EP1660060A2 - Pharmaceutical compositions for preventing breast and ovarian cancer - Google Patents
Pharmaceutical compositions for preventing breast and ovarian cancerInfo
- Publication number
- EP1660060A2 EP1660060A2 EP04775169A EP04775169A EP1660060A2 EP 1660060 A2 EP1660060 A2 EP 1660060A2 EP 04775169 A EP04775169 A EP 04775169A EP 04775169 A EP04775169 A EP 04775169A EP 1660060 A2 EP1660060 A2 EP 1660060A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- selenium
- composition
- breast
- brcal
- carriers
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 206010033128 Ovarian cancer Diseases 0.000 title claims description 15
- 239000011669 selenium Substances 0.000 claims abstract description 84
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- 229960003180 glutathione Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960001913 mecysteine Drugs 0.000 description 1
- 230000031864 metaphase Effects 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- ZNXZGRMVNNHPCA-VIFPVBQESA-N pantetheine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS ZNXZGRMVNNHPCA-VIFPVBQESA-N 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001629 sign test Methods 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 229960001881 sodium selenate Drugs 0.000 description 1
- 235000018716 sodium selenate Nutrition 0.000 description 1
- VPQBLCVGUWPDHV-UHFFFAOYSA-N sodium selenide Chemical compound [Na+].[Na+].[Se-2] VPQBLCVGUWPDHV-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- NJRXVEJTAYWCQJ-UHFFFAOYSA-N thiomalic acid Chemical compound OC(=O)CC(S)C(O)=O NJRXVEJTAYWCQJ-UHFFFAOYSA-N 0.000 description 1
- 210000004906 toe nail Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- 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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- Animal Behavior & Ethology (AREA)
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- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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PL361597A PL214402B1 (pl) | 2003-08-11 | 2003-08-11 | Zastosowanie selenu albo jego zwiazku do otrzymywania srodka do obnizania odziedziczonego ryzyka zachorowania na raka piersi lub jajnika |
PCT/PL2004/000063 WO2005013951A2 (en) | 2003-08-11 | 2004-08-10 | Pharmaceutical compositions for preventing breast and ovarian cancer |
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JP (1) | JP2007502270A (ja) |
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US20080081039A1 (en) * | 2004-09-21 | 2008-04-03 | Velacor Therapeutics Pty. Ltd. | Inorganic Selenium For Treatment Of Cancer |
EP2137324A2 (en) * | 2007-03-26 | 2009-12-30 | Decode Genetics EHF | Genetic variants on chr2 and chr16 as markers for use in breast cancer risk assessment, diagnosis, prognosis and treatment |
CN100548311C (zh) * | 2007-06-13 | 2009-10-14 | 中国科学技术大学 | 硒代硫酸钠在制备临床补硒和治疗癌症药物中的应用及快速制备方法 |
WO2009043106A1 (en) * | 2007-10-03 | 2009-04-09 | Velacor Therapeutics Pty Ltd | Inorganic selenium and angiogenesis |
EP2313529A2 (en) * | 2008-03-13 | 2011-04-27 | Pomorska Akademia Medyczna | Method for determining reduced predisposition to cancer based on genetic profile |
KR101026291B1 (ko) * | 2008-06-30 | 2011-03-31 | 주식회사 태강 | SeO2 doped W-Mo-Li 화합물을 함유한 항암제 조성물 |
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 |
EP2694045B1 (en) | 2011-04-01 | 2019-10-30 | Iasomai AB | New combination comprising n-acetyl-l-cysteine and its use |
RU2663127C2 (ru) | 2013-03-15 | 2018-08-01 | Олтек, Инк. | Селенсодержащие композиции и их применение для лечения и предотвращения заболеваний или состояний, связанных с митохондриальной дисфункцией |
DK3116511T3 (da) * | 2014-03-14 | 2020-11-23 | Alltech Inc | Sammensætninger af selenoorganiske forbindelser og fremgangsmåder til anvendelse deraf |
PL442921A1 (pl) * | 2022-11-23 | 2024-05-27 | Read-Gene Spółka Akcyjna | Obniżanie ryzyka zgonów u kobiet z dziedziczną predyspozycją do raka piersi |
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