KR20010108719A - Composition for and method of preventing or treating breast cancer - Google Patents

Abstract

The present invention provides compositions for preventing, minimizing or reversing the development or progression of breast cancer. The composition comprises a selective estrogen receptor modulator selected from one or more of raloxifene, droroxifene, toremifene, 4-iodotamoxifen and iodoxifene, genistein, dydzein, biocanin A, formonenetine and Combinations of one or more isoflavones selected from each of these naturally occurring glucosides and glucoside conjugates. The present invention also relates to a selective estrogen receptor modulator selected from one or more of raloxifene, droroxifene, toremifene, 4-iodotamoxifen and iodoxifen to women with breast cancer or predisposition to breast cancer, genistein, A method of co-administering one or more isoflavones selected from Dydzein, Biocanin A, Formononetin and their respective natural glucosides and glucoside conjugates to prevent, minimize or reverse the development and progression of breast cancer To provide.

Description

COMPOSITION FOR AND METHOD OF PREVENTING OR TREATING BREAST CANCER

The present invention relates to compositions containing selective estrogen receptor modulators and one or more isoflavones and to methods of treating breast cancer and inhibiting the uterine aromatic effects induced by selective estrogen receptor modulators.

Breast cancer is the most common cause of cancer death in Western women, and it is believed that it will soon become the most common cause of cancer death in Asian women such as Japan. The American Cancer Society found that one in nine women is at risk for the disease, and about a quarter of those suffering from it are fatal.

Tamoxifen (FIG. 1), a synthetic nonsteroidal selective estrogen receptor modulator, has been used effectively for the treatment of breast cancer for the past 20 years. Tamoxifen is one of the most widely prescribed anti-tumor drugs in the United States and the United Kingdom, and is one of the good early hormonal treatments for premenopausal and postmenopausal women with estrogen receptor positive metastatic disease. In addition, adjuvant therapy studies have shown a significant reduction in contralateral primary breast carcinoma in women treated with tamoxifen, suggesting that tamoxifen can be used to prevent breast cancer.

Tamoxifen has both tissue specific estrogen and antiestrogenic effects. The ovarian hormone estrogen increases the risk of breast and endometrial cancer by inducing an increase in the number of breast and endometrial cell divisions mediated by estrogen receptors. Cell division itself is essential for complex cancer development processes because it increases the risk of genetic errors, in particular genetic errors such as inactivation of tumor suppressor genes.

Tamoxifen has an antiestrogenic effect in breast tissue. The antiestrogenic effect of tamoxifen in breast tissue is the primary mechanism, by which tamoxifen inhibits the proliferation of breast cancer cells. Tamoxifen competes with estrogen to bind to the cytoplasmic estrogen receptor ("ER"), which then inhibits much of the activity of endogenous endogenous estrogen in tumor cells by the tamoxifen / ER complex.

Endogenous estrogens bind ERs to estrogen / ER mediated gene transcription, DNA synthesis, cancer cell growth, and autocrine polypeptides such as transforming growth factor α, epidermal growth factor, insulin-like growth factor II and cell proliferation Enhance cellular activity, such as an increase in other growth factors that may be associated with Tamoxifen competitively inhibits the binding of estrogens to ERs, thereby reducing or preventing the cancer proliferation that induces cell activity. As a result of the antiestrogenic activity of tamoxifen in breast tissue, tamoxifen prevents the transfer of breast cancer cells from the initial G1 phase to the intermediate G1 phase of the cell cycle, and has an inhibitory effect on cell proliferation on breast cancer cells. Tamoxifen is known to reduce distant breast cancer metastasis as well as to reduce local recurrence of the cancer in both nodular and nodular positive women.

However, when the endogenous estrogen content is low, tamoxifen has an estrogen effect on uterine tissue, which occurs in postmenopausal women and in ovarian extraction women. Uterine epithelial cell height is markedly increased by the estrogen effect of tamoxifen in postmenopausal and ovarian isolated women resulting in uterine hypertrophy. Tamoxifen also causes marked uterine eosinophilia. Since this effect is associated with endometrial carcinoma, long-term use of tamoxifen has been associated with increasing the risk of endometrial cancer by up to five times compared to women not treated with tamoxifen. Therefore, the use of tamoxifen in the long-term prevention of breast cancer and in the long-term treatment of breast cancer has distinct associated risks.

Many efforts have been made to develop novel selective estrogen receptor modulators ("SERMs") that act as mechanisms similar to those of tamoxifen in breast tissue, and to avoid the risks caused by the estrogen effects of tamoxifen in uterine tissues. It became. Some of these SERMs are triphenylethylene tamoxifen homologues. As shown in FIG. 2, droroxifene is a tamoxifen homologue in which a 3′-hydroxyphenyl moiety is substituted in place of the phenyl moiety of tamoxifen. Droloxifene has a binding affinity for estrogen receptors ten times that of tamoxifen for estrogen receptors, has antiestrogens activity in breast tissue, and is effective in the treatment of advanced breast cancer, but is still more effective than tamoxifen in uterine tissue. Shows low estrogen activity. See , Droloxifene, a New Estrogen Antagonist / Agonist, Prevents Bone Loss in Ovariectomized Rats , Ke et al., Endocrinology 136: 2435-2441 (1995).

Toremifene shown in FIG. 2 is an analog of tamoxifen having a 4-chloro substituent. Pharmacologically, toremifene acts as a powerful anti-estrogen and has quite similar effects to tamoxifen in breast tissue. In addition, toremifene shows antitumor cell fusion effects at high doses, irrespective of its antiestrogenic properties, which effect is not seen at high doses of tamoxifen. References: Antiestrogenic Potency of Toremifene and Tamoxifen in Postmenopausal Women, Homesley et al. , Am, J. Clin. Onc . 16 (2): 117-122 (1993).

The 4-iodotamoxifen shown in FIG. 2 is another homolog of tamoxifen having a 4'-iodophenyl substituent instead of a phenyl substituent of tamoxifen. Iodide at the 4'-phenyl position of tamoxifen mimics the high antiestrogenic activity of the tamoxifen metabolite 4'-hydroxytamoxifen to reduce estrogen activity, while blocking the rapidly metabolized 4'-hydroxytamoxifen metabolite Prolonged in vivo action of the compound. See Pyrrolidino-4-iodotamoxifen and 4-Iodotamoxifen, New Analogues of the Antiestrogen Tamoxifen for the Treatment of Breast Cancer , Chander et al. Cancer Research , 51, 5851-5858 (November 1, 1991); Idoxifene: Report of a Phase I Study in Patients with Metastatic Breast Cancer , Coombes et al. Cancer Research , 55: 1070-1074 (March 1, 1995). Since 4-iodotamoxifen is known to have lower estrogen agonist activity in uterine tissues than tamoxifen, it tends to cause less endometrial cancer during long-term administration.

Iodoxifene, also known as pyrrolidino-4-iodotamoxifen shown in FIG. 2, is another tamoxifen homologue, modeled on the 4'-iodotamoxifene homologue. Iodoxifene has the same general molecular structure as 4'-iodotamoxifen, except that the N, N-dimethylamino site of 4'-iodotamoxifen is replaced by a pyrrolidino site. Substitution of a dimethylamino group with a pyrrolidino group reduces the potential toxic side effects by inhibiting the compound from metabolizing to desmethyl metabolites by the liver with the simultaneous release of potential toxic formaldehyde. Iodoxifene has an affinity for ER 2.5-5 times greater than tamoxifen and is 1.5 times more effective at inhibiting proliferation of MCF-7 breast cancer cells. In addition, iodoxifene has a lower uterine-oriented estrogen effect than tamoxifen and 4'-iodotamoxifen and exhibits a uterine-tropic effect comparable to tamoxifen only when the dose is 10-fold larger. See Pyrrolidino-4-Iodotamoxifen and 4-Iodotamoxifen, New Analogues of the Antiestrogen Tamoxifen for the Treatment of Breast Cancer , Cancer Research , 51: 5851-5858 (Nov. 1991); Idoxifene: Report of a Phase I Study in Patients with Metastatic Breast Cancer , Coombes et al. Cancer Research , 55: 1070-1074 (March 1, 1995).

Other SERMs that are not tamoxifen homologues are known to be effective in preventing or minimizing the development of breast cancer. Raloxifene, a benzothiophene derivative (FIG. 3), shows potent antiestrogenic activity of estradiol binding to ER and significantly inhibits estrogen dependent proliferation of MCF-7 cells derived from human breast tissue. Unlike tamoxifen and its homologues, raloxifene has an antiestrogenic effect in uterine tissue and almost completely blocks the uterine-directed response to estrogen as well as tamoxifen. References to Selective Estrogen Receptor Modulators, Kauffman & Bryant, DN & P , 8 (9) 531-539 (Nov. 1995).

It is desirable to use the SERMs to develop new compositions that can be used to improve the prevention or minimization of the progression of breast cancer by SERMs and possibly reduce uterine aromatic activity.

1 is a molecular structure of tamoxifen.

2 is a molecular structure of selective estrogen modulators droroxifene, toremifene, 4′-iodotamoxifen and iodoxifene.

3 is the molecular structure of the selective estrogen receptor modulator raloxifene.

Figure 4 is the molecular structure of genistein, dydzein, biocanin A and formonenetine.

5 is a molecular structure of the natural glucoside of genistein and dydzein.

According to one feature of the invention, the invention provides compositions that prevent or minimize the onset or progression of breast cancer. The composition comprises a selective estrogen receptor modulator selected from one or more of raloxifene, droroxifene, toremifene, 4-iodotamoxifen and iodoxifene and genisteine, dydzein, biocanin A, formonenetine or these Combinations of one or more isoflavones selected from each of the naturally occurring glucosides or glucoside conjugates.

According to yet another aspect, the present invention provides a method for preventing or minimizing the onset or progression of breast cancer in humans. Selective estrogen receptor modulators and isoflavones are coadministered to the human body to prevent or minimize the development and progression of breast cancer. The selective estrogen receptor is selected from one or more of raloxifene, droroxifene, 4'-iodotamoxifen, and iodoxifene. Isoflavones are selected from one or more of genistein, dydzein, babiocanin A, formoninetin or their natural glucosides or glucoside conjugates.

Description of the Preferred Embodiments

The term "ER" as used herein refers to "estrogen receptor". The term "breast cancer" refers to all cancers derived from breast cells and includes the metastatic and local forms of breast cancer (nodular and nodular positive) as well as the ER positive and ER negative forms of breast cancer. The term "uterine effect" refers to the proliferation of uterine epithelial cells and is often a side effect of administering selective estrogen receptor modulators to women and appears to be directly related to the development of endometrial cancer. The term "Mal" as used herein refers to "malonyl" and "Ac" refers to "acetyl". The term “minimize” or derivatives thereof refers to the complete or partial inhibition of a particular biological effect (which is clearly understood in the context of using the term minimize). The term "isoflavones" means both a single isoflavone or multiple isoflavones when the isoflavones are defined as one or more of the selected groups of isoflavones. "SERM" refers to an optional estrogen receptor modulator other than tamoxifen and its physiologically acceptable salts, which produce an estrogen antagonistic effect in one or more predetermined target tissues (e.g. breast tissue and uterine tissue) In other non-target tissues, estrogen is a compound that produces an effect or minimal agonism.

The present invention can be used in combination with certain isoflavones and selected SERMs to treat or prevent breast cancer in women suffering from or with such predisposition, and isoflavones inhibit the development or progression of breast cancer induced by SERMs. The findings are based on the finding that, in addition to promoting minimization or reversal, they also prevent or minimize the uterine directional effects associated with some SERMs. SERMs usefully used in the compositions and methods of the present invention are droloxifene, toremifene, 4'-iodomoxifen, iodoxifene and raloxifene. Isoflavones usefully employed in the compositions and methods of the present invention include genistein, dydzein, glycinein, biocanin A, formmononetin, its natural glycosides and its natural glycoside conjugates, 4 and 5.

material

Selective estrogen receptor modulator compounds used in the compositions and methods of the present invention may be chemically synthesized by known methods and include salt forms of each of the compounds. Raloxifene, 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene (FIG. 3) and its physiologically acceptable Possible salts can be prepared according to the methods described in US Pat. Nos. 4,418,068 and 4,133,814, which are incorporated herein by reference. Droloxifene, E-1- [4 '-(2-dimethylaminoethoxy) phenyl] -1- (3'-hydroxyphenyl) -2-phenyl-1-butene (FIG. 2) and its physiological Salts can be prepared according to the methods described in US Pat. No. 5,047,431, which is incorporated herein by reference. Toremifene, 4-chloro-1,2-diphenyl-1- {4- [2- (N, N-dimethylamino) ethoxy] -phenyl} -1-butene (FIG. 2) and its physiological Acceptable salts can be prepared according to the methods described in US Pat. No. 4,696,949, which is incorporated herein by reference. 4'-iodotamoxifen, E-1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-iodophenyl) -2-phenyl-1-butene (FIG. 2) and this The physiologically acceptable salts of these are described in Stereoselective Olefin Formation from the Dehydration of 1- (p-Alkoxyphenyl) -1,2-diphenylbutan-1-ols: Application to the Synthesis of Tamoxifen, McCague, J. Chem. Soc. Perkin Trans., 1: 1011-1015 (1987) and Derivatives of Tamoxifen. Dependence of Antiestrogenicity on the 4-Substituent, McCague et al. J. Med. Chem ., 32 (12): 2527-2533 (1989). Iodoxifene, E-1- (4-iodophenyl) -1- [4- (2-pyrrolidinoethoxy) phenyl] -2-phenyl-1-butene (FIG. 2) is 4'-iodoxixi It can be made by combining the methods described in the foregoing references, which provide a method of making a pen.

The isoflavone compounds used in the compositions and methods of the present invention are natural substances that can be found in plants such as legumes, clover and roots of root vines. Common legume sources of these isoflavone compounds include soybeans, cheekpies and various other types of beans and peas. Clover sources of these isoflavone compounds are red clover and subterranean clover. Soybeans are a particularly preferred source of isoflavone compounds (except for biocanin A, which is not present in soybeans).

Isoflavone compounds can be isolated from natural plant sources or from plant sources that can be synthesized by methods known in the art. For example, DydeJane is isolated from red clover or is disclosed in Ganguly and Sarre as described by Wong in J. Sci . Food Agr ., Vol 13, p. 304 (1962). It can be isolated from the fungus Micromonospora halophytica as provided by Sarre, Chem. & Ind. (London) , p 201 (1970). All of these references are incorporated herein by reference. Dyezein is described in Baker, J. Chem. Soc. , P. 274 (1933), Wesley et al ., Ber . Vol. 66, p. 685, which is incorporated herein by reference. (1933)), Mahal et al . ( J. Chem. Soc. P 1769 (1934)), Baker's ( J. Chem. Soc ., P. 1852 (1953)) and Farkas. And Ber . Vol. 90 p. 2940 (1959). Glucoside dydazine, an isoflavone, can be synthesized by the method of Parcas et al. ( Ber. Vol. 92 p . 819 (1959)), which is incorporated herein by reference. The isoflavone glucoside conjugates 6'-O-Mal didazine and 6'-O-Ac didazine, which are the died agents, can be prepared by conventional saponification of didazine with malonyl or acetyl anhydride respectively.

Genistein is described in Baker, J. Chem . Soc ., P 3115 (1928), each of which is incorporated herein by reference; Narasimhachari et al ., J. Sci. Ind. Res. Vol. 12, p. 287 (1953); Yoder et al ., Proc. Iowa Acad. Sci . Vol. 61, p. 271 (1954); And Zemplen et al ., Acta. Chim. Acad. Sci. Hung , Vol. 19 p. 277 (1959). Isoflavone glucoside conjugates of Genistein, 6'-O-Mal Genistin and 6'-O-Ac Genistin can be prepared by conventional saponification of genitine with malonyl or acetyl anhydride, respectively.

Biocanin A can be synthesized by the method provided in Baker et al., Nature 169: 706 (1952), which is incorporated herein by reference. Biocanin A can also be isolated from red clover by the method provided by Pope et al. ( Chem & Ind. (London) p. 1092 (1953)). Formononetine can be synthesized according to the methods disclosed in Wesley et al. ( Ber. 66: 685 (1933)) and Kagel et al. ( Tetrahedron Letters , p. 593 (1962)), Both references are incorporated herein by reference. Formonenetine can be isolated from soybean paste by the method of Walz ( Ann . 489: 118 (1931)) or by Bradbury et al ., J. Chem. Soc . P. 3447 (1951). ) Can be isolated from clover species. Both references are incorporated herein by reference.

Isoflavones useful in the compositions and methods of the present invention are preferably extracted from natural plant material. A preferred separation method of the isoflavone compound is to separate the isoflavone from the plant material by extracting the plant material with an alcohol, preferably methanol or ethanol or an aqueous solution, preferably an aqueous alkali solution. It is preferable to maximize the recovery rate of the isoflavone compound from the plant material by grinding the plant material before extraction of the isoflavone compound. Isoflavone compounds may also be separated from the extract by conventional separation methods, such as reverse phase high performance liquid chromatography ("HPLC").

In a preferred embodiment, the isoflavone compounds genistein, genistin, 6'-O-Mal genistin, 6'-O-Ac genistin, dydzein, dydazine, 6'-O-Mal dydazine , 6'-O-Ac dydazine, glycinein, glycidine and 6'-0-Mal glycidine are isolated from soybean material, preferably commercially available soybean material. Soybeans from which isoflavones can be isolated include soybeans, shelled soybeans, soybean paste, soy flour, soybean grit, soy flakes (bean and skim soy flakes), soy cotyledon, soy molasses, whole protein concentrate, soy whey, soy Whey protein, and soy protein isolate. In one embodiment, the isoflavones are prepared from soybeans, molten beans, soybean paste, soybean grit, soy flakes, soy protein concentrate, soy whey protein or soy protein isolates, preferably soybean soybeans, soy flour, soybean grit or soy flakes. From a low molecular weight organic extraction solvent, preferably alcohol, ethyl acetate, acetone or ether, most preferably aqueous ethyl alcohol or methyl alcohol. The extraction solvent most preferably has a constant pH (pH 4 to pH 5) near the isoelectric point of the soy protein to minimize the amount of soy protein extracted by the extraction solvent.

Extraction solvents containing isoflavones are separated from insoluble soybean materials to form extracts enriched in isoflavones. If desired, the isoflavone rich material can be recovered by concentrating the extract to remove the solvent, thereby producing a solid isoflavone rich material.

In a more preferred embodiment, the isoflavone compound is further purified from other soybean material that can be dissolved in the extract, which contacts the extract with a substance that adsorbs the isoflavone in the extract and differentially separates the isoflavone from the adsorbent. By eluting isoflavones adsorbed using an eluting solvent out of the adsorbent.

In another preferred embodiment, the isoflavones are separated from impurities in the extract by conventional reverse phase chromatography (HPLC). After isoflavones are extracted from the soybean material and the extract is separated from the insoluble soybean material, the extract is filtered to remove insoluble material that may clog the HPLC column. HPLC columns are prepared by charging a conventional commercial HPLC column with a particulate adsorbent that desorbs the isoflavones and impurities in the extract in a compound specific manner. The adsorbent can be any reverse phase HPLC filler, but the preferred filler can be selected based on load capacity, separation efficiency and cost. One preferred filler material is Kromasil C18 16 μm 100 μs beads commercially available from Eka Nobel, Novel Industries, Sweden.

The filtered extract was passed through a packed HPLC column until all binding sites of the column were sufficiently saturated with isoflavones, which is perceived by the appearance of isoflavones in the effluent coming from the column. The HPLC column was then eluted with solvent to effect separation. In a preferred embodiment, the eluate is a polar solvent such as ethanol, methanol, ethyl acetate or acetonitrile, more preferably an aqueous alcohol having an alcohol content of about 30% to about 90%, most preferably about 50%, Most preferably the alcohol is ethanol.

The isoflavone compound and impurities are collected separately from the column effluent. The isoflavone fraction of the effluent can be judged from other effluent fractions according to conventional HPLC and analytical chemistry. In a preferred embodiment, the effluent fractions containing aglucon isoflavones are recovered separately. This is because the aglucon isoflavones are considered to be tyrosine kinase inhibitors and anti-angiogenic agents that are particularly active in inhibiting the onset or progression of breast cancer. Of the aglucon isoflavone materials, the effluent fraction containing dydzein is first run out of the column, followed by the glycidine fraction and the more polar genistein.

The isoflavone fractions of the effluent can be collected from the column and the volatile components of the solvent (eg alcohols) can be removed by evaporation. The isoflavone compound can be recovered directly when all of the solvent is removed by evaporation, or it can be recovered by cooling the remaining solvent (e.g. water) to crystallize the isoflavone and centrifuging or filtering the crystallized isoflavone. have.

In a particularly preferred embodiment, soy isoflavone glucoside and isoflavone glucoside conjugate-6'-O-Mal genistin, 6'-O-Ac genistin, 6'-O-Mal dydazine, 6 ' -O-Ac dydazine, 6'-O-Mal glycidine, genistine, dydazine, and glycidine-are in their respective aglucon isoflavone forms-genistein, dyedzein and Glycinein-switch to. Conversion of isoflavone glucoside conjugate and its isoflavone glucoside to aglucon isoflavone is carried out in the substrate to be extracted isoflavone before extraction or in isoflavone rich extract after separation of the extract from insoluble material. Can be. Aglucon isoflavone compounds are particularly preferred in the compositions and methods of the present invention. Because, as mentioned above, the aglucon isoflavone compound is considered to be particularly active in inhibiting angiogenesis and inhibiting tyrosine kinase activity.

6 "-O-Mal Genistin, 6" -O-Ac Genistin, 6 "-O-Mal Didezine, 6" -O-Ac Didezin, and 6 "-O- Mal glycidine is a time sufficient to form an alkaline aqueous solution of a substrate containing isoflavones having a pH of about 6 to about 13, preferably about 9 to about 11, and cause the alkaline aqueous solution to undergo a conversion reaction, preferably Is treated at a temperature of about 2 to about 121 ° C, preferably about 25 to about 75 ° C, for about 30 minutes to about 5 hours, more preferably about 30 minutes to about 1.5 hours, And isoflavone glucosides, such as isynflavone glucoside, genistin, dydazine, and glycidin bind 1,4-β-glucoside to this isoflavone glucoside. Enzymes capable of degrading--preferably commercially available β-glucosidase enzymes, α or β-galacto A time sufficient to cause a conversion reaction, preferably at a pH at which the enzyme is active, typically at a pH of about 3 to about 9, with a cedase enzyme, pectinase enzyme, lactase enzyme or glucoamylase enzyme In the form of their respective aglucon by contacting at a temperature of about 25 to about 75 ° C., preferably about 45 to about 65 ° C. for about 1 to about 24 hours, more preferably about 1 to about 3 hours. Can be converted to genistein, dydzein and glycidane.

Conventional separation methods can be used to separate the aglucon isoflavones from the substrate. For example, aglucon isoflavones can be extracted from the substrate using low molecular weight alcohols. Aglucon isoflavones can be separated from the extract by conventional recrystallization methods or by HPLC method. In a particularly preferred embodiment, the isoflavone composition isolated from the soybean substrate for blending into the composition used in the method of the present invention comprises at least 40% genistein, at least 15% dydzein and at least 1% glycidane. In another particularly preferred embodiment of the present invention, the isoflavone composition isolated from the soybean substrate for blending into the composition used in the method of the present invention comprises at least 85% genistein, at least 5% dydzein and at least 0.5% glycy Contains tain. In another preferred embodiment, each isoflavone is recovered separately in tablet form.

Since several isoflavone compounds are commercially available, they can be purchased for blending into the compositions provided in the present invention or for use in the methods of the present invention. For example, Genistein, Dyzezein, and Glycsteine are described, for example, in 08876, New Jersey, Somerville, P. Oh. Available from Indopine Chemical Company, Inc., Box 473, Biocanin A is available from Aldrich Chemical Company, West Saint Paul Avenue 940, Milwaukee, 53233, Wisconsin.

Way

The present invention provides at least one SERM selected from raloxifene, droroxifene, toremifene, 4-iodotamoxifen, and iodoxifen, and genistein, dydzein, biocanin A, formonenetine, and their respective glucosides. And co-administering at least one isoflavone selected from each of its glucoside conjugates to prevent or minimize the onset or progression of breast cancer in humans. Co-administration of SERM and isoflavones can prevent the development of breast cancer in women with predisposition to breast cancer, or co-administration of SERM and isoflavones can prevent, minimize or prevent the development and progression of breast cancer. By reversing, breast cancer can be treated. SERMs may be prepared for use in the methods of the invention described above or may preferably be provided in the compositions of the invention as described below. Isoflavones may be prepared for use in the process of the invention described above or may preferably be provided in the composition of the invention as described below.

SERMs and isoflavones may be co-administered for a certain period of time, preferably daily, simultaneously or sequentially. Most preferably, SERM and isoflavones are co-administered simultaneously to the compositions of the invention periodically, preferably daily, as described above. Alternatively, SERM and isoflavones are administered sequentially as separate components. As used herein, the term "sequential" means that a predetermined amount of SERM and isoflavone are each administered within a specific periodic period, for example daily, but is intended to limit the immediate and continuous administration of SERM and isoflavone. It is not.

SERM is administered in combination with isoflavones in an amount sufficient to prevent or treat the development and progression of breast cancer. The amount of SERMs that are sufficient to prevent or treat the development or progression of breast cancer in combination with isoflavones may include the type of SERMs used, the amount and activity of isoflavones used, the body dimensions of patients receiving SERMs, and SERMs for the prevention of breast cancers. Or whether it is administered for the purpose of treating breast cancer, depending on the extent of cancer in the case of therapeutic use. The amount of SERM sufficient to prevent the development of breast cancer in women with breast cancer predisposition is preferably at least 0.5 mg per day, more preferably about 0.5 mg to about 100 mg, most preferably about 5 mg to about 50 mg. The amount of SERM sufficient to prevent, minimize or reverse breast cancer by treating the onset or progression of breast cancer is preferably at least 0.5 mg per day, more preferably from about 0.5 to about 500 mg, and from about 40 mg to about 400 mg Most preferred. Although the daily dose of SERMs sufficient to prevent or treat breast cancer may be divided into several daily doses, the daily requirement of SERMs is preferably administered once or twice.

Isoflavones are coadministered with humans in an amount sufficient to prevent or treat the onset or progression of breast cancer. The amount of isoflavones sufficient to prevent or treat the development or progression of breast cancer in conjunction with SERM depends on the type of isoflavones used, the amount and activity of co-administered SERMs, the patient's body size, isoflavones for the prevention of breast cancer, or Whether administered for the purpose of treating breast cancer depends on the extent of the cancer for therapeutic use. In the methods of the invention, the amount of isoflavones sufficient to prevent the development of breast cancer in women with breast cancer predisposition is at least 1 mg per day, more preferably about 10 mg to about 200 mg. The amount of isoflavones sufficient to treat, minimize, or reverse breast cancer by treating the onset or progression of breast cancer is preferably at least 1 mg per day, more preferably from about 1 mg to about 1000 mg, more preferably from about 50 mg to about 500 Mg is most preferred.

Isoflavones used in the methods of the invention prevent, minimize or treat the onset or progression of breast cancer by several mechanisms, which increase the relative breast cancer inhibitory activity of each compound along with antiestrogenic activity in breast tissue. First, isoflavones are anti-estrogen substances in breast tissue that competitively inhibit the division of breast cancer cells induced by estrogen by binding to the ER of cells. In this case, the isoflavone / ER complex inhibits cancer cell growth in much the same way as tamoxifen and SERMs (e.g., Dyzedine prevents cell growth on G1 of the cell cycle, and Genistein on G2 of the cell cycle). Prevents cell growth). Secondly, some of the isoflavones, in particular Genistein and Biocanin A and at least Dyzedine and Formonenetine, are tyrosine kinase inhibitors that inhibit enzymatic tyrosine kinase activity. Tyrosine kinase activity is required for the production of proteins that cancer cells require for cell differentiation and growth. Third, isoflavones inhibit angiogenesis, preventing cancer cell bodies from developing the vascular network structures needed to support them and limiting the continued growth of cancer cell bodies. Fourth, isoflavones reduce internal growth estrogen levels by disrupting the pituitary and hypothalamic feedback mechanisms that regulate gonadotropin release, such as estradiol. The effect of combining the mechanisms of action is to further prevent or minimize the onset or progression of breast cancer when co-administered with SERMs effective to prevent or minimize the progression of breast cancer.

In a particularly preferred embodiment of the method of the invention, the isoflavones are co-administered with SERMs in an amount sufficient to prevent or minimize SERM induced uterine aromatic effects. Although the SERM used in the present invention is less uterine oriented than tamoxifen, each SERM except raloxifene induces a uterine directional effect at relatively high doses. Isoflavones used in the methods of the present invention have an antiestrogenic effect in uterine tissues when the concentration of SERM, an estrogen or estrogen agonist, is relatively high. As long as isoflavones tend to produce antiestrogenic effects in uterine tissues in the presence of SERM, the uterine estrogen agonist, the mechanism binds to ER, the uterine cell, and competitively inhibits the binding of the estrogen agonist, SERM, to ER. By Unlike SERM, a uterine tissue estrogen agonist, isoflavones do not produce an estrogen response as soon as they bind to the uterine cell ER, so isoflavones prevent, inhibit, or inhibit the uterine aromatic effects caused by the uterine epithelial ER / SERM complex. Or minimize. Isoflavones are cavities in combination with SERM in a weight / weight ratio of from about 0.25: 1 to about 100: 1, more preferably from about 0.5: 1 to about 20: 1 with SERM to prevent or minimize uterine directional effects. It is preferred to be administered.

In a particularly preferred embodiment of the invention, co-administration of an isoflavone with an amount of isoflavone and uterine tissue estrogen agonist SERM sufficient to prevent or minimize the uterine directional effect also results in endometrial cancer when SERM is used for the prevention or treatment of breast cancer. It is also effective in preventing or minimizing the occurrence of As mentioned above, tamoxifen and uterine tissue estrogen agonist SERM increase the risk of developing endometrial cancer as a result of estrogen-like activity in the uterine tissue and its uterine aromatic effect. Co-administration of isoflavones with the uterine tissue estrogen agonist SERM prevents or minimizes the progression of endometrial cancer by preventing or minimizing SERM-induced uterine aromatic effects.

Composition

According to another feature, the present invention provides a composition useful for preventing or minimizing the onset or progression of breast cancer. The composition comprises selective estrogen receptor modulators selected from raloxifene, droroxifene, toremifene, 4-iodotamoxifen and iodoxifene and genistein, dydzein, biocanin A, formonine, Combinations of one or more isoflavones selected from each of the naturally occurring glucosides and glucoside conjugates. These SERMs and isoflavone materials required for forming the compositions of the present invention can be obtained as described above. The composition comprises about 1% to about 99% by weight SERM and about 1% to about 99% by weight isoflavones, based on the weight of the biologically active ingredient.

SERM is present in the composition in an amount sufficient to prevent, minimize, or reverse the onset or progression of breast cancer in women when co-administered with isoflavones. Preferably, at least 0.5 mg of SERM is present in the composition, more preferably from about 0.5 mg to about 500 mg, most preferably from about 5 mg to about 100 mg. SERM is most preferably present in the composition in an amount sufficient to prevent, minimize or reverse the onset or development of breast cancer.

Isoflavones are preferably present in the composition at least 1 mg, more preferably from about 1 mg to about 1000 mg, most preferably from about 10 mg to about 200 mg. In a preferred embodiment, the isoflavone is present in the composition in an amount sufficient to enhance the prevention or minimization of the onset or progression of SERM induced breast cancer of the composition when the composition is administered to a female. In a more preferred embodiment, isoflavones are present in the composition alone in an amount sufficient to prevent, minimize or reverse the onset or progression of breast cancer.

In another preferred embodiment, the isoflavones are present in the composition in an amount sufficient to prevent or minimize the SERM induced uterine aromatic effects of the composition when the composition is administered to a female. In order for the isoflavones to be present in the composition in an amount sufficient to prevent or minimize the SERM induced uterine aromatic effects of the composition, the isoflavones must be present in an isoflavone: SERM weight ratio of about 0.25: 1 to about 100: 1. In the most preferred embodiment, when the composition is administered to a female, isoflavones enhance or prevent the onset or progression of SERM-induced breast cancer of the composition, and prevent or minimize the SERM-induced cervical effects of the composition. Present in the composition in an amount sufficient to:

Compositions of the invention containing SERMs and isoflavones can be prepared by conventional methods of blending and mixing compounds. The composition also preferably includes excipients, most preferably pharmaceutical excipients. Compositions containing excipients and comprising SERMs and isoflavones can be prepared by methods known in the art. For example, SERMs and isoflavones can be administered transdermally in the form of tablets, capsules, powders, suspensions, solutions for parenteral administration, including intravenous, intramuscular and subcutaneous administration, and with conventional conventional carriers, binders, diluents and excipients. It can be formulated in the form of a solution for application on the patch.

Pharmaceutically acceptable inert carriers useful in forming the pharmaceutical compositions of the invention include starch, mannitol, calcium sulfate, dicalcium phosphate, magnesium stearate, silicon derivatives and / or sugars (eg sucrose, lactose, and glucose). Include. Binders include carboxymethylcellulose and other cellulose derivatives, gelatin, natural and synthetic gums (eg, alginates such as sodium alginate), polyethylene glycols, waxes, and the like. Diluents useful in the present invention include suitable oils, saline, sugar solutions such as aqueous dextrose or aqueous glucose, and glycols such as polyethylene or polypropylene glycol. Other excipients include lubricants such as sodium oleate, sodium acetate, sodium stearate, sodium chloride, sodium benzoate, talc and magnesium stearate, and the like; Disintegrants such as agar, calcium carbonate, sodium bicarbonate, starch, xanthan gum and the like; And adsorbent carriers such as bentonite and kaolin. Coloring and sweetening agents may also be added to the pharmaceutical composition.

The following formulations illustrate the pharmaceutical compositions of the invention, but are not intended to limit the invention thereto.

Formulation

The following formulations 1-4 illustrate pharmaceutical compositions comprising SERMs and isoflavones.

Formulation 1

Gelatin capsules

Hard gelatine capsules were prepared using the following ingredients: SERM 0.5-100 mg / capsule; Isoflavones 0.1-1000 mg / capsules; Starch, NF 0-600 mg / capsules; Starch flowable powder 0-600 mg / capsule; Silicone fluid 350 cst 0-20 mg / capsule.

The ingredients were mixed and passed through a sieve and then filled into capsules.

Formulation 2

refine

Tablets were prepared using the following ingredients: SERM 0.5-100 mg / tablet; Isoflavones 0.1-1000 mg / tablet; Microcrystalline cellulose, 20 to 300 mg / tablet; Starch 0-50 mg / tablet; Magnesium stearate or stearic acid 0-15 mg / tablet; Fumed silicon dioxide 0-400 mg / tablet; Colloidal silicon dioxide 0-1 mg / tablet and lactose 0-100 mg / tablet. The components were blended and pressed to form tablets.

Formulation 3

Suspension

A suspension was prepared using the following ingredients: SERM 0.5-100 mg / 5 mL; Isoflavones 0.1-1000 mg / 5 ml; 50-700 mg / 5 ml of sodium carboxymethyl cellulose; Sodium benzoate 0-10 mg / 5 ml; 5 ml of purified water and sweetening and coloring agents as necessary.

Formulation 4

Parenteral solution

The parenteral composition was prepared by stirring 1.5% by weight of active ingredients (SERM and isoflavone weight / weight ratio 10: 1 to 1:10) in 10% by volume polypropylene glycol and water. The solution was made of sodium chloride and isotonic solution and sterilized.

The above is for demonstrating this invention, and does not intend to limit this invention to this. Other embodiments are also included within the claims of the present invention.

The compositions and methods of the present invention prevent or minimize the development or progression of endometrial cancer by preventing or minimizing or reversing the onset or progression of breast cancer and possibly reducing uterine aromatic activity.

Claims (23)

Selective estrogen receptor modulators (SERMs) selected from one or more of raloxifene, droroxifene, toremifene, 4-iodotamoxifen and iodoxifene, genistein, dydzein, biocanin A, formonenetine and A composition characterized by preventing, minimizing or reversing the onset or progression of breast cancer, comprising a combination of one or more isoflavones selected from each of these naturally occurring glucosides and glucoside conjugates. The composition of claim 1, wherein the SERM is present in an amount sufficient to prevent, minimize or reverse the onset or progression of breast cancer when the compound is administered to the human body. The composition of claim 1, wherein about 0.5 mg to about 500 mg of SERM is present in the composition. The composition of claim 3, wherein about 5 mg to about 100 mg of SERM is present in the composition. The composition of claim 1, wherein the isoflavone is present in an amount sufficient to enhance the prevention or minimization of the onset or progression of breast cancer provided by the SERM when the composition is administered to the human body. The composition of claim 1, wherein about 1 mg to about 1000 mg of isoflavone is present in the composition. 7. The composition of claim 6, wherein about 10 mg to about 200 mg of isoflavones are present in the composition. The composition of claim 1, wherein the composition contains from about 1% to about 99% by weight SERM and from about 1% to about 99% by weight isoflavones, based on the weight of the biologically active ingredient. The composition of claim 1 further comprising an excipient. The composition of claim 9, wherein the SERM, the isoflavone, and the excipient are combined in a pharmaceutical formulation. Selective estrogen receptor modulators (SERMs) selected from one or more of raloxifene, droroxifene, toremifene, 4-iodotamoxifen, and iodoxifene, genistein, daidzein, biocanin A, formonenetine and Isoflavones selected from each of these natural glucosides and one or more glucoside conjugates are co-administered to the human body to prevent the development or progression of breast cancer or to prevent or minimize the development or progression of breast cancer. , Minimizing or reversing. 12. The method of claim 11, wherein the SERM and the isoflavones are co-administered simultaneously. 12. The method of claim 11, wherein the SERM and the isoflavones are co-administered sequentially. The method of claim 11, wherein the SERM is administered to the human body in an amount of about 0.5 mg to about 500 mg per day. The method of claim 14, wherein the SERM is administered to the human body in an amount of about 5 mg to about 100 mg per day. The method of claim 11, wherein the isoflavone is administered to the human body in an amount of about 1 mg to about 1000 mg per day. The method of claim 16, wherein the isoflavone is administered to the human body in an amount of about 10 mg to about 200 mg per day. The method of claim 11, wherein the SERM is administered to the human body in an amount sufficient to prevent, minimize, or reverse the onset or progression of breast cancer. The method of claim 11, wherein the isoflavone is administered to the human body in an amount sufficient to enhance the inhibition, minimization or reversal of the onset or progression of breast cancer provided by the SERM. The method of claim 11, wherein the isoflavone is administered to the human body in an amount sufficient to prevent or minimize the uterine aromatic effects induced by SERMs. 21. The method of claim 20, wherein said isoflavone is administered to the human body in an amount sufficient to prevent or minimize the progression of endometrial cancer. The method of claim 11, wherein said SERM and said isoflavone are administered in the form of a pharmaceutical formulation. The method of claim 22, wherein the pharmaceutical formulation is a tablet, capsule, powder, suspension or solution.