WO2005013951A2 - Pharmaceutical compositions for preventing breast and ovarian cancer - Google Patents

Pharmaceutical compositions for preventing breast and ovarian cancer Download PDF

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Publication number
WO2005013951A2
WO2005013951A2 PCT/PL2004/000063 PL2004000063W WO2005013951A2 WO 2005013951 A2 WO2005013951 A2 WO 2005013951A2 PL 2004000063 W PL2004000063 W PL 2004000063W WO 2005013951 A2 WO2005013951 A2 WO 2005013951A2
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Prior art keywords
selenium
composition
breast
brcal
carriers
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PCT/PL2004/000063
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French (fr)
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WO2005013951A3 (en
Inventor
Jan Lubinski
Steven Narod
Stanislaw Zajaczek
Elzbieta Kowalska
Bohdan Gorski
Tomasz Huzarski
Tomasz Byrski
Jacek Gronwald
Jowita Huzarska
Barbara Gawronska-Szklarz
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Pomeranian Academy Of Medicine
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Priority to CA002535506A priority Critical patent/CA2535506A1/en
Priority to EP04775169A priority patent/EP1660060A2/en
Priority to AU2004263070A priority patent/AU2004263070A1/en
Priority to JP2006523155A priority patent/JP2007502270A/en
Priority to EA200600386A priority patent/EA200600386A1/en
Publication of WO2005013951A2 publication Critical patent/WO2005013951A2/en
Publication of WO2005013951A3 publication Critical patent/WO2005013951A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • compositions and methods for the prevention of breast and ovarian cancer FIELD OF THE INVENTION
  • the present invention relates to a composition of selenium (or its salts or derivatives or any other selenium compound) as well as methods for the prevention of breast / ovarian cancer in females with inherited high risk of cancer, particularly in carriers of BRCAl gene mutations.
  • BRCAl US5654155
  • BRCA2 genes are related to high genetic predispositions to cancers.
  • BRCAl and BRCA2 genes have been cloned and, at present, their abnormalities can be detected at DNA and RNA levels. Carriers of mutations within above genes have high risk of breast and / or ovarian cancers.
  • BRCAl is the first gene recognized to be associated with high risk of breast and ovarian cancer (Miki et al, Science, 266-271, 1994).
  • BRCAl gene (GENBANK Accession Numbers: U14680 and 15595) contains 24 exons dispersed within 100 kbp of genomic DNA and its mRNA is of 7.8 kbp of the length. Intensive studies of this gene allowed to identify numerous BRCAl mutations. For example, US5693473 is reporting large registry of such changes. WO 99/29903 is describing the next fifteen BRCAl mutations.
  • BRCA2 gene (GENBANK accession Number U43746) contains 27 exons dispersed within 70 kbp of genomic DNA and its mRNA is of 11-12 kbp of the length.
  • BRCA2 gene Numerous mutations of BRCA2 gene have been reported as associated with cancer predisposition (for example WO 9928506). All of described BRCAl and BRCA2 gene mutations are available on page: http://www.nchgr.nih.gov/dir/lab-transfer/bic. BRCAl and BRCA2 mutations can be located in different exons. Increased frequency of selected particular mutations in families with breast / ovarian cancer aggregation has been recognized in some ethnic groups / populations such as Ashkenazi Jews among whom the high incidence of BRCAl 185delAG and 5382insC and BRCA2 6174delT are well known.
  • an object of the invention to provide pharmaceutical compositions and methodology of their application allowing efficient lowering of the risk of breast / ovarian cancers in individuals with high genetic predisposition to these tumors, especially in carriers of BRCAl gene mutations.
  • Another object of the invention is to provide such pharmaceuticals for chemoprevention of breast / ovarian cancers, which should be offered to females with constitutional mutations of BRCAl gene.
  • the present invention is directed to pharmaceutical composition for lowering the risk of breast / ovarian cancer in person with inherited high risk of disease, especially in carrier of BRCAl mutation, characterized by contents of therapeutically-effective amount of selenium (e.g. in form of its salt or other derivatives thereof or any other known selenium comprising compound) and, if necessary, pharmaceutically acceptable carrier.
  • selenium is selected among its organic forms such as methylselenocysteine, methyloseleninic acid, selenomethinine, selenocysteine or inorganic forms such as selenium dioxide, selenonic acid, selenic acid and their salts.
  • selenium compound is a salt selected among: barium selenite, lithium selenite, calcium selenite and, what is particularly valuable, sodium selenite.
  • pharmaceutical composition is an isotonic solution, containing selenium at concentration 0.1 - 10% w/w. It can be recommended to use as a dissolvent an aqueous solution of ethanol at concentration 10 - 96% w/w., distilled water, physiologic solution preferably buffered. It can be recommended as well if composition according to invention contains selenium salt in aqueous solution of ethanol.
  • the subject of invention is also the method of prevention of breast / ovarian cancer in person with inherited high genetic risk of tumor particularly in female carrier of BRCAl characterized by supplementation of patient with compounds containing selenium (or its salts or derivatives), and using compositions as described above. It can be recommended that in methodology according to invention patient is supplemented with selenium at doses 50 - 1000 ⁇ g per day. It is valuable, in methodology according to invention, to use composition containing selenium after detection in patient the constitutional BRCAl gene mutation. Unexpectedly, increased sensitivity to bleomycin as measured using cytogenetic test according to Hsu was detected in BRCAl mutation carriers (0.58 vs.
  • BRCAl carriers matched for mutation type and year of birth.
  • 1 breast cancer case was observed in the group supplemented with selenium and 4 breast cancers plus 1 ovarian cancer in the control group.
  • occurrence of new breast/ovarian cancers was analysed in the group of 200, initially unaffected, carriers of BRCAl mutations supplemented with ethanol solution of sodium selenite at dose 300 ⁇ g per day and in the control group of 200 BRCAl carriers matched for mutation type and age/average age 38.6 yrs).
  • 1 breast and 1 peritoneal cancers were observed in the group supplemented with selenium, whereas 2 breast and 2 ovarian cancers were diagnosed in the control group.
  • inventions and methodology of their application allowing efficient lowering of the risk of breast / ovarian cancers in individuals with high genetic predisposition to these tumors, especially in carriers of BRCAl gene mutations. Further, the invention provides such pharmaceuticals for chemoprevention of breast / ovarian cancers, which should be offered to females with constitutional mutations of BRCAl gene.
  • invention provides the pharmaceutical composition for lowering the risk of breast / ovarian cancer in person with inherited high risk of disease, especially in carrier of BRCAl mutation, which composition contains selenium (or its salt or derivatives or any other selenium comprising compound) and, if necessary, pharmaceutically acceptable carrier.
  • selenium or its salt or derivatives refers to any known selenium comprising compound.
  • the selenium can be present in elemental form and/or as all other organic or inorganic selenium compounds. In such compounds selenium can have -2, 0, +2, +4, and +6 oxidation states.
  • the body detoxifies the higher oxidation state forms by reducing them to -2 and methylating to form dimethyl selenide. Dimethyl selenide is preferred and it can be used in conjunction with other selenium containing compounds.
  • inorganic selenium compounds such compounds as selenium dioxide, selenonic acid, selenic acid and their salts, especially metal selenides or selenites (e.g. potassium selenide, sodium selenide, sodium selenite, zinc selenide, barium selenite, lithium selenite, calcium selenite and other metal selenides or selenites).
  • metal selenides or selenites e.g. potassium selenide, sodium selenide, sodium selenite, zinc selenide, barium selenite, lithium selenite, calcium selenite and other metal selenides or selenites.
  • selenium can be used in its organic forms such as seleno-amino acid e.g. methylselenocysteine, methyloseleninic acid, selenomethinine, selenocysteine.
  • selenium examples include dimethyl selenide, all other organic selenides, selenoglutathione, and the organo-selenium complex Factor 3. It can be recommended also that selenium originates from such natural products like Se-enriched yeast or broccoli. Selenium occurs naturally in varying amounts in a wide variety of foods and also is present as an impurity in the natural form of the sulfur- containing amino acids, e.g., with methionine as the compound selenomethionine. This latter is due to the fact that the chemical behavior and reactivity of sulfur and selenium are very similar. Thus, in food grade sulfur-containing amino acids, the corresponding seleno-amino acid is normally present and thus contains selenium in significant amounts.
  • Examples of such useful edible sulfur-containing amino acids are: cysteine, methionine, cystine, cystathionine, pencillamine cysteine disulfide, penicillamine, 2-amino-4,4-dimethyl-mercaptobutyric acid, vitamin U, brasinine, djenkolic acid, 2-amino-4-isopropyl-mercaptobutyric acid, 2-amino-4-butyl mercaptobutyric acid, 2-amino-4,4-diethyl-mercaptobutyric acid, dibenzo-yldjenkolic acid, the monohydrochloride of djenkolic acid, the hydrochloride of cysteine, 2-amino-2-ethyl-3- mercapto-propanoic acid, 2-thiolhistidine, thiomalic acid, the hydrochloride of cysteine, homocysteine, pantetheine, panthethine, Coenzyme A, and cysteic acid.
  • the sulfur-containing amino acids, proteins, and peptides are normally used in the hydrochloride form or in weak acid or base salt form because they are more readily water soluble.
  • Examples of useful natural sulfur-containing peptides are: glutathione (a tripeptide of glutamic acid, cystein and glycine, also termed gamma-glutamyl-cysteinyl-glycine), cysteinyl- glycine, and gamma-cysteinyl-methionyl-glycine.
  • Examples of useful sulfur-containing proteins are: keratin, insulin, albumin, ribonuclease, fibroin, collagen and elastin. All of the scleroproteins
  • albuminoids some of which are mentioned above, may be also useful as natural source of selenium.
  • pharmaceutically acceptable carrier refers to term very well know for the person skilled in the art. Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, USA. Further information on preferred formulations is also provided in the more detailed description of the invention set out below (see example 1).
  • therapeutically-effective amount means an amount of a selenium comprising compound, as defined above, to yield a desired therapeutic response, i.e.
  • the specific "therapeutically- effective amount” will, obviously, vary with such factors as the physical condition of the subject, the specific formulations employed and the structure of the used "selenium or its salt or derivatives". Particularly, it can be recommended that in methodology according to invention patient is supplemented with selenium at doses 50 - 1000 ⁇ g per day or appropriate dose of selenium comprising compounds which dose includes such amount of selenium.
  • the compound of the invention may be administered in conjunction with one or more other known anti- neoplastic and/or cancer preventive agents.
  • the compound of the invention and the second agent may be administered together or sequentially.
  • selenium can be chosen from organic forms such as methylcysteine, methylseleninic acid, selenomethionine, selenocysteine or from inorganic forms such as selenium dioxide, selenic acid, (H 2 SeO 3 ) or its salts.
  • selenium (IV) salt valuable for preparation of compositions according to invention is sodium selenite. Natural products with high concentration of selenium such as selenium-enriched yeast or broccoli are attractive compounds as well. Particularly valuable, although not the only one, composition according to invention are solutions of selenium at concentration 0.1 - 10% w/w, especially isotonic solutions.
  • Such solutions can be made, for example, using such dissolvents as aqueous solution of ethanol at concentration 10 - 96% w/w, distilled water, physiologic solution especially if buffered. It has been shown that the optimum of pharmacological effect can be achieved if daily dose is 50 - 1000 ⁇ g of selenium.
  • the above values are modifiable depending on biological access of selenium applied to preparation of composition, as well depending on influence of associated compounds, pharmaceutical carriers. Selected, although not the only ones, examples of such compositions are presented below: A) Ethanol solution of sodium selenite.
  • composition - 2.03 g of sodium selenite (Na 2 SeO 3 ) is dissolved in 334.32 g of H 2 O. To aqueous solution of sodium selenite obtained as above 663.65 g of 96% aqueous solution of ethanol is added, and the solution is carefully mixed. Composition prepared in such way can be used for oral supplementation of patient, 2 times 10 drops per day, what corresponds to daily dose around 300 ⁇ g of pure selenium. It can be recommended to divide composition into bottles containing 11-12 g, because such amount covers one-month supplementation. Described composition is stable, maintains its form and activity at least 18 months if stored at 4° C. It can be used by patients without giving side effects.
  • Composition based on aqua can be prepared by replacement of ethanol by distilled water or physiologic solution (preferably buffered) in recipe as in A.
  • Example 2.1ncreased rates of chromosome breakage in BRCAl carriers are reduced by oral selenium supplementation.
  • Study subjects were recruited from among the attendees of a single familial cancer clinic of the Hereditary Cancer Centre of the Pomeranian Academy of Medicine in Szczecin, Poland. Women were referred to this clinic because of a family history of breast or ovarian cancer. The women who participated in this study had previously been offered, and had consented to, genetic testing. Case women were recruited from among those who had been found to be carriers of a deleterious mutation in the BRCAl gene.
  • the most common mutation was the Polish founder mutation 5382 ins C (16 carriers) but there were 10 women with other BRCAl mutations. Control subjects were recruited from among the family members of the carriers (cases), but who had been determined not to carry the deleterious mutation. It was possible to generate 26 case- control pairs. In 20 instances the control was the sister of the case and in six instances she was a more distant relative. Only healthy women were invited to participate in this study; women with a past history of breast, ovary or other form of cancer were excluded. Each woman provided a blood sample at some time during one year study. Chromosome sensitivity to bleomycin was measured according to the method of Hsu et al.
  • Bleomycin (Nippon-Kayuka) was added to the cell culture five hours before the end of the culture at a concentration of 0.03 IU/ml. Conventional harvesting and Giemsa staining were made. For each subject, 100 consecutive euploid cells in metaphase were read (cells with overlapping chromosomes were excluded). Each chromatid aberration (excluding gaps) was scored as one breakpoint and each exchange-type aberration was scored as two breakpoints. The total number of breakpoints per 100 cells was recorded for each subject. Reading of coded slides was performed blindly by one of us.
  • the mean number of breaks per cell was calculated after inspection of 100 cells.
  • the mean level of chromosome breaks was compared in the 26 case-control pairs using the paired t-test.
  • the mean number of chromosome breaks per cell was 0.58 for the BRCAl mutatin carriers (range 0.34 to 0.73) and was 0.39 for the controls (range 0.28 to 0.62) (table 1).
  • the value for the carrier exceeded that for the related control, for two pairs the control value was the higher of the two and for one pair the two values were equal (p ⁇ 0.0001; sign test).
  • the mean difference between the two groups was highly significant (p ⁇ 0.0001).
  • a second group of BRCAl carriers was recruited from this clinic for the purpose of studying the effect of selenium supplementation on frequencies of chromosome breaks. Thirty-five women with BRCAl mutations agreed to participate in this phase of the study. Blood samples were taken prior to the onset of selenium supplementation, and again at a time from one month to three months following the start of daily selenium supplementation. Prior to selenium supplementation, the mean number of induced chromosome breaks per cell was 0.63 (range 0.42 to 0.81). An oral selenium solution was provided to the study subjects which contained 690 ⁇ g of pure selenium, in the form of sodium selenite (Na 2 SeO 3 ) per ml of 70% ethanol.
  • Subjects were requested to consume 0.2 ml of the solution twice daily.
  • a second blood sample was taken at a time from one month to three months after commencement of selenium supplementation and the bleomycin test was repeated.
  • the mean number of chromosome breaks per cell was reduced to 0.40 (range 0.27 to 0.60).
  • the post-supplementation level showed a decline from the baseline level (table 2) and the mean difference was highly significant (p ⁇ 10 "10 ).
  • Example 3 Supplementation of female BRCAl mutation carriers with selenium is reducing significantly the risk of breast / ovarian cancers. Occurrence of breast / ovarian cancers in the group of 30, initially healthy, carriers of BRCAl mutations taking orally ethanol solution of sodium selenite at dose 300 ⁇ g daily and in the control group of 30 BRCAl carriers matched for mutation type and year of birth, was observed during two years. Average age in both groups was 46.5 years. During the period of observation 1 breast cancer case was diagnosed in the group supplemented with selenium and 4 breast cancers plus 1 ovarian cancer have been diagnosed in control group. (Tab. 3).

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Abstract

The present invention concerns pharmaceutical composition of selenium (or its salts or derivatives or any other selenium comprising compound) and a method of its use for the prevention of breast / ovarian cancers, especially in carriers of BRCA1 mutations. Preferred compounds are selenic acid and its salt, selenomethylcysteine, methylseleninic acid, selenomethionine and selenocysteine.

Description

Pharmaceutical compositions and methods for the prevention of breast and ovarian cancer FIELD OF THE INVENTION The present invention relates to a composition of selenium (or its salts or derivatives or any other selenium compound) as well as methods for the prevention of breast / ovarian cancer in females with inherited high risk of cancer, particularly in carriers of BRCAl gene mutations. BACKGROUND OF THE INVENTION BRCAl (US5654155) and BRCA2 genes are related to high genetic predispositions to cancers. BRCAl and BRCA2 genes have been cloned and, at present, their abnormalities can be detected at DNA and RNA levels. Carriers of mutations within above genes have high risk of breast and / or ovarian cancers. BRCAl is the first gene recognized to be associated with high risk of breast and ovarian cancer (Miki et al, Science, 266-271, 1994). BRCAl gene (GENBANK Accession Numbers: U14680 and 15595) contains 24 exons dispersed within 100 kbp of genomic DNA and its mRNA is of 7.8 kbp of the length. Intensive studies of this gene allowed to identify numerous BRCAl mutations. For example, US5693473 is reporting large registry of such changes. WO 99/29903 is describing the next fifteen BRCAl mutations. BRCA2 gene (GENBANK accession Number U43746) contains 27 exons dispersed within 70 kbp of genomic DNA and its mRNA is of 11-12 kbp of the length. Numerous mutations of BRCA2 gene have been reported as associated with cancer predisposition (for example WO 9928506). All of described BRCAl and BRCA2 gene mutations are available on page: http://www.nchgr.nih.gov/dir/lab-transfer/bic. BRCAl and BRCA2 mutations can be located in different exons. Increased frequency of selected particular mutations in families with breast / ovarian cancer aggregation has been recognized in some ethnic groups / populations such as Ashkenazi Jews among whom the high incidence of BRCAl 185delAG and 5382insC and BRCA2 6174delT are well known. In Poland, increased frequency of the following BRCAl mutations has been reported: ex 2 - 185delAG, ex 5 - 300T→ G, ex 5 - 309T→ C, ex 11.15 - 3819delGTAAA, ex 11.17 - 4153delN ex 20 - 5382insC (Polish patent P 335917). Opportunity of DNA testing based on analysis of limited number of mutations without significant loss of sensitivity in detection of abnormalities is creating a chance, valuable for several countries, of BRCAl /BRCA2 examination with cost- effectiveness extremely high. In Poland, around 100,000 of women are carriers of BRCAl mutation. Research spanning the last 25 years has established that selenium is effective in the reduction of cancer incidence when provided to animals at doses only 5 - to 10 - fold above nutritional requirement (El-Bayoumy K., The role of selenium in cancer prevention, Philadelphia, Lippincott, 1-15, 1991). Chemoprevention studies with selenium in animal model systems have indicated that this element is effective for most, if not all of the organ systems and is protective against the carcinogenic effects of a wide variety of insults (El-Bayoumy K., The role of selenium in cancer prevention, Philadelphia, Lippincott, 1-15, 1991). Both epidemiological studies and supplementation trails have also supported its efficacy in lowering the incidence of cancers of the liver, colon, prostate and lung (Yu SN. et al. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong, Biol Trace Elem Res, 56: 117-124, 1997, Clark L.C. et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. J Am Med Assoc, 276: 1957-1963, 1996, Yoshizawa K. et al. Study of prediagnostic selenium level in toenails and risk of advanced prostate cancer, J Νatl Cancer Inst (Betsheda), 90: 1219-1224, 1998; Brooks J.D. et al. Plasma selenium level before diagnosis and risk of prostate cancer development, J Urol, 166: 2034-2038, 2001). The latest literature data are, however, not supporting negative correlation between the level of selenium in the body of patients and the risk of breast cancer. Garland M. et al. concluded that diet supplementation with selenium does not influence the risk of female breast cancer (J. Am. Coll Nutr. 1993, Aug; 12(4): 400-11, J Natl Cancer Inst
1995, Apr 5; 87(7) :497-505). Similar conclusions have been reported by Ghadirian P. et al. (A case-control study of noenail selenium and cancer of the breast, colon and prostate, Cancer
Detect Prev, 24: 305-13, 2000). Further, in EP 1003760 relating to selenium-containing compounds and methods for using these compounds to protect mammals from toxic insults, it has been stated that: "Current selenium supplements rely on inorganic forms, such as sodium selenite (Na2SeO3) or sodium selenate (Na2SeO4). While these forms have some value, they are considered more toxic than necessary, and are unlikely to be useful in cancer chemo-prevention". OBJECTS OF THE INVENTION It has been recognized, recently, that breast cancer is a heterogeneous disorder and around 10% of consecutive breast/ovarian cancers occurs as a result of inherited high genetic predisposition to cancers. It is, therefore, an object of the invention to provide pharmaceutical compositions and methodology of their application allowing efficient lowering of the risk of breast / ovarian cancers in individuals with high genetic predisposition to these tumors, especially in carriers of BRCAl gene mutations. Another object of the invention is to provide such pharmaceuticals for chemoprevention of breast / ovarian cancers, which should be offered to females with constitutional mutations of BRCAl gene. SUMMARY OF THE INVENTION Unexpectedly, the problem described as above has been solved, at least in large part, due to this invention. The present invention is directed to pharmaceutical composition for lowering the risk of breast / ovarian cancer in person with inherited high risk of disease, especially in carrier of BRCAl mutation, characterized by contents of therapeutically-effective amount of selenium (e.g. in form of its salt or other derivatives thereof or any other known selenium comprising compound) and, if necessary, pharmaceutically acceptable carrier. According to one embodiment of the invention, selenium is selected among its organic forms such as methylselenocysteine, methyloseleninic acid, selenomethinine, selenocysteine or inorganic forms such as selenium dioxide, selenonic acid, selenic acid and their salts. It can be recommended also that selenium originates from such natural products like Se-enriched yeast or broccoli. According to next embodiment of the invention, selenium compound is a salt selected among: barium selenite, lithium selenite, calcium selenite and, what is particularly valuable, sodium selenite. Preferably, pharmaceutical composition is an isotonic solution, containing selenium at concentration 0.1 - 10% w/w. It can be recommended to use as a dissolvent an aqueous solution of ethanol at concentration 10 - 96% w/w., distilled water, physiologic solution preferably buffered. It can be recommended as well if composition according to invention contains selenium salt in aqueous solution of ethanol. The subject of invention is also the method of prevention of breast / ovarian cancer in person with inherited high genetic risk of tumor particularly in female carrier of BRCAl characterized by supplementation of patient with compounds containing selenium (or its salts or derivatives), and using compositions as described above. It can be recommended that in methodology according to invention patient is supplemented with selenium at doses 50 - 1000 μg per day. It is valuable, in methodology according to invention, to use composition containing selenium after detection in patient the constitutional BRCAl gene mutation. Unexpectedly, increased sensitivity to bleomycin as measured using cytogenetic test according to Hsu was detected in BRCAl mutation carriers (0.58 vs. 0.39 chromosome breaks per cell; p < 10"4) , that was normalized after 1 -month supplementation of diet with selenium at doses around 300 μg per day. Additionally, unexpectedly as well, the lowering of breast / ovarian cancer risk, was observed (see example 3). For the period of 2 years, occurrence of new breast / ovarian cancers was analyzed in the group of 30, initially healthy, carriers of BRCAl mutation supplemented with ethanol solution of sodium selenite at dose 300 μg per day and in the control group of 30
BRCAl carriers matched for mutation type and year of birth. During above pilot studies, 1 breast cancer case was observed in the group supplemented with selenium and 4 breast cancers plus 1 ovarian cancer in the control group. Additionally, for the period of 1 year, occurrence of new breast/ovarian cancers was analysed in the group of 200, initially unaffected, carriers of BRCAl mutations supplemented with ethanol solution of sodium selenite at dose 300 μg per day and in the control group of 200 BRCAl carriers matched for mutation type and age/average age 38.6 yrs). During above pilot studies 1 breast and 1 peritoneal cancers were observed in the group supplemented with selenium, whereas 2 breast and 2 ovarian cancers were diagnosed in the control group. DETAILED DESCRIPTION OF THIS INVENTION Invention provides pharmaceutical compositions and methodology of their application allowing efficient lowering of the risk of breast / ovarian cancers in individuals with high genetic predisposition to these tumors, especially in carriers of BRCAl gene mutations. Further, the invention provides such pharmaceuticals for chemoprevention of breast / ovarian cancers, which should be offered to females with constitutional mutations of BRCAl gene. Invention provides the pharmaceutical composition for lowering the risk of breast / ovarian cancer in person with inherited high risk of disease, especially in carrier of BRCAl mutation, which composition contains selenium (or its salt or derivatives or any other selenium comprising compound) and, if necessary, pharmaceutically acceptable carrier. The term "selenium or its salt or derivatives" as used herein, unless otherwise specified, refers to any known selenium comprising compound. The selenium can be present in elemental form and/or as all other organic or inorganic selenium compounds. In such compounds selenium can have -2, 0, +2, +4, and +6 oxidation states. Usually, the body detoxifies the higher oxidation state forms by reducing them to -2 and methylating to form dimethyl selenide. Dimethyl selenide is preferred and it can be used in conjunction with other selenium containing compounds. Particularly, as inorganic selenium compounds may be used such compounds as selenium dioxide, selenonic acid, selenic acid and their salts, especially metal selenides or selenites (e.g. potassium selenide, sodium selenide, sodium selenite, zinc selenide, barium selenite, lithium selenite, calcium selenite and other metal selenides or selenites). Moreover, selenium can be used in its organic forms such as seleno-amino acid e.g. methylselenocysteine, methyloseleninic acid, selenomethinine, selenocysteine. Examples of other useful organic selenium compounds are dimethyl selenide, all other organic selenides, selenoglutathione, and the organo-selenium complex Factor 3. It can be recommended also that selenium originates from such natural products like Se-enriched yeast or broccoli. Selenium occurs naturally in varying amounts in a wide variety of foods and also is present as an impurity in the natural form of the sulfur- containing amino acids, e.g., with methionine as the compound selenomethionine. This latter is due to the fact that the chemical behavior and reactivity of sulfur and selenium are very similar. Thus, in food grade sulfur-containing amino acids, the corresponding seleno-amino acid is normally present and thus contains selenium in significant amounts. Examples of such useful edible sulfur-containing amino acids are: cysteine, methionine, cystine, cystathionine, pencillamine cysteine disulfide, penicillamine, 2-amino-4,4-dimethyl-mercaptobutyric acid, vitamin U, brasinine, djenkolic acid, 2-amino-4-isopropyl-mercaptobutyric acid, 2-amino-4-butyl mercaptobutyric acid, 2-amino-4,4-diethyl-mercaptobutyric acid, dibenzo-yldjenkolic acid, the monohydrochloride of djenkolic acid, the hydrochloride of cysteine, 2-amino-2-ethyl-3- mercapto-propanoic acid, 2-thiolhistidine, thiomalic acid, the hydrochloride of cysteine, homocysteine, pantetheine, panthethine, Coenzyme A, and cysteic acid. All isomeric forms can be used. The sulfur-containing amino acids, proteins, and peptides are normally used in the hydrochloride form or in weak acid or base salt form because they are more readily water soluble. Examples of useful natural sulfur-containing peptides are: glutathione (a tripeptide of glutamic acid, cystein and glycine, also termed gamma-glutamyl-cysteinyl-glycine), cysteinyl- glycine, and gamma-cysteinyl-methionyl-glycine. Examples of useful sulfur-containing proteins are: keratin, insulin, albumin, ribonuclease, fibroin, collagen and elastin. All of the scleroproteins
(albuminoids), some of which are mentioned above, may be also useful as natural source of selenium. The term "pharmaceutically acceptable carrier" as used herein refers to term very well know for the person skilled in the art. Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, USA. Further information on preferred formulations is also provided in the more detailed description of the invention set out below (see example 1). The term "therapeutically-effective amount" means an amount of a selenium comprising compound, as defined above, to yield a desired therapeutic response, i.e. allowing efficient lowering of the risk of breast / ovarian cancers in individuals with high genetic predisposition to these tumors, especially in carriers of BRCAl gene mutations. The specific "therapeutically- effective amount" will, obviously, vary with such factors as the physical condition of the subject, the specific formulations employed and the structure of the used "selenium or its salt or derivatives". Particularly, it can be recommended that in methodology according to invention patient is supplemented with selenium at doses 50 - 1000 μg per day or appropriate dose of selenium comprising compounds which dose includes such amount of selenium. The compound of the invention may be administered in conjunction with one or more other known anti- neoplastic and/or cancer preventive agents. The compound of the invention and the second agent may be administered together or sequentially. In order to present the sense of invention, the description of invention is expanded by examples 1-3. However, it is not our intention to introduce claims limited to embodiments described in examples, because basing on presented sense of invention combined with knowledge generally available, experts will be able to prepare other variants comprised in defined claims. Example 1. Compositions containing selenium. Basing on information available from pharmakopoeia, experts are able to prepare different variants of compositions containing selenium, especially selenium (IV). For example, selenium can be chosen from organic forms such as methylcysteine, methylseleninic acid, selenomethionine, selenocysteine or from inorganic forms such as selenium dioxide, selenic acid, (H2SeO3) or its salts. For example selenium (IV) salt valuable for preparation of compositions according to invention is sodium selenite. Natural products with high concentration of selenium such as selenium-enriched yeast or broccoli are attractive compounds as well. Particularly valuable, although not the only one, composition according to invention are solutions of selenium at concentration 0.1 - 10% w/w, especially isotonic solutions. Such solutions can be made, for example, using such dissolvents as aqueous solution of ethanol at concentration 10 - 96% w/w, distilled water, physiologic solution especially if buffered. It has been shown that the optimum of pharmacological effect can be achieved if daily dose is 50 - 1000 μg of selenium. The above values are modifiable depending on biological access of selenium applied to preparation of composition, as well depending on influence of associated compounds, pharmaceutical carriers. Selected, although not the only ones, examples of such compositions are presented below: A) Ethanol solution of sodium selenite. In order to prepare 1000 g of composition - 2.03 g of sodium selenite (Na2SeO3) is dissolved in 334.32 g of H2O. To aqueous solution of sodium selenite obtained as above 663.65 g of 96% aqueous solution of ethanol is added, and the solution is carefully mixed. Composition prepared in such way can be used for oral supplementation of patient, 2 times 10 drops per day, what corresponds to daily dose around 300 μg of pure selenium. It can be recommended to divide composition into bottles containing 11-12 g, because such amount covers one-month supplementation. Described composition is stable, maintains its form and activity at least 18 months if stored at 4° C. It can be used by patients without giving side effects. B) Aqueous solution. Composition based on aqua can be prepared by replacement of ethanol by distilled water or physiologic solution (preferably buffered) in recipe as in A. Example 2.1ncreased rates of chromosome breakage in BRCAl carriers are reduced by oral selenium supplementation. Study subjects were recruited from among the attendees of a single familial cancer clinic of the Hereditary Cancer Centre of the Pomeranian Academy of Medicine in Szczecin, Poland. Women were referred to this clinic because of a family history of breast or ovarian cancer. The women who participated in this study had previously been offered, and had consented to, genetic testing. Case women were recruited from among those who had been found to be carriers of a deleterious mutation in the BRCAl gene. The most common mutation was the Polish founder mutation 5382 ins C (16 carriers) but there were 10 women with other BRCAl mutations. Control subjects were recruited from among the family members of the carriers (cases), but who had been determined not to carry the deleterious mutation. It was possible to generate 26 case- control pairs. In 20 instances the control was the sister of the case and in six instances she was a more distant relative. Only healthy women were invited to participate in this study; women with a past history of breast, ovary or other form of cancer were excluded. Each woman provided a blood sample at some time during one year study. Chromosome sensitivity to bleomycin was measured according to the method of Hsu et al. (Sensitivity to the genotoxic effects of bleomycin in humans; possible relationship to environmental carcinogenesis, Int J Cancer, 1989, 43, 403-409). Bleomycin (Nippon-Kayuka) was added to the cell culture five hours before the end of the culture at a concentration of 0.03 IU/ml. Conventional harvesting and Giemsa staining were made. For each subject, 100 consecutive euploid cells in metaphase were read (cells with overlapping chromosomes were excluded). Each chromatid aberration (excluding gaps) was scored as one breakpoint and each exchange-type aberration was scored as two breakpoints. The total number of breakpoints per 100 cells was recorded for each subject. Reading of coded slides was performed blindly by one of us. For twenty randomly selected cases the counts were determined independently by two cytogenetic technicians with good agreement. The mean number of breaks per cell was calculated after inspection of 100 cells. The mean level of chromosome breaks was compared in the 26 case-control pairs using the paired t-test. The mean number of chromosome breaks per cell was 0.58 for the BRCAl mutatin carriers (range 0.34 to 0.73) and was 0.39 for the controls (range 0.28 to 0.62) (table 1). For 23 of the 26 pairs, the value for the carrier exceeded that for the related control, for two pairs the control value was the higher of the two and for one pair the two values were equal (p < 0.0001; sign test). The mean difference between the two groups was highly significant (p < 0.0001).
Table 1. Comparison of chromosomes breaks per cell in BRCA1 carriers and matched controls.
Figure imgf000012_0001
A second group of BRCAl carriers was recruited from this clinic for the purpose of studying the effect of selenium supplementation on frequencies of chromosome breaks. Thirty-five women with BRCAl mutations agreed to participate in this phase of the study. Blood samples were taken prior to the onset of selenium supplementation, and again at a time from one month to three months following the start of daily selenium supplementation. Prior to selenium supplementation, the mean number of induced chromosome breaks per cell was 0.63 (range 0.42 to 0.81). An oral selenium solution was provided to the study subjects which contained 690 μg of pure selenium, in the form of sodium selenite (Na2SeO3) per ml of 70% ethanol. Subjects were requested to consume 0.2 ml of the solution twice daily. A second blood sample was taken at a time from one month to three months after commencement of selenium supplementation and the bleomycin test was repeated. After a mean of 1.5 months of selenium supplementation, the mean number of chromosome breaks per cell was reduced to 0.40 (range 0.27 to 0.60). In every case, the post-supplementation level showed a decline from the baseline level (table 2) and the mean difference was highly significant (p < 10"10).
Table 2. Comparison of chromosome breaks per cell in BRCA1 carriers before and after selenium supplementation.
Figure imgf000013_0001
Summarising, oral selenium is a good candidate for chemoprevention in women who carry a mutation in the BRCAl gene.
Example 3. Supplementation of female BRCAl mutation carriers with selenium is reducing significantly the risk of breast / ovarian cancers. Occurrence of breast / ovarian cancers in the group of 30, initially healthy, carriers of BRCAl mutations taking orally ethanol solution of sodium selenite at dose 300 μg daily and in the control group of 30 BRCAl carriers matched for mutation type and year of birth, was observed during two years. Average age in both groups was 46.5 years. During the period of observation 1 breast cancer case was diagnosed in the group supplemented with selenium and 4 breast cancers plus 1 ovarian cancer have been diagnosed in control group. (Tab. 3). Additionally, for the period of 1 year, occurrence of new breast/ovarian cancers was analysed in the group of 200, initially unaffected, carriers of BRCAl mutations supplemented with ethanol solution of sodium selenite at dose 300 μg per day and in the control group of 200 BRCAl carriers matched for mutation type and age/average age 38.6 yrs). During above pilot studies 1 breast and 1 peritoneal cancers were observed in the group supplemented with selenium, whereas 2 breast and 2 ovarian cancers were diagnosed in the control group.
Table 3. Occurence of breast / ovarian cancers In initially healthy carriers of BRCA1 mutations after supplementation with selenium and in matched controls.
Figure imgf000015_0001

Claims

Claims 1. Pharmaceutical composition lowering the risk of breast / ovarian cancer in person with inherited high risk of these tumors, especially in female carriers of BRCAl gene mutation, said composition comprising therapeutically-effective amount selenium, its salt or derivatives, and possibly pharmaceutically acceptable carrier.
2. The composition as claimed in claim 1, wherein selenium is selected from its organic or inorganic form.
3. The composition as claimed in claim 2, wherein organic form of selenium is compound selected among selenomethylcysteine, methylseleninic acid, selenomethionine and selenocysteine.
4. The composition as claimed in claim 2, wherein inorganic form of selenium is compound selected among selelnium dioxiale, selenic acid (H2SeO3) or salts thereof.
5. The composition as claimed in claim 1, wherein selenium is derived from natural products.
6. The composition as claimed in claim 1, wherein natural product is plant product such as broccoli or selenium-enriched yeast.
7. The composition as claimed in claim 1, wherein selenium is a selenium (IV) salt selected among: sodium-, barium-, lithium-, calcium- of selenite.
8. The composition as claimed in claim 7, wherein compound including selenium is sodium selenite.
9. The composition as claimed in claim 1, characterized in that it is isotonic solution.
10. The composition as claimed in claim 1, wherein selenium compound is a solution at concentration of 0.1 - 10 % w/w.
11. The composition as claimed in claim 6, wherein dissolvent contains aqueous solution of ethanol at concentration 10-96% w/w in pharmaceutical acceptable solvent.
12. The composition as claimed in claim 6, wherein solvent is selected among distilled water, physiologic solution, or buffered physiologic saline.
13. The composition as claimed in claim 1, containing aqueous ethanol solution of selenium salt.
14. The method of preventing breast / ovarian cancer in person with inherited high risk of these tumors, especially in female carriers of BRCAl gene mutations, comprising administration to the subject selenium or its salts or derivatives or composition according to claims 1-13.
15. The method of breast / ovarian cancer prevention in person with inherited high risk of these tumors, especially in BRCAl gene mutation carriers, comprising administration to the subject of selenium or its salt or derivatives or composition according to 1-13.
16. The method of claim 15, comprising administration to the subject of 50 - 1000 μgs of selenium per day.
17. The method of claim 15, wherein a decision about adminsitration of composition containing selenium can be taken after detection of the constitutional mutation in BRCAl gene in patient DNA.
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ZA200602081B (en) 2007-05-30
JP2007502270A (en) 2007-02-08
AU2004263070A1 (en) 2005-02-17
WO2005013951A3 (en) 2005-09-15
EA200600386A1 (en) 2006-12-29
PL361597A1 (en) 2005-02-21
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