAAAQBAJ&pg=PA437|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60447-8|pages=437–}} The affinities (K_i) 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. 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.{{cite journal | vauthors = Kangas L | title = Biochemical and pharmacological effects of toremifene metabolites | journal = Cancer Chemother Pharmacol | volume = 27 | issue = 1 | pages = 8–12 | date = 1990 | pmid = 2147128 | doi = 10.1007/BF00689269 | s2cid = 11502291 }}{{cite journal | vauthors = Robinson SP, Parker CJ, Jordan VC | title = Preclinical studies with toremifene as an antitumor agent | journal = Breast Cancer Res Treat | volume = 16 | issue = Suppl | pages = S9–17 | date = August 1990 | pmid = 2149286 | doi = 10.1007/BF01807139 | s2cid = 19989845 }}{{cite book| vauthors = Osborne CK |title=Endocrine Therapies in Breast and Prostate Cancer|url=https://books.google.com/books?id=gW0eBAAAQBAJ&pg=PA104|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4613-1731-9|pages=104–}} The affinity of another metabolite, 4-hydroxy-N-desmethyltoremifene, was not assessed. 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic potency than toremifene in vitro in one study, but not in another. 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenic in vitro. The metabolites of toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication. On the other hand, some authorities consider toremifene not to be a prodrug.{{cite journal | vauthors = Vogel CL, Johnston MA, Capers C, Braccia D | title = Toremifene for breast cancer: a review of 20 years of data | journal = Clin Breast Cancer | volume = 14 | issue = 1 | pages = 1–9 | date = February 2014 | pmid = 24439786 | doi = 10.1016/j.clbc.2013.10.014 | doi-access = free }}

Toremifene is very similar to tamoxifen and shares most of its properties. 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. 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. 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.{{cite journal | vauthors = MacGregor JI, Jordan VC | title = Basic guide to the mechanisms of antiestrogen action | journal = Pharmacol. Rev. | volume = 50 | issue = 2 | pages = 151–96 | date = June 1998 | pmid = 9647865 | url = http://pharmrev.aspetjournals.org/content/50/2/151.short}}

Toremifene has been found to have antigonadotropic effects in postmenopausal women,{{cite journal | vauthors = Ellmén J, Hakulinen P, Partanen A, Hayes DF | title = Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients | journal = Breast Cancer Res. Treat. | volume = 82 | issue = 2 | pages = 103–11 | date = November 2003 | pmid = 14692654 | doi = 10.1023/B:BREA.0000003957.54851.11 | url =https://deepblue.lib.umich.edu/bitstream/2027.42/44217/1/10549_2004_Article_5150739.pdf | hdl = 2027.42/44217 | s2cid = 207694212 | hdl-access = free }} progonadotropic effects in men,{{cite journal | vauthors = Tsourdi E, Kourtis A, Farmakiotis D, Katsikis I, Salmas M, Panidis D | title = The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia | journal = Fertil. Steril. | volume = 91 | issue = 4 Suppl | pages = 1427–30 | date = April 2009 | pmid = 18692782 | doi = 10.1016/j.fertnstert.2008.06.002 | doi-access = free }} to increase sex hormone-binding globulin levels, and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men.{{cite journal | vauthors = Roelfsema F, Yang RJ, Takahashi PY, Erickson D, Bowers CY, Veldhuis JD | title = 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 = Journal of the Endocrine Society| volume = 2 | issue = 2 | pages = 154–165 | date = February 2018 | pmid = 29383334 | pmc = 5789038 | doi = 10.1210/js.2017-00457 }}

In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the estrogen-related receptor γ (ERRγ).{{cite journal | vauthors = Ariazi EA, Jordan VC | title = Estrogen-related receptors as emerging targets in cancer and metabolic disorders | journal = Curr Top Med Chem | volume = 6 | issue = 3 | pages = 203–15 | date = 2006 | pmid = 16515477 | doi = 10.2174/1568026610606030203 }}

The bioavailability of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%. Levels of toremifene at steady state with a dosage of 60 mg/day are 800 to 879 ng/mL. 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. 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. Concentrations of toremifene increase linearly across a dose range of 10 to 680 mg.{{cite journal | vauthors = Gennari L, Merlotti D, Stolakis K, Nuti R | title = Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis | journal = Expert Opin Drug Metab Toxicol | volume = 8 | issue = 4 | pages = 505–13 | date = April 2012 | pmid = 22356442 | doi = 10.1517/17425255.2012.665873 | s2cid = 19547631 }}{{cite journal | vauthors = Anttila M, Valavaara R, Kivinen S, Mäenpää J | title = Pharmacokinetics of toremifene | journal = J Steroid Biochem | volume = 36 | issue = 3 | pages = 249–52 | date = June 1990 | pmid = 2142247 | doi = 10.1016/0022-4731(90)90019-o }}

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.{{cite journal | vauthors = Taras TL, Wurz GT, Linares GR, DeGregorio MW | title = Clinical pharmacokinetics of toremifene | journal = Clin Pharmacokinet | volume = 39 | issue = 5 | pages = 327–34 | date = November 2000 | pmid = 11108432 | doi = 10.2165/00003088-200039050-00002 | s2cid = 26647296 }} The apparent volume of distribution of toremifene ranged from 457 to 958 L.

Toremifene is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation. The metabolites of toremifene include N-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-N-desmethyltoremifene, among others.{{cite book| vauthors = Brenner GM, Stevens C |title=Brenner and Stevens' Pharmacology E-Book|url=https://books.google.com/books?id=v3g4DwAAQBAJ&pg=PA394|date=28 September 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-39172-6|pages=394–}} Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene.

The elimination half-life of toremifene is 3 to 7 days in healthy individuals. In people with impaired liver function, the half-life is 11 days. 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. The long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding. Toremifene is eliminated 70% in the feces, as metabolites.

{{See also|List of selective estrogen receptor modulators|Triphenylethylene}}

Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen.{{cite book| vauthors = Cano A, Calaf i Alsina J, Duenas-Diez JL |title=Selective Estrogen Receptor Modulators: A New Brand of Multitarget Drugs|url=https://books.google.com/books?id=heJDAAAAQBAJ&pg=PA52|date=22 September 2006|publisher=Springer Science & Business Media|isbn=978-3-540-34742-2|pages=52–}} It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene).{{cite book| vauthors = Weber GF |title=Molecular Therapies of Cancer|url=https://books.google.com/books?id=dhs_CgAAQBAJ&pg=PA304|date=22 July 2015|publisher=Springer|isbn=978-3-319-13278-5|pages=304–}}{{cite book| vauthors = Maximov PY, McDaniel RE, Jordan VC |title=Tamoxifen: Pioneering Medicine in Breast Cancer |url= https://books.google.com/books?id=p-W5BAAAQBAJ&pg=PA170 |date=23 July 2013 |publisher=Springer Science & Business Media |isbn=978-3-0348-0664-0 |pages=170–}}

Toremifene was introduced in the United States in 1997.{{cite book| vauthors = Silva OE, Zurrida S |title=Breast Cancer: A Practical Guide|url=https://books.google.com/books?id=fqZqYKQLzfMC&pg=PA355|year=2005|publisher=Elsevier Health Sciences|isbn=0-7020-2744-8|pages=355–}}{{cite book| vauthors = Bidlack WR, Omaye ST, Meskin MS, Topham DK |title=Phytochemicals as Bioactive Agents|url=https://books.google.com/books?id=-3DwAnmgyFYC&pg=PA26|date=16 March 2000|publisher=CRC Press|isbn=978-1-56676-788-0|pages=26–}} It was the first antiestrogen to be introduced in this country since tamoxifen in 1978.{{cite book| vauthors = DiSaia PJ, Creasman WT, Mannel RS, McMeekin DS, Mutch DG |title=Clinical Gynecologic Oncology E-Book|url=https://books.google.com/books?id=MkoQDgAAQBAJ&pg=PA124|date=4 February 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-44316-6|pages=124–}}

Toremifene is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while toremifene citrate is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|JAN|Japanese Accepted Name}} and torémifène is its {{abbrlink|DCF|Dénomination Commune Française}}.{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1222|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1222–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1048|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=1048–}}{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA277|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=277–}}{{Cite news|url=https://www.drugs.com/international/toremifene.html|title=Toremifene - Drugs.com|work=Drugs.com|access-date=2018-02-08|language=en-US}}

Toremifene is marketed almost exclusively under the brand name Fareston.

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.

Toremifene was also evaluated for prevention of prostate cancer and had the tentative brand name Acapodene.{{cite journal | vauthors = Price N, Sartor O, Hutson T, Mariani S | year = 2005 | title = Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer | journal = Clin Prostate Cancer | volume = 3 | issue = 4| pages = 211–4 | pmid = 15882476 | doi = 10.1016/s1540-0352(11)70089-0 }}

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{{cite press release

| title = GTx's Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review | publisher = GTx Inc. | date = 2007-07-12

| url = http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1025420&highlight= | access-date = 2006-07-14 }}

An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,{{cite press release

| title = GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1257471&highlight= }} and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.{{cite web |url=http://www.genengnews.com/gen-news-highlights/gtx-and-ipsen-end-prostate-cancer-collaboration-due-to-costs-of-fda-requested-phase-iii-study/81244761/ |title=GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study |date=2 Mar 2011 }}

Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.{{Cite web|url=http://adisinsight.springer.com/drugs/800004087|title=Toremifene - AdisInsight|website=adisinsight.springer.com|language=en|access-date=2018-02-08}}

Toremifene may be useful in the prevention of bicalutamide-induced gynecomastia.{{cite journal | vauthors = Sieber PR | title = Treatment of bicalutamide-induced breast events | journal = Expert Rev Anticancer Ther | volume = 7 | issue = 12 | pages = 1773–9 | date = December 2007 | pmid = 18062751 | doi = 10.1586/14737140.7.12.1773 | s2cid = 40410461 }}

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.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={{Dead link|date=April 2023 |bot=InternetArchiveBot |fix-attempted=yes }} Retrieved 31 July 2019

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.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={{Dead link|date=April 2023 |bot=InternetArchiveBot |fix-attempted=yes }} Retrieved 31 July 2019

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.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

{{Reflist}}

{{refbegin|30em}}

• {{cite journal | vauthors = Taras TL, Wurz GT, Linares GR, DeGregorio MW | title = Clinical pharmacokinetics of toremifene | journal = Clin Pharmacokinet | volume = 39 | issue = 5 | pages = 327–34 | year = 2000 | pmid = 11108432 | doi = 10.2165/00003088-200039050-00002 | s2cid = 26647296 }}
• {{cite journal | vauthors = Harvey HA, Kimura M, Hajba A | title = Toremifene: an evaluation of its safety profile | journal = Breast | volume = 15 | issue = 2 | pages = 142–57 | year = 2006 | pmid = 16289904 | doi = 10.1016/j.breast.2005.09.007 }}
• {{cite journal | vauthors = Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA | title = Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy | journal = Expert Opin Investig Drugs | volume = 15 | issue = 3 | pages = 293–305 | year = 2006 | pmid = 16503765 | doi = 10.1517/13543784.15.3.293 | s2cid = 29510508 }}
• {{cite journal | vauthors = Zhou WB, Ding Q, Chen L, Liu XA, Wang S | title = Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials | journal = Breast Cancer Res. Treat. | volume = 128 | issue = 3 | pages = 625–31 | year = 2011 | pmid = 21553116 | doi = 10.1007/s10549-011-1556-5 | s2cid = 36985808 }}
• {{cite journal | vauthors = Gennari L, Merlotti D, Stolakis K, Nuti R | title = Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis | journal = Expert Opin Drug Metab Toxicol | volume = 8 | issue = 4 | pages = 505–13 | year = 2012 | pmid = 22356442 | doi = 10.1517/17425255.2012.665873 | s2cid = 19547631 }}
• {{cite journal | vauthors = Mao C, Yang ZY, He BF, Liu S, Zhou JH, Luo RC, Chen Q, Tang JL | title = Toremifene versus tamoxifen for advanced breast cancer | journal = Cochrane Database Syst Rev | issue = 7 | pages = CD008926 | year = 2012 | volume = 2021 | pmid = 22786516 | doi = 10.1002/14651858.CD008926.pub2 | pmc = 8407374 }}
• {{cite journal | vauthors = Vogel CL, Johnston MA, Capers C, Braccia D | title = Toremifene for breast cancer: a review of 20 years of data | journal = Clin. Breast Cancer | volume = 14 | issue = 1 | pages = 1–9 | year = 2014 | pmid = 24439786 | doi = 10.1016/j.clbc.2013.10.014 | doi-access = free }}
• {{cite journal | vauthors = Mustonen MV, Pyrhönen S, Kellokumpu-Lehtinen PL | title = Toremifene in the treatment of breast cancer | journal = World J Clin Oncol | volume = 5 | issue = 3 | pages = 393–405 | year = 2014 | pmid = 25114854 | pmc = 4127610 | doi = 10.5306/wjco.v5.i3.393 | doi-access = free }}

{{refend}}

• [http://adisinsight.springer.com/drugs/800004087 Toremifene - AdisInsight]

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