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Toremifene Citrate and its Applications in Animal Studies

This is a selective estrogen receptor modulator currently associated with the treatment of metastatic breast cancer and disorders associated with menopause in humans. Toremifene is associated with a reduced potential for genotoxicity in comparison to other similar drugs such as tamoxifen¹. It is in common use as a standard against which new estrogen receptor modulators (or other agonists/antagonists) are compared in animal trials². Toremifene was also recently used to validate a transgenic rat assay designed to detect the carcinogenicity of chemicals under evaluation³. Female transgenic rats were given 40mg/kg toremifene by gavage every day for three weeks, to simulate a repeated-dose regimen³. This was found not to result in mutations in comparison to the same dose of tamoxifen at the same frequency³. The transgenic adenocarcinoma of the mouse prostate model is a model of cancer in this organ. Toremifene was found to protect against cancer development in studies using this model⁴.

This drug is also incorporated into animal studies of combined cancer therapies. Toremifene alone and in combination with atamestane (an irreversible estrogen synthesis blocker) were associated with significant decreases in the low-density lipoprotein and serum cholesterol of ovarectomized rats (a model of estrogen-blocking therapy in breast cancer)⁵. It was also associated with significant positive effects on bones in these rats⁵. This combination (1mg toremifene plus 1mg atamestane per day) was found to be equal in effect to toremifene alone in reducing uterine tumor growth in mice injected with Ac1 cancer cells⁶. A combination of 30 or 120mg/day toremifene and local hyperthermia in nude mice injected with MCF-7 breast cancer line cells found that the anti-tumor effects were significantly greater in the groups receiving these treatments than groups receiving either dose of toremifene alone⁷.

Toremifene as an Anti-Infective

Toremifene has been shown to prevent the formation of biofilms associated with micro-organisms including several subspecies of Staphylococcus (including S. aureus) and Candida, as well as Pseudomonas aeruginosa⁸. A rat model of subcutaneous catheter placement demonstrated the efficacy of toremifene against the biofilm formation of S. aureus and C. albicans⁸. This may indicate the potential role of toremifene in preventing infection in porous implants incorporating metal and other materials⁹. The pre-incubation of subinhibitory concentrations of toremifene also significantly enhanced the inhibition of C. albicans and C. glabrata biofilms by the classic antifungals caspofungin and amphotericin B¹⁰. This also enhanced the inhibition of mixed S. epidermis and C. albicans biofilms by caspofungin¹⁰.

Toremifene may also be a potent anti-Ebola virus drug¹¹. An in vivo mouse model found that this drug inhibited Ebola virus infection, even in the absence of estrogen receptors¹¹. Toremifene inhibited viral entry after internalization. These findings indicate that the drug may act through alternative pathways to prevent infection¹¹.

References:

1. Kim SY, Suzuki N, Laxmi YR, Umemoto A, Matsuda T, Shibutani S. Antiestrogens and the formation of DNA damage in rats: a comparison. Chemical research in toxicology. 2006;19(6):852-858.

2. Kangas L, Harkonen P, Vaananen K, Keskitalo J, Eigeliene N. Effects of ospemifene on breast tissue morphology and proliferation: a comparative study versus other selective estrogen receptor modulators in ovariectomized rats. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2014;46(5):328-332.

3. Kawamura Y, Hayashi H, Kurata Y, Hiratsuka K, Masumura K, Nohmi T. Evaluation of the genotoxicity of tamoxifen in the liver and kidney of F344 gpt delta transgenic rat in 3-week and 13-week repeated dose studies. Toxicology. 2013;312:56-62.

4. Nguewa PA, Calvo A. Use of transgenic mice as models for prostate cancer chemoprevention. Current molecular medicine. 2010;10(8):705-718.

5. Goss PE, Qi S, Hu H. Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats. The Journal of steroid biochemistry and molecular biology. 2009;113(3-5):233-240.

6. Sabnis GJ, Macedo L, Goloubeva O, Schayowitz A, Zhu Y, Brodie A. Toremifene-atamestane; alone or in combination: predictions from the preclinical intratumoral aromatase model. The Journal of steroid biochemistry and molecular biology. 2008;108(1-2):1-7.

7. Kanaya Y, Doihara H, Shiroma K, Ogasawara Y, Date H. Effect of combined therapy with the antiestrogen agent toremifene and local hyperthermia on breast cancer cells implanted in nude mice. Surgery today. 2008;38(10):911-920.

8. De Cremer K, Delattin N, De Brucker K, et al. Oral administration of the broad-spectrum antibiofilm compound toremifene inhibits Candida albicans and Staphylococcus aureus biofilm formation in vivo. Antimicrobial agents and chemotherapy. 2014;58(12):7606-7610.

9. Braem A, De Cremer K, Delattin N, et al. Novel anti-infective implant substrates: Controlled release of antibiofilm compounds from mesoporous silica-containing macroporous titanium. Colloids and surfaces. B, Biointerfaces. 2015.

10. Delattin N, De Brucker K, Vandamme K, et al. Repurposing as a means to increase the activity of amphotericin B and caspofungin against Candida albicans biofilms. The Journal of antimicrobial chemotherapy. 2014;69(4):1035-1044.

11. Johansen LM, Brannan JM, Delos SE, et al. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Science translational medicine. 2013;5(190):190ra179.