COMPOUNDS USEFUL IN REDUCING THE LEVEL OF INSULIN LIKE GROWTH FACTOR-1 (IGF-1) IN BLOOD

Abstract: The present invention provides a pharmaceutical or dietary composition for lowering the level of IGF-I in blood of mammals which comprises an IGF-I reducing effective amount of a carotenoid. Furthermore, a method for reducing IGF-I levels is provided which comprises administering an IGF-I reducing effective amount of a carotenoid to a subject in need thereof.

Description: COMPOUNDS USEFUL IN REDUCING THE LEVEL OF INSULIN LIKE GROWTH FACTOR -1 QGF-1 IN BLOOD Field of the Invention This invention relates to pharmaceutical and dietary compositions comprising a combination of compounds useful in preventing cancer and to the use of said compositions and said combination of compounds for said purpose. This invention more particularly relates to a pharmaceutical or dietary composition for lowering the plasma level of insulin-like growth factor I (IGF-I) levels in mammals. Background of the Invention The IGF-I level was found to be a major risk factor for prostate (Chan J.M., Stampfer M.J., Giovannucci E., Gann P.H., Winkinson P., Hannekens C.H., and Pollak M. "Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study," Science. 279:563-566, 1998) and breast cancer (Hankinson S.E., Willett W.C., Colditz G.A., Hunter D.J., Michaud D.S., Deroo B., Rosner B., Speizer F.E., and Pollak M. "Circulating concentrations of insulin-like growth factor-I and risk of breast cancer," Lancet. 351: 1396-1397, 1988). It is believed that the level of this growth factor in the human circulation is related directly to the risk for these and other malignancies. Carotenoids are colored pigments with lipophilic properties, widely distributed in f uits and vegetables (e.g. β-carotene in carrots and lycopene in tomatoes) and active in interfering with IGF-I action (Unpublished results). Carotenoids are transported within circulating lipoproteins when ingested in the human body. Carotenoids consumption was shown in previous epidemiological studies to be associated with reduced cancer mortality, although recent data did not demonstrate similar beneficial effects (see e.g.: Hennekens C.h., Buring J.E., Manson J.E., Stampfer M., Rosier B., Cook N.R., Belanger C, LaMotte F., Gaziano J.M., Ridker P.M., Willet W. and Peto R, "Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease" (N. Engl. J. Med. 1996; 334: 1145-1149). Data on the ability of β-carotene supplementation in vitro or in vivo to protect from cancer are conflicting: Some studies found an inhibitory effect of β-carotene supplementation, whereas several others did not find such an effect. Lycopene, the open chain analog of β-carotene, shares with it a similar structure comprising extended conjugated double bonds. In human plasma, lycopene and β-carotene are quantitatively the major carotenoids. Lycopene was shown to possess the greatest quenching ability of singlet oxygen among the various carotenoids (DiMascio P., Kaiser S. and Sies H., "Lycopene as the most efficient biological carotenoid singlet oxygen quencher," Arch. Biochem. Biophys., 1989, 274: 532-538) and it was shown to be at least twice as effective an antoxidant as β-carotene in protecting blood lymphocytes from NO 2 radical damage (Bohm F., Tinkler J.H., and Truscott T.G., "Carotenoids protect against cell membrane damage by the nitrogen dioxide radical," Nature Medicine, 1995, 2: 98-99). Lycopene has been shown to significantly reduce IGF-induced tyrosine phosphorylation of insulin receptor substrate-I and up-regulation of binding capacity of the AP-I transcription complex (Karas et al. 2000. Nutr. Cancer 36(1): 101-111). However, until now lycopene has not been shown to cause a decrease in the plasma levels of IGF-I. Objective of the Invention It is a purpose of this invention to provide a pharmaceutical or dietary composition or preparation comprising a combination of compounds including lycopene and other carotenoids that is effective in reducing plasma IGF-1 levels with the attending beneficial effects. It is another purpose of this invention to provide such a composition or preparation that is based on carotenoids, though it does not consist exclusively of carotenoids. It is a further purpose of this invention to provide such a composition or preparation that comprises products that are acceptable and desirable components of the human diet. Summary of the Invention The present invention is based on the discovery that there is an unexpected and surprising reduction in plasma levels of insulin like growth factor-I (IGF-I) after lycopene or other carotenoid supplementation in mammals. Accordingly, the present invention provides a pharmaceutical or dietary composition which comprises a carotenoid selected from, but not limited to, a group comprising of lycopene, alpha-, beta-, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin astaxantine and mixtures thereof, wherein said composition is effective in reducing IGF-I levels in plasma in a mammal. The present invention further provides a use of a carotenoid selected from, but not limited to, a group comprising of lycopene, alpha-, beta-, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin and astaxantine and mixtures thereof in the preparation of a pharmaceutical or dietar - composition which is effective in reducing IGF-I levels in plasma in a mammal. Furthermore, the present invention provides a method for reducing IGF-I levels in plasma in a mammal wherein said method comprises administering to a mammal in need thereof, an IGF-I reducing effective amount of a carotenoid selected from, but not limited to, a group comprising of lycopene, alpha-, beta-, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin and astaxantine and mixtures thereof. Detailed Description of the Invention The following description is illustrative of preferred embodiments of the invention. The following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations to the invention. The carotenoids referred to throughout the specification are from natural or synthetic sources or from genetically modified organisms. The invention comprises a method for reduction in plasma level of IGF-I which comprises administering to a patient lycopene or a carotenoid selected from, but not limited to, a group comprising of alpha-, beta-, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin astaxantine and mixtures thereof, in the amount of at least 3 mg per day. Lycopene is a natural product and is present in tomatoes in various concentrations, but it can also be produced synthetically, and synthetic lycopene, compositions comprising it and their use are comprised in the present invention. The composition may contain other dietary components, additives, excipients, binding agents, coatings, etc., or other compounds that have no significant effect in reducing IGF-I. The compositions according to the invention, in view of their purpose, are pharmaceutical composition. However, since their components are individually acceptable ingredients of the human diet, and, in fact, are individually present in foodstuffs, they may be considered and used as dietary or health compositions. Tomato oleoresin comprises a combination of lycopene with vitamin E, β-carotene, phytoene and phytofluene, and therefore the use of tomato oleoresin for the reduction of plasma levels of insulin like growth factor I is a specific aspect of the present invention. Both tomato oleoresin and pure lycopene reduce plasma levels of IGF-I by at least 10% in responding individuals. In a preferred way of carrying out the invention, and in the example that will be described, lycopene was obtained from tomato oleoresin. The oleoresin was supplied by LycoRed Natural Products Industries, Ltd., Beer Sheva, Israel. It contained crystalline lycopene (5%) suspended in the lipid phase of the tomato. Fatty acids as triglycerides constituted the major part (72%) of the oleoresin, whereas 19% were non-saponified materials including inter alia 5% lycopene, 0.1% β-carotene, 1% vitamin E, as well as phytoene and phytofluene. The lycopene used was extracted and purified mainly in the all-trans configuration. Lycopene can be extracted from tomato oleoresin, known in the art by crystallization followed by filtration. According to a further preferred embodiment of the present invention carotenoids selected from, but not limited to, a group comprising of lycopene, alpha-, beta-, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin and astaxantin and mixtures thereof are used in the preparation of pharmaceutical or dietary compositions effective in reducing IGF-I levels in mammalian plasma. The compositions are prepared according to common practices wherein a carotenoid in the amount of at least 3 mg is added to the composition. According to yet a further preferred embodiment of the present invention a pharmaceutical or dietary composition for lowering IGF-I levels in mammalian blood is provided, wherein said composition is characterized in that it comprises a carotenoid selected from, but not limited to, a group comprising of lycopene, alpha-, beta-, zeta-carotene, phytoene, phytofluene, lutein, zeaxanthin, cryptoxanthin and astaxantin and mixtures thereof. Said composition may be prepared according to common practices well known in the art wherein a carotenoid or a mixture thereof are added to the composition. EXAMPLE Example 1: Effect of tomato oleoresin supplementation on plasma levels of IGF-1 The effect of lycopene supplementation on IGF-I blood levels in patients undergoing elective hemorrhoidectomy was studied. Lycopene (5% in tomato oleoresin, two 15 mg capsules per day) or a placebo were administered for three to four weeks prior to surgery. Lycopene concentration and isomer distribution in blood and in the excised tissues were measured by HPLC. Lycopene blood levels increased in most of the subjects who received lycopene supplementation . In the placebo group, the lycopene plasma level before supplementation was similar to that of the lycopene treated group and did not change significantly after supplementation. IGF-I level was measured using the IRMA kit (DSL-5600 Active. Diagnostic System Laboratories, Webster, TX). Basal IGF-I plasma levels varied considerably between subjects. In 15 out of 28 patients in the lycopene-treated group (53%), IGF-I blood level decreased by more than 10%. In 7 patients (25%) there was no change. In contrast, only 4 out of 28 placebo-treated patients (14%) exhibited a decrease in IGF-I plasma level and in 20 (71%), no change was occurred. These data clearly indicate lycopene supplementation is effective in significantly reducing IGF-1 levels in a certain proportion of subjects who are "responders". In contrast, when the effects of lycopene supplementation on blood levels of IGF-II and IGF-BP-3 were examined, no differences were found between the lycopene treated group and the placebo group. IGF-II was measured by ELIZA (DSL- 10-91000) and IGF-BP-3 by IRMA (DSL-6600), using kits from Diagnostic System Laboratories, Webster, TX. While embodiments of the invention and experimental data have been described by way of illustration, it should be understood that the invention is not limited thereto and may be carried out with many modifications, variations and adaptations, without departing from its spirit or exceeding the scope of the claims.

Claims: CLAIMS 1. A pharmaceutical or dietary composition for lowering the level of IGF-I in blood of mammals which comprises an IGF-I reducing effective amount of a carotenoid. 2. A composition in accordance with Claim 1 wherein said carotenoid is selected from the group comprising lycopene, alpha-, beta-, zeta-carotene, lutein, cryptoxanthin, astaxantine, canthaxanthin, zeaxanthin, phytoene, phytofluene and mixtures thereof. 3. A composition in accordance with Claim 1 wherein the source of said carotenoid is selected from the group comprising natural oleoresin, algae, fungi, genetically modified organism (GMO), fermentation process, synthetic process and mixtures thereof. 4. A composition in accordance with Claim 1 which comprises lycopene from tomatoes. 5. A composition in accordance with Claim 1 which comprises tomato oleoresin. 6. A composition in accordance with Claim 1 which comprises synthetic lycopene. 7. A composition in accordance with Claim 1 wherein the unit dose of said composition comprises at least about 3 mg of carotenoid. 8. A composition in accordance with any of Claims 1 to 7 wherein the composition contains compounds selected from the group comprising dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof. 9. A composition in accordance with any of Claims 1 to 8 wherein the composition is contained in dosage forms selected from the group comprising tablets, caplets, vegecaps and hard shell gelatin capsules. 10. Use of a carotenoid for the preparation of pharmaceutical or dietary compositions for lowering the level of IGF-I in the blood of mammals. 11. Use in accordance with Claim 10 wherein said carotenoid is selected from the group comprising lycopene, alpha-, beta-, zeta-carotene, lutein, cryptoxanthin, astaxantine, canthaxanthin, zeaxanthin, phytoene, and phytofluene and mixtures thereof. 12 Use in accordance with Claim 10 wherein the source of said carotenoid is selected from the group comprising natural oleoresin, algae, fungi, genetically modified organism (GMO), fermentation process, synthetic process and mixtures thereof. 13 Use in accordance with Claim 10 wherein said carotenoid is lycopene from tomatoes. 14. Use in accordance with Claim 10 wherein said carotenoid is synthetic lycopene. 15. Use in accordance with Claim 10 wherein said carotenoid is from tomato oleoresin. 16. Use in accordance with Claim 10 wherein the unit dose of said composition comprises at least about 3 mg of lycopene. 17. A use in accordance with any of Claims 10 to 16 wherein the composition contains compounds selected from the group comprising dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof. 18. A use in accordance with any of Claims 10 to 17 wherein the composition is contained in dosage forms selected from the group comprising tablets, caplets, vegecaps and hard shell gelatin capsules. 19. A method for lowering the level of IGF-I in the blood of mammals in need thereof which comprises administering an effective amount of a carotenoid to said mammal. 20. A method in accordance with Claim 19 wherein said carotenoid is selected from the group comprising lycopene, alpha-, beta-, zeta-carotene, lutein, cryptoxanthin, astaxantine, canthaxanthin, zeaxanthin, phytoene, and phytofluene and mixtures thereof. 21. A method in accordance with Claim 19 wherein the source of said carotenoid is selected from the group comprising natural oleoresin, algae, fungi, genetically modified organism (GMO), fermentation process, synthetic process and mixtures thereof. 22. A method in accordance with Claim 19 wherein said carotenoid is lycopene from tomatoes. 23. A method in accordance with Claim 19 wherein said carotenoid is synthetic lycopene. 24. A method in accordance with Claim 19 wherein said carotenoid is from tomato oleoresin. 25. A method in accordance with Claim 19 wherein the unit dose of said composition comprises at least about 3 mg of lycopene. 26. A method in accordance with any of Claims 19 to 25 wherein the composition contains compounds selected from the group comprising of dietary components, additives, excipients, binding agents, coatings, preservatives, and mixtures thereof. 27. A method in accordance with any of Claims 19 to 26 wherein the composition is contained in dosage forms selected from the group comprising tablets, caplets, vegecaps and hard shell gelatin capsules.

Inventors: LEVY JOSEPH M, SHARONI YOAV, LEVY, JOSEPH, M., SHARONI, YOAV
Applicants: LEVY JOSEPH M, LYCORED NATURAL PROD IND LTD, SHARONI YOAV, LEVY, JOSEPH, M., LYCORED NATURAL PRODUCTS INDUSTRIES LTD., SHARONI, YOAV
Application year: 2000
Main classification: A61K31
IPC codes: A23L1, A61K9, A61K31, A61K36, A61P35, A61P39, A61P43