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(12) Patent Application Publication (10) Pub. No.: US 2001/0047033 A1 Taylor Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2001/0047033 A1 Taylor Et Al US 20010047033A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2001/0047033 A1 Taylor et al. (43) Pub. Date: Nov. 29, 2001 (54) COMPOSITION FOR AND METHOD OF Publication Classification PREVENTING OR TREATING BREAST CANCER (51) Int. Cl." ........................ A61K 31/35; A61K 31/138 (52) U.S. Cl. ............................................ 514/456; 514/651 (75) Inventors: Richard B. Taylor, Valley Park, MO (US); Edna C. Henley, Athens, GA (57) ABSTRACT (US) The present invention is a composition for preventing, Correspondence Address: minimizing, or reversing the development or growth of Richard B. Taylor breast cancer. The composition contains a combination of a Protein Technologies International, Inc. Selective estrogen receptor modulator Selected from at least P.O. BOX 88940 one of raloxifene, droloxifene, toremifene, 4'-iodotamox St. Louis, MO 63188 (US) ifen, and idoxifene and at least one isoflavone Selected from genistein, daidzein, biochanin A, formononetin, and their (73) Assignee: Protein Technologies International, respective naturally occurring glucosides and glucoside con Inc., St. Louis, MO jugates. The present invention also provides a method of (21) Appl. No.: 09/900,573 preventing, minimizing, or reversing the development or growth of breast cancer in which a Selective estrogen (22) Filed: Jul. 6, 2001 receptor modulator Selected from at least one of raloxifene, droloxifene, toremifene, 4'-iodotamoxifen, and idoxifene is Related U.S. Application Data co-administered with at least one isoflavone Selected from genistein, daidzein, biochanin A, formononetin, and their (62) Division of application No. 09/294,519, filed on Apr. naturally occuring glucosides and glucoside conjugates to a 20, 1999. woman having or predisposed to having breast cancer. Patent Application Publication Nov. 29, 2001 Sheet 1 of 4 US 2001/0047033A1 FIG. 1 O CH N-1N-1 3 HC N CH, Patent Application Publication Nov. 29, 2001 Sheet 2 of 4 US 2001/0047033A1 FG 2 Compound Droloxifene NMe2 Toremifene CH2Cl NMe2 4-Iodotamoxifen CH NMe2 Idoxifene CH pyrrolidino Patent Application Publication Nov. 29, 2001 Sheet 3 of 4 US 2001/0047033A1 FIG. 3 'N-1\ O OH HO Compound Genistein Daidzein Glycitein Biochanin A Formononetin Patent Application Publication Nov. 29, 2001 Sheet 4 of 4 US 2001/0047033A1 Compound Genistin 6'-OMall genistin COCH2COH 6'-OAc genistin COCH, Daidzin H 6'-OMal daidzin COCHCO2H 6'-OAc daidzin COCH, Glycitin H 6'-OMal glycitin COCH US 2001/0047033 A1 Nov. 29, 2001 COMPOSITION FOR AND METHOD OF 0006 Tamoxifen, however, has an estrogenic effect on PREVENTING OR TREATING BREAST CANCER uterine tissues when endogenous estrogen levels are low, which occurs in postmenopausal women and Oopherectim FIELD OF THE INVENTION ized women. Uterine epithelial cell heights are significantly increased by the estrogenic effect of tamoxifen in postmeno 0001. The present invention relates to a composition pausal and oopherectimized women, leading to uterine containing a Selective estrogen receptor modulator and at hypertrophy. Tamoxifen also causes marked uterine eosino least one isoflavone, and a method of treating breast cancer philia. These effects have been associated with endometrial while inhibiting Selective estrogen receptor modulator carcinoma, and long term use of tamoxifen is linked to an induced uterotrophic effects. increased risk of endometrial cancer, up to a fivefold exceSS of risk relative to women not treated with tamoxifen therapy. BACKGROUND OF THE INVENTION Therefore, application of tamoxifen for long term breast 0002 Breast cancer is one of the leading causes of cancer cancer prevention and long term treatment of breast cancer mortality among Western women, and is predicted to has significant associated riskS. become a leading cause of cancer death in Oriental women 0007 Efforts have been made to develop new selective in countries Such as Japan in the near future. The American estrogen receptor modulators (“SERMS") which act in a Cancer Society estimates that 1 in 9 women face a lifetime mechanism similar to that of tamoxifen in breast tissue, risk of this disease, which will prove fatal for about one while avoiding the risks caused by the estrogenic effects of quarter of those afflicted with the disease. tamoxifen in uterine tissue. Several of these SERMS are 0003 Tamoxifen (FIG. 1), a synthetic nonsteroidal selec triphenylethylene tamoxifen analogs. As shown in FIG. 2, tive estrogen receptor modulator, has been used effectively droloxifene is a tamoxifen analog in which a 3'-hydroxyphe in the treatment of breast cancer for over twenty years. nyl moiety is Substituted in place of a phenyl moiety of Tamoxifen is one of the most widely prescribed antineoplas tamoxifen. Droloxifene has a binding affinity for the estro tic agents in the United States and Great Britain, and is one gen receptor which is ten times that of tamoxifen, has been of the initial hormonal treatments of choice in both pre shown to have antiestrogenic activity in breast tissue and to menopausal and postmenopausal women with estrogen be efficacious in treatment of advanced breast cancer, yet has receptor positive metastatic disease. Furthermore, adjuvant lower estrogenic effects in uterus tissue than tamoxifen. therapy Studies show a Substantial reduction of contralateral Droloxifene, a New Estrogen Antagonist/Agonist, Prevents primary breast carcinoma in tamoxifen treated women, Bone Loss in Ovariectomized Rats, Ke at al., Endocrinology which indicates that tamoxifen may be of use in breast 136:2435-2441 (1995). cancer prevention. 0008 Toremifene, shown in FIG. 2, is a tamoxifen 0004 Tamoxifen has tissue-specific estrogenic and anti analog having a 4-chloro Substituent. Pharmacologically estrogenic effects. Estrogen, an ovarian hormone, increases toremifene has quite similar effects as tamoxifen on breast the risk of breast and endometrial cancer by inducing an tissue, acting as potent antiestrogen. Toremifene also exhib estrogen receptor mediated increase in the frequency of its anti-tumor cytolytic effects at high doses which are breast and endometrial cell division. Cell division is essen independent of its antiestogenicity, effects which do not tial in the complex process of genesis of human cancer Since occur with high doses of tamoxifen. Antiestrogenic Potency it per Se increases the risk of genetic error-particularly of Toremifene and Tamoxifen in Postmenopausal Women, genetic errorS Such as inactivation of tumor Suppressor Homesley et al., Am. J. Clin. Onc., 16(2):117-122 (1993). geneS. 0009) 4-Iodotamoxifen, shown in FIG. 2, is another 0005 Tamoxifen has antiestrogenic effects in breast tis tamoxifen analog, having a 4'-iodophenyl Substituent in Sue. Tamoxifen's antiestrogenic effect in breast tissue is a place of a phenyl Substituent of tamoxifen. lodination of primary mechanism by which tamoxifen inhibits the prolif tamoxifen at the 4'-phenyl postion reduces estrogenic activ eration of breast cancer cells. Tamoxifen competes with ity, mimicking the high antiestrogenic activity of the tamox estrogen for binding to cytoplasmic estrogen receptors ifen metabolite 4'-hydroxytamoxifen, while giving the com (“ER”), with subsequent inhibition by the tamoxifen/ER pound a longer duration of action in Vivo by blocking complex of many of the activities of endogenous estrogen formation of the rapidly metabolized 4'-hydroxytamoxifen within tumor cells. Endogenous estrogen binds with ERS to metabolite. Pyrrolidino-4-iodotamoxifen and 4-Iodotamox promote cellular activities Such as estrogen/ER-mediated ifen, New Analogues of the AntieStrogen Tamoxifen for the gene transcription, DNA Synthesis, cancer cell growth, and Treatment of Breast Cancer, Chander et al., Cancer increases in autocrine polypeptides Such as transforming Research, 51:5851-5858 (Nov. 1, 1991); Idoxifene: Report growth factor-alpha, epidermal growth factor, insulin-like of a Phase I Study in Patients with Metastatic Breast Cancer, growth factor-II, and other growth factors that may be Coombes et al., Cancer Research, 55:1070-1074 (Mar. 1, involved in cell proliferation. Competitive inhibition of 1995). 4-Iodotamoxifen has been shown to have less estro estrogen binding to ERS by tamoxifen reduces or prevents genic agonist activity in uterine tissue than tamoxifen, and, Such cancer growth inducing cellular activities. As a result therefore, is less likely to cause endometrial cancer when of tamoxifen's antiestrogenic activity in breast tissue, administered over a long term. tamoxifen prevents the transition of breast cancer cells from the early G1 phase to the mid-G1 phase of the cell cycle and 0010 Idoxifene, also known as pyrrolidino-4-iodotamox exhibits a cytostatic effect on breast cancer cells. Tamoxifen ifen, shown in FIG. 2, is another tamoxifen analog, and is has been shown to reduce distant breast cancer metastasis as modeled on the 4'-iodotamoxifen analog. Idoxifene has the well as local-regional recurrence of Such cancers in both Same general molecular structure as 4'-iodotamoxifen, node-negative and node-positive women. except that the N,N-dimethylamino moiety of 4'-iodotamox US 2001/0047033 A1 Nov. 29, 2001 ifen is replaced with a pyrrolidino moiety. Substitution of the 0017 FIG. 3 is a molecular representation of the selec pyrrolidino group for the dimethylamino group reduces tive estrogen receptor modulator raloxifene. possible toxic side effects by inhibiting the metabolization of the compound by the liver to a desmethyl metabolite with 0018 FIG. 4 is
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