11017 Manklin Meadows Lane
Berlin, MD 21811

SeNRC

 

 

European Patent Office                                          (11)      EP 0 750 911 B1

(12)                                         EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention                                     (51) Int Cl.7: A61 K 33/04, A61 K 31/095,

       of the grant of the patent:                                                                  A61K 31/66 A61P 35/00

       10.09.2003 Bulletin 2003/37                                                                   //(A61K31/66, 31:355, 31:195,

                                                                                          31:085

(21) Application number: 96109035.4

(22) Date of filing: 05.06.1996

(54) Composition containing selenium to reduce cancer incidence and extend lifespan.

        Selen enthaltende Zusammensetzung zur Reduzierung der Krebshaufigkeit und zur Verlangerung

        des Lebensalters

       Composition contenant du selenium pour la reduction de la frequence des cancers et pour

        I'allongement de la duree de vie

(84) Designated Contracting States:                                 (74) Representative: Muller-Bore & Partner

        CH DE GB LI                                                                                Patentanwalte

Grafinger Strasse 2

                                                81671 Munchen (DE)

(30) Priority: 07.06.1995 US 911 81671

(43) Date of publication of application:                            (56) References cited:

        02.01.1997 Bulletin 1997/01                                           DE-A- 3 542 309          US-A-5 230 998

(73) Proprietor: Life Science Labs, Inc.                               PATENT ABSTRACTS OF JAPAN vol. 016, no.

      Minneapolis, MN 55423 (US)                                         273 (C.0953), 18 June 1992 & JP-A-04 066567

(KENJI SODA;OTHERS: 01), 2 March 1992,

(72) Inventors:                                                                        J. LABELLED COMPD RADIOPHARM. , vol. 30,

        Olson, David M.                                                             1991, page 143 XPOOO579305 ENGELSKIRCHEN

        Minneapolis, Minnesota 55423 (US)                             G. ET AL.: “N.C.A.selenium-73-labeled

       Passwater, Richard A.                                                compounds basic studies on a selenation

        Berlin, MD 21811 (US)                                                  strategy via triphenylphosphine selenide using

N.C.A. selenlum-75”

 

 

Note: Within nine months from the publication of the mention 01 the grant of the European patent, any person may give

notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be flied in

a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.

99(1) European Patent Convention).

Printed by Jouve. 70001 PARIS (FR)


 

EP 0 750 911 B1

Description

[0001] The present invention relates to a composition comprising a compound including the element Se as well as

the use of said compound for preventing or reducing cancer.

 [0002] The many chemicals that cause cancer as carcinogens or radiation or predisposed genetic flows do so by

 causing DNA damage by adding oxygen molecules where the oxygen should not be. To the degree that any other of

 a few chemicals prevent that DNA damage, the chemicals also prevent cancer. Since not all the damage can be

 prevented from occurring, the most important step is the repair of this damage.

[0003] DE-A 1-35 42 309 describes a medical antioxidant comprising inter alia selenomethionine. The abstract of

 Japanese Patent JP-A-4066567 describes a medicine including an active ingredient of active oxygen production sup-

pressing agent comprising a selenoglutathione derivative and/or a dimer thereof. Engelskirchen et al. (J. Labelled Compd. Radiopharm, 1991,30: 143) describes the use of a radiolabelled compound as intermediate reagent for the synthesis of radiopharmaceuticals including a selenation strategy via triphenylphosphine selenide using selenium-75.

US-A-5,230,998 discloses inter alia chemical tests for the inhibitory activity on the reaction between HIV-1 GP 120 and antibodies specific for the V3 hypervariable loop, wherein for example triphenylphosphine sulfide and oxide have been tested.

[0004] Thus, the technical problem underlying the present invention is to provide a new composition for preventing and/or repairing DNA damage caused by oxygen and oxygen-containing molecules, respectively.

[0005] The solution to the above technical problem is achieved by providing a composition comprising a compound  (“chemical”) including the element Se, for preventing or reducing a cancer, wherein the expression “element Se” means

all forms of selenium containing compounds, selected from the group comprising -Se-Se-Se- (triselenide), N = C = Se

(isoselenocyanate), R3P=Se (phosphine selenide), and R2C=Se, where R is any radical. Additionally, this term covers also forms which will be converted within the body into the above effective forms before being eliminated. As a preferred embodiment of the present invention, the compound including the element Se is triphenyl phosphine selenide. In the following, examples of the compound including the element Se are listed:

[0006] The triselenide structure -Se-Se-Se- covers CH2 = CH-CH2-Se-Se-Se-CH2-CH = CH2 diallyl triselenide, the

chemicals which constitute most of the Se in garlic.

[0007] Selenide also covers CH2 = CH-CH2-N = C = Se allyl isoselenocyanate.

[0008] R2C = Se covers CH3-CH = Se ethylidene selenide and  

Se

C

(Chemical structure presented here)

                                                                            NH2     NH2

selenourea and other similar structures where R does not contain a carbon atom, but is organic because of the bond

to carbon.

[0009] The form of chemical in which selenium is present varies the efficacy over a very wide range. Elemental

selenium passes through the body after ingestion without becoming biologically available. More preferred forms of

selenium will be taken into the bloodstream rather than eliminated from the body quickly as selenonium ion in the urine

or exhaled through the lungs as dimethyl selenide. Some forms of selenium are not eliminated, but become stored in tissues where they are less effective than in the bloodstream.

[0010 Any double bond Within DNA (or messenger RNA and transfer RNA} can be attacked by a chemical carcin-

ogen, free radical, or radiation to form an epoxide (C=C becomes

 

O

(chemical structure presented here)

                                                                                 C – C.)

Any 2 epoxides on base pairs can form a crosslink  (chemical reaction presented here)

                                    C                            C                    C – O – C

                                         O                  O                         C – O – C

                                    C                            C

            as proposed in United States Application OS/271,655 filed July 14, 1972 (which corresponds to DE-OS 2336176, and

EPO75091181

claimed that some forms of Se prevented and reversed those crosslinks in some way). This strong crosslink bond then replaces the weak hydrogen bonding that holds base pairs together In DNA. In effect, the zipper of DNA no longer unzips due to the oxygen crosslink, so causes replication to stutter and form random uncontrolled division called cancer. These 2 steps are what the United States National Cancer Institute (NCI) now calls initiation (epoxide formation) and propagation (crosslinking). Many antioxidants help the body keep the epoxide from forming initially. Selenium in the form of e.g., triphenyl phosphine selenide actually attacks the epoxide and reverts it back to a double bond without loss of configuration of the remaining base pair

 (chemical structure presented here)

reverts to C=C). The mechanism is:

(chemical reaction presented here)

[0011] The oxidized forms of selenium can be biologically reduced by vitamin C to the useless elemental form of  selenium. The preferred form is the most reduced minus 2 oxidation state of the selenides. Within this class, the best

form is that which reacts with epoxides to yield an olefin without change in configuration. Selenides have the general structure -Se- and diselenides -Se-Se- and triselenides -Se-Se-Se- and even better is R2C=Se. The best form has the structure R3P=Se where R is any organic radical. An example is Ph3P=Se, triphenyl phosphine selenide.

[0012] In a further embodiment of the present invention, the above defined composition comprises additionally as  component vitamin E or a derivative thereof. Vitamin E has a synergistic relationship with selenium such that the two

together are almost always better than the best by itself.

[0013] In a further embodiment of the present invention, the above defined composition comprises additionally as component a sulphur amino acid such as cysteine, or a derivative thereof, such as glutathione.

[0014] In a further embodiment of the present invention, the above defined composition comprises additionally as  component a synthetic antioxidant which is edible without toxicity in humans such as tert-butyl methoxyphenole (BHA), 2,6-dl-tert.-butyl-4-methyl phenole (BH11 or ethoxyquin. The preferred synthetic ant-oxidant is BHA.

[0015] In a preferred embodiment of the present invention, the relative value of each of the 4 above components - i.e. a compound including the element Se, vitamin E, a sulphur amino acid, and a synthetic antioxidant - is such that selenium is much greater than vitamin E and the sulfur amino acid and synthetic antioxidant are about equal to each other and to vitamin E. It is therefore possible to get most of the effect by using a selenium with high efficacy like triphenyl phosphine selenide alone without the other 3 components. The maximum effect is by using all 4 components and a biological synergism is achieved whereby adding anyone is better than it would be without adding the additional one.

[0016] The level of carcinogen exposure is different for different people and can even be different for the same person when diet, environment and genetic predisposition are considered. For maximum benefit to a whole population, there must be a minimum that everyone needs and a maximum that can be given and knowingly exceeding the minimum need without causing problems in those who have only minimum need. With selenium, for some forms this range is very narrow.

[0017) With the other 3 ingredients, this range is much wider. The ranges and optimum of a preferred composition of the present invention for each of the 4 components daily is:

1)      400 mcg of selenium in the form of e.g. triphenyl phosphine selenide as optimum within a range of 20 mcg

 to 20  mg, and other selenium chemicals to 1. g;

2)      0.4 g Vitamin E as optimum within a range of 50 mg to 1 g;

3)      0.6 g cysteine as optimum within a range of 50 mg to 2 g;

4} 50 mg BHA as optimum within a range of 20 mcg to 200 mg.

[0018] There is over a 1000 fold difference between the most effective and the least effective forms of Se.

 

EP 0 750 911 81

 

Claims

1. A composition comprising a compound including the element Se, for preventing or reducing cancer, wherein the compound is selected from triselenides, isoselenocyanates, phosphine selenides and compounds having the structure R2C=Se, wherein R is any radical.

2. The composition according to claim 1, wherein the compound is triphenyl phosphine selenide.

3. The composition according to claim 1 or 2, further comprising vitamin E or a derivative thereof.

4. The composition according to anyone of claims 1 to 3, further comprising a sulfur amino acid or a derivative thereof.

5. The composition according to claim 4, wherein the sulfur amino acid is cysteine.

6. The composition according to claim 4, wherein the sulfur amino acid derivative is glutathione.

7. The composition according to anyone of claims 1 to 6, further comprising a synthetic antioxidant.

8. The composition according to claim 7, wherein the synthetic antioxidant is tert-butyl methoxyphenole, 2,6-di-tert- butyl-4-methylphenole or ethoxyquin.

9. The composition according to anyone of the preceding claims, comprising 20 mcg to 200 mg of triphenyl phosphine selenide, 50 mg to 1 g of vitamin E, 50 mg to 2 g cysteine, and 20 mcg to 200 mg tert-butyl methoxyphenole.

10. The composition according to claim 9, comprising 400 mcg of Se as triphenyl phosphine selenide, 0.4 g vitamin E, 0.6 g cysteine, and 50 mg tert-butylmethoxyphenole.

11. Use of a composition as defined in anyone of the preceding claims 1 to 10 for the preparation of a medicament for preventing or reducing cancer.

12. Use of a composition as defined in anyone of the preceding claims 1 to 10 by a human diagnosed with any type of cancer for the preparation of a medicament which prevents or retards metastasis or spread of cancer to other sites.

Patentansprflche

1. Zusammensetzung, umfassend eine Verbindung, die das Element Se einschlieBt, zur Verhinderung oder Vermin- derung von Krebs, wobei die Verbindung aus Triseleniden, Isoselenocyanaten. Phosphinseleniden und Verbin- dungen mit der Struktur R2C=Se, wobei der Rest R jedweder Rest ist, ausgewahlt ist.

2. Zusammensetzung nach Anspruch 1, wobei die Verbindung Triphenylphosphinselenid ist.

3. Zusammensetzung nach Anspruch 1 oder 2, welter umfassend VItamin E oder ein Derivat davon. 

4. Zusammensetzung nach einem der Ansprt"khe 1 bis 3, welter umfassend eine Schwefelaminosaure oder ein De- rivat davon.

5. Zusammensetzung nach Anspruch 4. wobei die Schwefelaminosaure Cystein ist.

6. Zusammensetzung nach Anspruch 4, wobel das Schwefelaminosaurederivat Glutathion 1st.

7. Zusammensetzung nach einem der AnsprflChe 1 bis 6, weiter umfassend ein synthetisches Antioxidans.

8. Zusammensetzung nach Anspruch 7, wobei das synthetische Antioxidans tert.-Butylmethoxyphenol, 2,6-Di-tert.-

butyl-4-methylphenol oder Ethoxyquin 1st.

9. Zusammensetzung nach elnem der vorhergehenden AnsprOche, umfassend 20 1t9 bis 200 mg Triphenylphosph- inselenid, 50 mg bis 1g Vitamin E, 50 mg bis 2 g Cystein und 20 mcg bis 200 mg tert-Butylmethoxyphenol.

10. Zusammensetzung nach Anspruch 9, umfassend 400 mcg als Triphenylphosphinselenid, 0.4 g Vitamin E, 0.6 g Cystein und 50 mg tert-Butylmethoxyphenol.

11. Verwendung einer Zusammensetzung, me in einem der vomergehenden Anspruche 1 bis 10 definiert, zur Her- stellung eines Medikaments zur Verhinderung oder Verminderung von Krebs.

12. Verwendung einer Zusammensetzung, wie in einem der vorhergehenden Anspruche 1 bis 10 definiert, bei einem  Menschen, bei dern eine Krebsart diagnostiziert worden ist, zur Herstellung eines Medikaments, welches Meta- stasen oder das Streuen von Krebs auf andere Stellen verhindert oder verzogert.

Revendlcations 

1. Composition qui comprend un compose comprenant relement 5e, pour la prevention ou la reduction du cancer, dans laquelle Ie compose est choisl entre des triselenlures, des isoselenocyanates, des seleniures de phosphines et des composes de structure R2C=Se, dans laquelle R represente n'importe quel radical.

2. Composition suivant la revendication 1, dans laquelle Ie compose consiste en seleniure de triphenylphosphine. 3. Composition sulvant revendication 1 ou 2, comprenant en outre de la vitamlne E ou un de ses derives.

4. Composition suivant rune quelconque des revendications 1 a. 3, comprenant en outre un amino-acide soufre ou un de ses derives.

5. Composition suivant la revendication 4, dans laquelle I'amino-acide soufre est la cysteine.

6. Composition suivant la revendication 4, dans laquelle Ie derlv6 d'amino-acide soufre est Ie glutathion.

7. Composition suivant I'une quelconque des revendications 1 a. 6, comprenant en outre un oxydant synthetique.

8. Composition suivant la revend~tion 7, dans laquelle I'oxydant synthetique est Ie tertio-butylmethoxyphenol, Ie 2,6-di-terl.io-butyl-4-methylphenol ou I'ethoxyquine.

9. Composition sulvant rune quelconque des revendicatlons pr~entes, comprenant 20 ~g a 200 mg de seleniure de triphenylphosphine, 50 mg a. 1 9 de vitamine E, 50 mg a 2 9 de cysteine et 20 ~g a 200 mg de tertiobutylme- thoxyphenol.

10. Composition suivant la revendication 9, comprenant 400 \1g de 5e sous forme de seleniure de triphenylphosphine, 0,4 9 de vitamine E, 0,6 9 de cysteine et 50 mg de tertiobutylrnethoxyphenol.

11. Utilisation d'une composition suivant rllne quelconque des revendicatlons 1 a 10 precedentes pour la preparation d'un medicament destine a la prevention ou la reduction du cancer.

12. Utilisation d'une composition suivant l'une quelconque des revendications 1 a. 10 precedentes, par un patient humain chez lequel a ete diagnostique n'importe quel type de cancer, pour la preparation d'un medicament qui previent ou retarde res metastases ou la dissemination du cancer a. d'autres sites.