Breast cancer, treatment

Commercialized for different indications breast cancer treatment, contraception, ovulation induction, prevention and treatment of postmenopausal osteoporosis. 

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... 

Van de Velde P, Nique F, Bremaud J, Hameau MC, Philibert D, Teutsch G (1995) Exploration of the therapeutic potential of the antiestrogen RU 58668 in breast cancer treatment. Ann NY Acad Sci 761 164-175... 

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... 

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. 

Medina, V., Croci, M., Crescenti, E., Mohamad, N., Sanchez-Jimenez, F., Massari, N., Nunez, M., Cricco, G., Martin, G., Bergoc, R., and Rivera, E. (2008). The role of histamine in human mammary carcinogenesis H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol. Ther. 7(1), 28-35. 

G. Other applications Herceptin has been combined with cisplatin in the treatment of heavily pretreated metastatic breast cancer. Treatment of patients with ovarian cancer is under investigation. A recent study demonstrated that Herceptin increased the clinical benefits of first-line chemotherapy—doxorubicin (or epiru-bicin) and cyclophosphamide or pacli-taxel—in metastatic breast cancer that overexpressed HER2. 

Fig. 2. BRCAl involved in regulation of mitotic checkpoint genes. (Reprinted with permission from Mullan et al. BRCAl A good predictive marker of drug sensitivity in breast cancer treatment Biochim Biophys Acta, in press,with kind permission from Elsevier).

Furthermore, it is critical for physicians to determine which combination of treatment is most suitable for each individual patient. However, it still remains challenging to make an accurate predictive assessment of a patient s risk or response to certain treatment regimens. Advances in microarray technology promise breakthroughs in personalized medicine for breast cancer treatment. To date, the prediction models based on microarray technology for breast cancer have focused mainly on either transcriptional profiles or proteomic profiles, instead of the integrated transcriptional and proteomic profiles. 

Phase trials and the FDA approval process often require seven to eight years. Raloxifene (2.28) (Figure 2.12) was initially approved to treat osteoporosis. After being on the market for several years, raloxifene was reported to be an effective treatment for certain forms of breast cancer. Estimate how much time would be required for clinical trials and approval of raloxifene as a breast cancer treatment. Justify your answer. 

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... 

Prevention of mammary carcinogenesis and breast cancer treatment Patent number US5721345 (1998)... 

Tumors that are steroid hormone-sensitive may be either (1) hormone-responsive, where the tumor regresses following treatment with a specific hormone (2) hormone-dependent, where removal of a hormonal stimulus causes tumor regression or (3) both. Hormone treatment of responsive tumors is usually only palliative, except in the case of the cytotoxic effect of glucocorticoids (for example, prednisone) on lymphomas. Removal of hormonal stimuli from hormone-dependent tumors can be accomplished by surgery, for example, in the case of orchiectomy for patients with advanced prostate cancer, or by drugs, for example in the case of breast cancer, treatment with the antiestrogen... 

A notable substitution product of ruthenocene is ethynyl-ruthenocene, which can be bound to estradiol, a form of estrogen studied for breast cancer treatment. With the rigid alkyne spacer, the steroid s affinity to the estrogen receptor was surprisingly unchanged upon addition of the metallocene. The addition of organometallic complexes to biomolecules may allow for the selective tuning of properties of the molecule. ... 

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. 

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