ZA200602081B - Pharmaceutical compositions for preventing breast and ovarian cancer - Google Patents
Pharmaceutical compositions for preventing breast and ovarian cancer Download PDFInfo
- Publication number
- ZA200602081B ZA200602081B ZA200602081A ZA200602081A ZA200602081B ZA 200602081 B ZA200602081 B ZA 200602081B ZA 200602081 A ZA200602081 A ZA 200602081A ZA 200602081 A ZA200602081 A ZA 200602081A ZA 200602081 B ZA200602081 B ZA 200602081B
- Authority
- ZA
- South Africa
- Prior art keywords
- selenium
- composition
- breast
- solution
- medicament
- Prior art date
Links
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
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- 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, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- 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
Description
Pharmaceutical compositions and methods for the prevemtion of breast and ovarian cancer
FIELD OF THE INV" ENTION
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 pre~vention of breast / ovarian cancer in females with inherited high risk of cancer, particularly in caTriers of BRCA1 gene mutatiosns.
BRCA1 (US5654155) and BRCA2 genes are relatecd to high genetic predisposistions to cancers. BRCA1 and BRCA2 genes have been cloned and, at present, their abnormalitie=s can be detected at DNA anc RNA levels. Carriers of mutations “within above-genes have high risk of breast and / or ovarican cancers. BRCAL is the first gene recognized to be associated w=ith high risk of breast and ovarian cancer (Miki et al, Scierce, 266-271, 1994). BRCM gene (GENBANK Access-ion Numbers: U14680 and 15595) contains 24 exons dispersed wi thin 100 kbp of genomic DN.A and its mRNA is of 7.8 kbp of the length. Intensive studies of this gene allowed to identify snumerous BRCAl mutations. For ex ample, US5693473 is reporting large registry of such ch anges. WO 99/29903 is describing the next fifteen BRCA1 mmutations.
BRCA2 gene (GEN_BANK accession Number U43746) contains 27 exons dispersed v=vithin 70 kbp of genomic DNJA and its mRNA is of 11-12 kbp of the length. Numerous mut-ations of
BRCA2 gene have been reported as associated with camcer predisposition (for example WO 9928506).
All of descritbed BRCAl and BRCA2 gene mutations are available amn page: http://www.nchgr.ni h.gov/dir/lab-transfer/bic.
BRCA1 and BRRCA2 mutations can be located in different exons. Increased freqguency 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 BRCA 1 185delAG and 5382insC and BRCA.2 6174delT are well known. I'n Poland,
increased frequency of the following BRCAL1 mutations has teeen reported: ex 2 — 185delAG, ex - 300T—G, ex 5 - 309*T—+C, ex 11.15 - 3819delGTAA_A, ex 11.17 — 4153delA, 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 abnornmalities is creating a chance, valuable for several countries, of BRCAI1/BRCA2 examination wwith cost- effectiveness extremely hmigh. In Poland, around 100,000 of women are carriers o-f 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-Bayoum:y K., The role of selenium ira cancer prevention, Philadelphia,
Lippincott, 1-15, 1991). Chemoprevention studies with selenium in animal model systems have indicated that this elememt is effective for most, if not all off 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 prev—ention, Philadelphia, Lippincott, 1-15, 1991). Both epide=miological studies and supplementat_ion trails have also supported its efficacy in lowering the ircidence of cancers of the liver, colo, prostate and lung (Yu S.Y. et all. Protective role of seleni um against hepatitis B virus and prirmary liver cancer in Qidong, Biol “Trace Elem Res, 56: 117—124, 1997,
Clark L.C. et al. Effectss of selenium supplementation fox cancer prevention in paatients 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 Natl - Cancer Inst (Betsheda), 90: 1219-12224, 1998; Brooks J.D. et al. Plasma selenium level before diaagnosis and risk of prostate cancer dezvelopment, J Urol, 166: 2034-2038, 2001). The latest literature data are, however, not supportingz negative correlation between th e level of selenium in tThe body of patients and the risk of bareast cancer.
Garland M. et al. concluded that diet supplementation with se=lenium does not influeence the risk of female breast cancer (J. Am. Coll Nutr. 1993, Aug; 12(48): 400-11, J Natl Carcer Inst 1995, Apr 5; 87(7) :497-505). Simmilar conclusions have been repeorted by Ghadirian P. et al. (A case-control study of noenail selenium and cancer of the breasst, colon and prostate., Cancer
Detect Prev, 24: 305-13, 2000).
Further, in EP1003760 relatimg to selenium-containing compounds and methods Sor using these compounds to protect mammals from toxic insults, it mas been stated that: “Current selenium supplements rely on imorganic forms, such as sodium selenite (Na;SeOs3) o-r sodium selenate (N2;SeO,). While these forms have some value, they are considered more toxic than necessary, and are unlikely to be useful in cancer chemo-preventieon”.
OBJECTS OF THE INVENTI®ON
It has been recognized, recently, that breast cancer is a hetesrogeneous disorder ard around 10% of consecutive breast/ovarian cancers occurs as a ressult of inherited highh genetic predisposition to cancers. It is, therefore, an object of the inveration to provide pharmmaceutical compositions and methodology of their application allowing efficient lowering of thhe risk of breast / ovarian cancers in imdividuals with high genetic predisposition to thesee tumors, especially in carriers of BRCAL gene mutations. Another object of the invention is ®o provide such pharmaceuticals for chemo-prevention of breast / ovarian c=ancers, which should Wbe offered to females with constitutional mutations of BRCA1 gene.
Unexpectedly, the problem clescribed as above has been solwed, at least in large p - art, due to this invention.
The present invention is di rected to pharmaceutical compeosition for lowering t-he risk of breast / ovarian cancer in person with inherited high risk of disease, especially in carrier of
BRCA! mutation, characterized by contents of therapeuticall-y-effective amount off selenium
(e.g. in fomm of its salt or other derivativ es thereof or any other knowmn selenium comprising compound) and, if necessary, pharmaceutically acceptable carrier.
According to one embodiment of the iravention, selenium is selected ammong its organic forms such as wmethylselenocysteine, methyloseleninic acid, selenomethinine, selenocysteine OT inorganic forms such as selenium dioxide, selenonic acid, selenic acid aand their salts. It can be recommernded also that selenium originates from such natural products like Se-enriched yeast or broccoli. =According to next embodiment ©f the invention, selenium commpound is a salt selected among: b arum selenite, lithium selenite, calcium selenite and, what iis particularly valuable, sodium selenite. Preferably, pharmaceutical composition is an isotoric solution, containing selenium at concentration 0.1 — 10% w/w. It can be recommended tom use as a dissolvent an aqueous ssolution of ethanol at concentration 10 — 96% wiw., distilled wamter, physiologic solution preferablwy buffered. It can be recommended as well if composition according to invention contains selenium salt in aqueous solutior of ethanol.
The subject of invention is also the method of prevention of breast / ovarian cancer in person with inhe=rited high genetic risk of tumor particularly in female carrier wof BRCA1 characterized by supplesmentation of patient with compsounds containing selenium (or its salts or derivatives), and usin_g compositions as described above. It can be recommende=d that in methodology according to invention patient is supplem ented with selenium at doses 580 — 1000 pg per day. It is valuable, in methodology according to imvention, to use composition containing selenium after detectionm in patient the constitutional BR€CA1 gene mutation.
Unexzpectedly, increased sensitivity to bleomycin as measured using cytogenetic test accordin:g to Hsu was detected in BRCA1 mutation carriers (0.58 vs. @0.39 chromosome breaks percell; p< 10%) , that was normalized after 1-month supplementatiorm of diet with selenium at doses around 300 ug per day.
Additionally, unexpectedly as well, the low~ering of breast / ovariarm cancer risk, was observed (see exzample 3). For the period of 2 yea xs, occurrence of new brea_st / ovarian cancers was analyzed in the group of 30, initially healthzy, carriers of BRCAI mutation supplemented with ethanol solution of sodium selenite at dose 3300 ug per day and in the control group of 30
BRCAL1 carriers matched for mutation type and year of birth. During above pmilot studies, 1 breast cancer case was observed in the group supplememted with selenium and 4 boreast cancers plus 1 ovarian cancer im the control group.
Additionally, for the period of 1 year, occurremce of new breast/ovarian cancers was analysed in the group o=f 200, initially unaffected, carriers of BRCA1 mutations- supplemented with ethanol solutior of sodium selenite at dose 300 ug per day and in the c=ontrol group of 200
BRCA1 carriers matched for mutation type and age/average age 38.6 yrsyw. During above pilot studies 1 breasst and 1 peritoneal cancers were observed in the groups supplemented with selenium, whereeas 2 breast and 2 ovarian cancerss were diagnosed in the control group.
Invention porovides pharmaceutical compositions and methodology of their application allowing efficient lowering of the risk of breast /~ ovarian cancers in individwuals with high genetic predisposition to these tumors, especially in carriers of BRCAI gene mutations. Further, the invention provides such pharmaceuticals for che=moprevention of breast / o-varian cancers, which should be offered to females with constitutional mutations of BRCAI gene.
Invention porovides the pharmaceutical compposition for lowering the risk of breast / ovarian cancer in perseon with inherited high risk of disease, especially in carrier of BRCAI mutation, which compos. ition contains selenium (or its salt or derivatives or any other selenium comprising compound) an d, if necessary, pharmaceutically acceptable carrier.
The term “selenium or its salt or derivatiwes™ as used herein, unlescs otherwise specified, refers to any k<nown selenium comprising comgoound. The selenium can bee present in elemental form and/or as all other organic or inorganic selenium compoumds. In such compounds selernium can have -2, 0, +2, +4, andl +6 oxidation states. Usually, the body detoxifies the higher oxidation state forms by reducing thesm to -2 and methylating to form dimethyl selenide. Dimethyl sele=nide is preferred and it can bee used in conjunction with other selenium containing compounds.
Particularly, as inorganic= selenium compounds may be used such compounds as selemnium dioxide, selenonic acid, se=lenic acid and their salts, especially’ metal selenides or selenites (¢.8. potassium selenide, soditam selenide, sodium selenite, zinc selenide, barium selenite, lit_hium selenite, calcium selenite and other metal selenides or selemites). Moreover, selenium can be used in its organic forms such as seleno-amino acid e.g. meth-ylselenocysteine, methyloselesninic acid, selenomethinine, se=lenocysteine. Examples of other useful organic selenium compounds are dimethyl! selenide, all other organic selenides, selenoglutathione, and the organo-selesnium complex Factor 3. It can be recommended also that selenium originates from such nazatural products like Se-enrichedll yeast or broccoli. Selenium occurs naturally in varying amount=s in a wide variety of foods amnd also is present as an impurity in the natural form of the s ulfur- containing amino acids, .g., with methionine as the compound selenomethionine. This la~tter is due to the fact that the cinemical behavior and reactivity of sulfur and selenium are very similar.
Thus, in food grade suMfur-containing amino acids, the corresponding seleno-amino aecid is normally present and thuas contains selenium in significant @mounts. Examples of such wuseful edible sulfur-containing: amino acids are: cysteine, methionine, cystine, cystathieonine, pencillamine cysteine Tisulfide, penicillamine, 2-amino-4-,4-dimethyl-mercaptobutyric acid, vitamin U, brasinine, djemnkolic acid, 2-amino-4-isopropyl-memrcaptobutyric 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-et hyl-3- mercapto-propanoic acied, 2-thiolhistidine, thiomalic acid, the hydrochloride of cysteine, homocysteine, pantetheire, panthethine, Coenzyme A, and cysteic acid. All isomeric forrms 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 mmnore readily water soluble. Examples of useful natural sulfur-containing peptides are: glutathiomne (a tripeptide of glutamic acid, cystefin and glycine, also termed gammaa-glutamyl-cysteinyl- glycine), cysteinyl- glycine, and gamma—cysteinyl-methionyl-glycine. Exammples of useful sulfur-=containing proteins _ are: keratin, insulin, albumin, ribonuclease, fibroin, collagen and elastin. All omf the scleroproteins (albuminoids), somes of which are mentioned above, rnay be also useful a=s natural source of selenium.
The term “pharmaceutically acceptable carrier” as umsed herein refers to tem very well know for the person skilled in the art. Methods and phamrmaceutical carriers for preparation of pharmaceutical conmpositions are well known in the art, as set out in textbooks such as
Remington's Pharmaceutical Sciences, 17th Editiorm, Mack Publishing Company, Easton,
Pennsylvania, USA _ Further information on preferred Formulations is also p—rovided in the more detailed description of the invention set out below (see example 1).
The term "theraapeutically-effective amount” mears an amount of a seelenium comprising compound, as defimed above, to yield a desired themrapeutic response, i.e=. allowing efficient lowering of the risk= of breast / ovarian cancers in indiv-iduals with high gene=tic predisposition to these tumors, especially in carriers of BRCA1 gene -mutations. The speci fic "therapeutically- effective amount” will, obviously, vary with such factors as the physical conadition of the subject, the specific formu lations employed and the structumre of the used “selenium or its salt or derivatives”. Particularly, it can be recommended that in methodology according to invention patient is suppleme=nted with selenium at doses 50 — 1000 pg per day or appropriate dose of selenium comprisinmg compounds which dose includes such amount of selen. ium. The compound of the invention may be administered in conjunction with one or more= other known anti-
neoplastic and/or ¢ ancer preventive agents. The compo-und of the invention and the second agent may be administeresd 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 presemmted sense of invention commbined with knowledge generzily available, experts will be ables 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, methylsesleninic acid, selenomethionine=, selenocysteine or from inorganic forms such as selenium dmoxide, selenic acid, (H;SeO;) =or its salts. For example seleniuxm (IV) salt valuable for gpreparation of compositions according to invention is sodium selenite. Natural products with hig concentration of selenium such as selenium-enriched yeast or broccoli are attractive compounds =as well.
Particularly waluable, although not the only onse, composition according toe invention are solutions of selenium at concentration 0.1 — 10% w/w, especially isotonic s-olutions. Such solutions can be made, for example, using such disssolvents as aqueous solutiom of ethanol at concentration 10 —96% w/w, distilled water, physiologic solution especially if bu_flered.
It has been shown that the optimum of pharmacological effect can be achieved if daily dose is 50 — 1000 pg eof selenium. The above values are modifiable depending on biological access of selenium applieci to preparation of composition, as well depending on influenc e of associated compounds, phammaceutical carriers.
Selected, altbhough not the only ones, examples off such compositions are prese=nted below:
A) Ethanol solution of sodium selenite.
In order to pregpare 1000 g of composition — 2.003 g of sodium selenite (Nam;8e0;) is dissolved in 334.32 g of H,#0. To aqueous solution of sodiu_m selenite obtained as abo=ve 663.65 g of 96% aqueous solution «of ethanol is added, and the solu_tion is carefully mixed. Composition prepared in such way can be used for oral supplementation of patient, 2 times 10 Crops per day, what corresponds to daily dose around 300 ug of pur-e selenium. It can be reccommended to divide composition inte bottles containing 11-12 g=, because such amount covers one-month supplementation. Described composition is stab le, maintains its form and activity at ]east 18 months if stored =at 4° C. It can be used by patient s 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 recigpe as in A.
Example 2.I ncreased rates of chromosome= breakage in BRCA1 carriers are reduced by oral selenium supplementation.
Study subjects were recruited from among tine attendees of a single fanmilial cancer clinic of the Hereditary (Cancer Centre of the Pomerani=an Academy of Medicine in Szczecin, Poland.
Women were referred to this clinic because of am family history of breast om ovarian cancer. The women who participated in this study had previously been offered, and had consented to, genetic testing. Case women were recruited from amormg those who had been found to be carriers of a deleterious mutation in the BRCA1 gene. The -most common mutation waas the Polish founder mutation 5382 ins C (16 carriers) but there vmvere 10 women with othe T BRCA1 mutations.
Control subjectss were recruited from among the family members of the carriers (cases), but who had been deterrnined not to carry the deleterioums mutation. It was possible to generate 26 case- control pairs. In_ 20 instances the control was the sister of the case and in sEx instances she was a more distant rel ative. Only healthy women were invited to participate in timis study; women with a past history o f breast, ovary or other form of cancer were excluded. Eaech 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 blezomycin in humans; posssible relationship to environmental ecarcinogenesis, Int J Cancer, 19989, 43, 403-409). Bleomywcin (Nippon-Kayuka)
was adde=d 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 e=ach subject, 100 consecut@ve euploid cells in metaphase were read (cells with overlapping clmromosomes were excluded). Each chromatid aberration (excluding gaps) was scored as one bre=akpoint and each exchanges-type aberration was scored as two breakpoints. The total number of breakpoints per 100 cellss was recorded for each subject. Readimg of coded slides was performmed blindly by one of us. Feor twenty randomly selected cases the counts were determined inde=pendently by two cytogenetic technicians with good agreemerat. The mean number of breaaks per cell was calculatezd after inspection of 100 cells. The mean level of chromosome breakss 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 BRC Aa.1 mutatin carriers (range O».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, thme value for the carrier exceeded that for the related control, for tweo pairs the control value w-as the higher of the two and for one ypair the two values were equal (p < 0.0001; sign test). Thue mean difference between the two grosups was highly significant (p < 0.0001).
Table 1. Comparison of chromosomes breal<s per cell in BRCA1 carriers and matched controfis.
Case ID Chromosome age age breaks per cell 8 breal=s per cell 1 22 | oss | a2 | ear 2 | ax | oe | sa | «55 — 3. 2» | _o03« | 33 | 044 — a 3s» | _oest__ | 36 | 06 — 5. |_| 04 | 31 | e3 6 | __2@ | _os7 kk 20 | 04 5. | 45 | oe0 Fg si [040 8 | 4@ | os2 FF ss | 0s 0. | sm | ee | 29 | as 10. | 2a | oe | 22 | 042 1. | as | os | 28 | 035 12. | 2a | oes | 2s | = 02 13. | 23 | oes | 22 | 04 15. | 3m | os | 34 | 0.32 16. | 23 | os | 38 | = 036 17. | a= | 0s | 35 1 036 — 18. | so | 048 | 58 | 030 19. | 53 | osa [et [020 20. | ss | 059 | so [ 034 21. | a= | ost | 46 | 038 22. | 22 | eer | 21 | = 045 23. | 34 | oe | 3 | 028 24. | 3a | em [| 3 | oa 25. | 1s | 059 | a1 [028 2. | 27 | 064 | 3 | 035 mean | 3=3 | 058 | 357 [| 03
A second group of BBRCA1 carriers was recruited from this clinic for the purp ose of studying the effect of selenium supplementation on frequencies of chromosome brea ks. Thirty-five women with BRCA1 mutations agreed to participate in this phase of the study. Blood samples were taken prior to the onset of selenium supplementa=tion, and again at a time from one month to three months following the start of daily selenium supplementation. Prieor to selenium supplementation, the maean number of induced chromossome breaks per cell was 0-63 (range 0.42 to 0.81). An oral selenium solution was provided to the study subjects which cont=ained 690 ug of pure selenium, in the fem of sodium selenite (Na;SeC;) per ml of 70% ethanol . Subjects were requested to consume .2 ml of the solution twice dail y. A second blood sample= was taken at a time from one month te three months after commencerment of selenium supplementation and the
Claims (19)
1. Pharmaceutical composition lowering the risk of breast / ovarian carcer in person with inherited high risk of these tumors, especially in female carriers of BRCA1 gene mutation, said composition Comprising therapeutically-effective zamount selenium, its salt or derivatives, and possibly pharmaceutically acceptable carrier.
2. The composition as claimed in claim 1, whaerein selenium is selected from its organic or inorganic forrm.
3. The composition as claimed in claim 2, wherein organic form of sel enium is compound selected among selenomethyicysteine, —metkaylseleninic acid, selemnomethionine and selenocysteine.
4. The ceomposition as claimed in claim 2, wherein inorganic form of se lenium is compound selected amomg selelnium dioxiale, selenic acid (H_5SeQ;) or salts thereof.
S. The composition as claimed in claim 1 , wherein selenium is deerived 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 selenimm (IV) salt selected among: sodiLim-, barium-, lithium-, calcium- of selenite.
8. The «composition as claimed in claim 7, whherein compound includingg selenium is sodium selenite.
9. The composition as claimed in claim 1, chazaracterized in that it is isoteonic solution.
10. The «composition as claimed in claim 1, wherein selenium compound is a solution at concentratiomn of 0.1 — 10 % w/w.
11. The composition as claimed in claim 6, wherein dissolvent contains aqueous solution of ethanol at cosncentration 10-96% w/w in pharmaceutical acceptable solvent.
PCCT/PL2004/000063
12. “The composition as claimed in cla im 6,wherein solvent is selected zamong distilled water, physiologic solution, or buffered physiologic saline.
13. “The composition as claimed in claim 1, containing aqueous ethanol solution of selenium. salt.
14. Use of selenium or its salts or deri vatives or composition accordings to claims 1-13, in the meanufacture of a medicament for preventing breast / ovarian cancer ir person with inherited high risk of these tumors, especially in female carriers of BRCAL _gene mutations.
15. Use of selenium or its salts or dexr-ivatives or composition accordin_g to claims 1-13, in the maanufacture of a medicament for prezventing breast / ovarian cancer ir person with inherited high risk of these tumors, especially in BRCA1 gene mutation carmiers.
16. Use of claim 15, wherein an effective dose of said medicament is S50 -- 10000 pgs per day.
17. Use of claim 15, wherein a decisi on about administration of said medicament can be taken after detection of the constitutional rnutation in BRCAI gene in patiemnt DNA.
18. A composition according to any one of claims 1 to 13, substantially as herein describe=d with reference to any of the exazmnples and as illustrated.
19.. Use according to any one of clairms 14 to 17, substantially as herei—n described with referencze to any of the examples and as ill ustrated. AMLCENDED SHEET
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US20110117545A1 (en) * | 2007-03-26 | 2011-05-19 | Decode Genetics Ehf | Genetic variants on chr2 and chr16 as markers for use in breast cancer risk assessment, diagnosis, prognosis and treatment |
CN100548311C (en) | 2007-06-13 | 2009-10-14 | 中国科学技术大学 | Application and the fast preparation method of sodium thiosulfate in preparation clinical selenium-complementing and treatment cancer drug |
WO2009043106A1 (en) * | 2007-10-03 | 2009-04-09 | Velacor Therapeutics Pty Ltd | Inorganic selenium and angiogenesis |
US20110105342A1 (en) * | 2008-03-13 | 2011-05-05 | Jan Lubinski | Method for determining reduced predisposition to cancer based on genetic profile |
KR101026291B1 (en) * | 2008-06-30 | 2011-03-31 | 주식회사 태강 | Anticancer composition of SeO2 doped W-Mo-Li |
GB0916010D0 (en) * | 2009-09-11 | 2009-10-28 | Isis Innovation | JMJD2 demethylase inhibitors |
WO2012067525A1 (en) | 2010-11-18 | 2012-05-24 | Pomorski Uniwersytet Medyczny | Genotypes and selenium level as a markers of breast/ovarian cancer risk in brca1 mutation carriers |
JP5895303B2 (en) * | 2011-04-01 | 2016-03-30 | イアソマイ エービー | Novel combinations comprising N-acetyl-L-cysteine and uses thereof |
SG10202101918RA (en) * | 2013-03-15 | 2021-03-30 | Alltech Inc | Compositions comprising selenium and use of same for the treatment and prevention of disease or conditions associated with mitochondrial dysfunction |
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