Breast cancer treatment, tamoxifen

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development. 

The main potential utility of the pure antiestrogens is in the treatment of breast cancer. Several studies on their effects on the breast demonstrate both the pure antiestrogenic action of the tested compounds and their beneficial effects on breast cancer treatment. In experiments conducted in nude mice xenotrans-planted with two different human estradiol-dependent breast tumors, a single injection of fulvestrant provided an antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks (Wakeling et al. 1991). Additionally, RU 58668 was able to induce up to 30% disappearance of MCF-7 breast... 

Jin, Y., Desta, Z., Stearns, V., et al. (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl. Cancer Inst. 97, 30-39. 

Another application of this chemistry is the asymmetric synthesis of the cyclopropane analog 25 of the breast cancer treatment agent tamoxifen 26 (Scheme 14.2) [53]. The Rh2(S-DOSP)4-catalyzed reaction of phenyldiazoacetate 3 with diarylethylene 23 at... 

The successful response of breast cancers to tamoxifen or progestin treatment depends on the presence of high-affinity receptors for estrogen, progesterone, or both. Fewer than 10% of mammary tumors that lack detectable ER levels will respond to hormonal therapies. Determination of hormone receptor levels in tumor samples is highly recommended before selecting a therapy. 

Nguyen, A., Marsaud, V., Bouclier, C., Top, S., Vessieres, A., Pigeon, R, Gref, E., Legrand, R, Jaouen, G., and Renoir, J. M. 2008. Nanoparticles loaded with ferrocenyl tamoxifen derivatives for breast cancer treatment. Int. J. Pharmaceut. 347 128-35. 

When assessing the risk of endometrial malignancy in women with breast cancer taking tamoxifen, it is worth taking into account evidence that patients with breast cancer may at the outset have some endometrial pathology. In women with breast cancer scheduled for tamoxifen there were endometrial polyps in 9.3%, endometrial cysts in 16%, and synechiae in 12% at the outset. Tamoxifen significantly increased the incidence of these benign endometrial lesions, usually after less than 1 year of treatment. There were no cases of endometrial carcinoma in 34 patients who had taken tamoxifen for 12-24 months, and only one in 78 patients who had taken it for 5-72 months (103). 

Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, Jin Y, Storniolo AM, Nikoloff DM, Wu L, Hillman G, Hayes DF, Stearns V, Flockhart DA (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80 61-74... 

Borges S et al (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80 61-74... 

Schroth W et al (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25 5187-5193... 

Ramon y Cajal T et al (2010) Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat 119 33-38... 

One of the most widely used treatments for breast cancer uses tamoxifen (Figure 14.8). It was originally developed as a contraceptive, but it was found that it inhibited oestrogen uptake by cells. Tamoxifen alters the shape of a protein on the surface of the oestrogen receptor and so stops it from giving the signal to grow . 

Tamoxifen is a nonsteroid competitive oestrogen antagonist on target organs. Although available for anovulatory infertility (20 mg daily on days 2, 3, 4 and 5 of the cycle) its main use now is in the treatment of oestrogen-dependent breast cancer. Treatment with tamoxifen delays the growth of metastases and increases survival if tolerated it should be continued for 5 years. 

Idoxifene has been evaluated as a breast cancer treatment for postmenopausal patients [296, 297]. In one study, 321 postmenopausal patients with unknown receptor status or hormone receptor-positive metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as first-line endocrine therapy for their advanced disease. Complete plus partial response rates were 9 and 13% for tamoxifen and idoxifene, respectively. The median time to progression was slightly higher for idoxifene (140 versus 166 days), but these differences were not statistically significant. Morbidity was similar for both groups. The authors concluded that in postmenopausal women with metastatic breast cancer idoxifene had similar efficacy and toxicity to tamoxifen [298]. However, idoxifene has not been developed further because of concerns about uterine prolapse [299]. This side-effect is not seen with tamoxifen. 

Blanchard R, Ngi en A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA CYP2D6 genotype, antidepressant use, and tamoxifen metabolic durii adjuvant breast cancer treatment. JNad Cancer Inst 97,30-9. 

A 37-year-old woman being treated for breast cancer with tamoxifen and goserelin was treated with moxifloxacin for left lower lobe pneumonia. Four days into treatment, she developed neutropenia (0.48xl0 /ul). Moxifloxacin was ceased and the neutrophil coxmt recovered rapidly, normalising by day 4 [56 ]. One case of immune thrombocytopenia was reported in a 39-year-old female following a 10-day course of oral moxifloxacin [57 ]. 

For some, while this has been touted as the way of the future, there is little doubt that, where effective, it reduces the chance of adverse effects and maximizes the possibility of a positive outcome. For example, the breast cancer drug tamoxifen, 24.4, is useful only for the treatment of estrogen-sensitive breast tumors, while the monoclonal antibody Herceptin is used on patients with tumors that overexpress the HER2 protein. 

For the purposes of this article, antiestrogens are compounds that counteract the biological activity of estrogens at the receptor level. In the late 1970s, there were no steroidal antiestrogens in widespread clinical use. Clomiphene [911 -45-5]( ) and tamoxifen/7(954(9-25 -/7(9) were nonsteroidal antiestrogens that had been employed for the treatment of female infertility and breast cancer, respectively. 

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