WO2008074437A2 - Angioinhibine - Google Patents

Angioinhibine Download PDF

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Publication number
WO2008074437A2
WO2008074437A2 PCT/EP2007/010963 EP2007010963W WO2008074437A2 WO 2008074437 A2 WO2008074437 A2 WO 2008074437A2 EP 2007010963 W EP2007010963 W EP 2007010963W WO 2008074437 A2 WO2008074437 A2 WO 2008074437A2
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WO
WIPO (PCT)
Prior art keywords
gum arabic
acacia
treatment
exudate
spec
Prior art date
Application number
PCT/EP2007/010963
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German (de)
English (en)
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WO2008074437A3 (fr
Inventor
Florian Lang
Omaima Nasir
Original Assignee
Eberhard-Karls-Universitaet Tuebingen Universitaetsklinikum
Priority date (The priority date 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 date listed.)
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Application filed by Eberhard-Karls-Universitaet Tuebingen Universitaetsklinikum filed Critical Eberhard-Karls-Universitaet Tuebingen Universitaetsklinikum
Priority to EP07856706A priority Critical patent/EP2109453A2/fr
Publication of WO2008074437A2 publication Critical patent/WO2008074437A2/fr
Publication of WO2008074437A3 publication Critical patent/WO2008074437A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel angioinhibin.
  • Angioinhibins also referred to as angiogenesis inhibitors, are well known in the art. These are substances that inhibit the formation of blood vessels.
  • angioinhibin fumagilin which is isolated from Aspergillus glamigatus and also has antibiotic properties, inhibits angiogenesis and tumor growth in vivo.
  • the Angioinhibin AMG-1740 is a synthetic derivative of fumagillin that still shows angiostatic activity in a 50-fold low dose.
  • the known angioinhibin suramin sodium is a poly-sulphonated naphthyl-urea compound which was originally used for the treatment of sleeping sickness.
  • Suramin sodium acts in the so-called Cam-Test, the bioassay for the identification of chemotactic and / or mitogenic angiogenesis factors and angioinhibins, which inhibit neovascularization. It prevents the binding of various growth factors, such as bFGF, PDGF, VEGF, to their receptors.
  • TNF- ⁇ TNF- ⁇ , INF- ⁇ , various steroids and retinoids
  • TNF- ⁇ TNF- ⁇
  • INF- ⁇ various steroids and retinoids
  • angioinhibins Protease inhibitors that prevent the breakdown of the extracellular matrix and thus the migration of endothelial cells are also referred to by some groups as angioinhibins.
  • Materials with binding properties for vascular endothelial cell integrins may have angioquinide activity by blocking the integrin-mediated and angiogenic important cell adhesion to extracellular matrix proteins.
  • Thalidomide also known as the thalidomide, has an antiangiogenic effect. Although the mechanism is still unclear, this effect is associated with the malformation of extremities of fetuses whose mothers had taken thalidomide.
  • Antibodies to angiogenesis factors e.g. against growth factors such as VEGF, can also prevent the formation of blood vessels and are therefore equally considered as angioinhibins in question.
  • the aim of current research is to find substances that specifically affect angiogenesis so that it can target all processes in which tissue neovascularization plays a role.
  • tissue neovascularization plays a role.
  • medical interest here is the growth of tumors, for the supply of nutrients the formation and reformation of blood vessels is essential.
  • such an angioinhibin is to be provided, which is cost-effective in its production and its use with as few side effects as possible.
  • gum arabic and / or an exudate derived from Acacia spec in particular Acacia Senegal, Acacia seyal, Acacia ka ⁇ oo, Acacia lutea, and / or at least one active ingredient thereof for the production of an angioinhibin , wherein gum arabic or said exudates or the active ingredient are provided as an active ingredient or as Angioinhibin.
  • gum arabic inhibits the expression of angiogenins. This effect was particularly surprising, since gum arabic is described in the prior art so far in a completely different context.
  • Gum arabic is extracted as an exudate from the sap of Saharan acacia (Acacia spec.). Further acacia species of the tropical and subtropical regions of Africa, India, Central and North America are known, from which this oldest known gum can be obtained.
  • gum arabic is a weakly acidic product naturally occurring as a neutral or weakly acidic potassium, calcium or magnesium salt.
  • Gum arabic is a complex and variable mixture of arabinogalactan oligosaccharides, polysaccharides and glycoproteins.
  • the main constituent of gum arabic is carbohydrate in the form of L-arabinose, L-rhamnose, D-galactose and D-glucuronic acid. The molar ratios of these sugars are highly dependent on the particular acacia species, cf. Table 1.
  • Gum arabic consists of a mixture of low molecular weight polysaccharides (MW> 0.25 ⁇ 10 6 , main component) and higher molecular weight hydroxyproline-rich glycoproteins (MG ⁇ 2.5 ⁇ 10 6 , minor component.)
  • the glycoprotein is a high molecular weight hydroxyproline-rich arabinogalactan ("2% protein) a repetitive and nearly symmetric consensus motif of 19 residues Ser-Hyp a -Hyp a -Thr-Leu-Ser-Hyp a -Ser-Hyp b -Ser-Hyp b -Thr-Hyp-Thr-Hyp a -Hyp a -Gly- Pro-His- containing contiguous hydroxyprolines ( a ) coupled to oligo- ⁇ -1,3-arabinofurans and non-contiguous hydroxyprolines ( b ) coupled to oligo
  • Table 3 below shows the amino acid composition of gum arabic from Acacia Senegal and Acacia seyal.
  • Gum arabic is very good water-soluble, 1 to 15% solutions have only low viscosity. At high concentrations, a tough gelatinous mass is formed. Gum arabic is soluble in hot ethylene glycol, glycerin and up to 60% aqueous ethanol, then precipitation occurs. In other organic solvents gum arabic is insoluble. Gum arabic lowers the surface tension of water. Heating above 90 to 95 ° C causes the cleavage of L-rhamnose, L-arabinose and D-galactose containing oligosaccharides. Gum arabic is acid sensitive. Even in the weakly acidic area, degradation occurs.
  • the tree bark is cut in a downward angle.
  • the exiting milk juice forms a drop with a diameter of 2 to 7 cm.
  • the juice is caught and dried.
  • the dried exudate is bleached in the air for several weeks.
  • the typical yield is 0.9 to 2 kg of gum per tree and crop.
  • Gum arabic is used in foods as a thickener, emulsifier and stabilizer (E 414). Gum arabic is mainly used in beverage emulsions and as a rubber product and coating of dragees in the confectionery sector. Gum arabic is also used in drug production for the surface stabilization of dragees; Verbeken et al., Exudates gums: occurrence, production, and applications. Appl. Microbiol. Biotechnol. 2003; 63: 10-21.
  • Gum arabic is largely stable to both humans and animals and, after passing through the small intestine in the colon, is fermented under the influence of microorganisms into short-chain fatty acids.
  • the US Food and Drug Administration sees gum arabic as one of the safest fibers; see. Anderson D.M., Evidence for the Safety of Gum Arabic (Acacia Senegal (L.) W illd.) As a food Additive - a letter review. Food Addit. Contam. 1986; 3: 225-230.
  • gum arabic exhibits pro-absorptive properties through increased sodium and water absorption; see. Teichberg S. et al., Effect of gum arabic in an oral rehydration solution to recovery from diarrhea in rats. J. Pediatr. Gastroenterol. Nutr. 1999; 29: 411-417; Wapnir R.A. et al., Gum arabic promotes rat jejunal sodium and water absorption from oral rehydration solutions in two modes of diarrhea. Gastroenterology 1997; 112: 1979-1985.
  • Gum arabic has been used in the traditional treatment of patients with chronic kidney disease and end stage renal disease (ESRD) in countries of the Middle East; see. Al Majed A. et al., Protective effects of oral arabic gum administration on gentamicin-induced nephrotoxicity in rats. Pharmacol. Res. 2002; 46: 445-451. However, the renal effects of gum arabic are poorly defined. In a study with patients suffering from kidney failure, it was found that gum arabic increases fecal nitrogen excretion, thus providing an approach to lowering serum urea nitrogen; see. Bliss D. Z., Dietary fiber in conservative management of chronic renal failure. Pediatr. Nephrol. 2004; 19: 1069-1070; Stephen A.M. and Cummings J.H., Mechanism of action of dietary fiber in the human colon. Nature 1980; 284: 283-284.
  • gum arabic shows a moderate improvement in histological and biochemical parameters; see. Ali BH et al., The effect of treatment with gum Arabic on gentamicin nephrotoxicity in rats: a preliminary study. Ren. Fail. 2003; 25: 15-20, which is attributed to the decreased production of free oxygen radicals; see. Al Majed et al. (Supra). An inhibitory effect of gum arabic on the activity or expression of angiogenins has not been described in the prior art.
  • TNP-470 a synthetic fumagillin termed TNP-470 studied by these authors; see. Miki T. et al. ; Angiogenesis inhibitor TNP-470 inhibits growth and metastasis of a hormone-independent rat prostatic carcinoma cell line, Journal of Urology 1998, 160: 210-213; Ueda N.
  • Natural gum arabic can be obtained from various acacia species, such as Acacia Senegal, Acacia seyal, Acacia ka ⁇ oo, Acacia laeta (Acacia spec). As Angioinhibin but are also exudates from with Acacia spec. suitable for related plants.
  • gum tragacanth is obtained from Astragalus gummifer. Rubber karaya is extracted from Sterculia urens. Grammagras gum is obtained from Prosopis juliflora. Such from with Acacia spec. Exudates derived from related plants are encompassed by the present invention. It is understood that not only gum arabic of natural origin is suitable for carrying out the invention.
  • individual active ingredients of gum arabic or the gums from those with Acacia spec. related species suitable as long as the angioinhibitowitz effect is maintained.
  • An angioinhibitory effect can readily be determined by means of measures known to the person skilled in the art.
  • the active ingredients may preferably be the carbohydrate fraction containing the sugars L-arabinose, L-rhamnose, D-galactose and D-glucuronic acid.
  • active ingredients of gum arabic or gums from those with Acacia spec. related species, of natural or synthetic origin are covered by the present invention.
  • Gum arabic, or the gums from the Acacia spec. related species, as well as the synthetic variants, the active ingredients mentioned and chemical modifications thereof can be present in any desired form, as a solid, preferably in powder form, in a soluble, preferably water-dissolved form and in other states of aggregation.
  • gum arabic or the with Acacia spec. related exudate and the synthetic variants, the active ingredients and chemical modifications thereof for the prevention and / or treatment of a tumor disease, inflammation, anemia or obesity is used.
  • the inventors have surprisingly found in the mouse model that gum arabic has both anticarcinogenic and anti-inflammatory properties. It is particularly advantageous that, according to findings of the inventors gum arabic or from with Acacia spec. related exudate is suitable for the treatment of a variety of tumors. This may be due to the fact that angiogenins are overexpressed in most tumors; see. Yoshioka N. et al., A therapeutic target for prostate cancer based on angiogenin-stimulated angiogenesis and cancer cell proliferation. Proc. Natl. Acad. Be. USA 2006; 103: from 14,519 to 14,524. Specifically, colonic angiogenins (see Li D.
  • gummi arabic inventors were able to reduce the development of anemia and obesity. Gum arabic or that made with Acacia spec. Exudate derived from related plants as well as the synthetic variants, the said active ingredients and chemical modifications thereof are therefore suitable to be used as medicaments for the prevention and / or treatment of the aforementioned diseases. It is preferred if gum arabic and / or from with Acacia spec. exudate derived from related plants as well as the synthetic variants, said active ingredients and chemical modifications thereof are used for the treatment of colon cancer.
  • compositions of the invention show a particularly good therapeutic efficacy in the treatment of colon cancer.
  • the present invention also relates to a process for the preparation of an angioinhibin, which comprises the following steps: (1) providing gum arabic and / or one having acacia spec. (2) Formulation of the gum arabic and / or the exudate and / or the variant and / or the constituent and / or a synthetic variant and / or one of the active ingredients mentioned and / or a chemical modification thereof; or modification into a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art. They include, for example, binders, disintegrants, fillers, lubricants and buffers, salts and other substances suitable for the formulation of medicaments; see. Row et al. (2006), Handbook of Pharmaceutical Excipients, 5 th Edition, Pharmaceutical Press; or Bauer et al. (1999), Textbook of Pharmaceutical Technology, 6th Edition, Academic Press mbH. The content of the present publications is incorporated herein by reference.
  • Another object of the present invention relates to a method for the therapeutic and / or prophylactic treatment of a living being, which is affected by a disease associated with increased angiogenin levels and / or activities, or / and in which the risk of such a disease, the following steps comprising: (1) providing gum arabic and / or a out with Acacia spec. and / or a synthetic variant and / or an active ingredient and / or a chemical modification, and (2) introduction of the gum arabic and / or the exudate and / or the variant and / or the constituent and / or the modification into the living being.
  • Fig. 1 shows the effect of gum arabic treatment on tumor incidence
  • Fig. 2 shows the effect of gum arabic treatment on the number of red blood cells
  • Fig. 3 shows the effect of gum arabic treatment on hemoglobin concentration
  • Fig. 4 shows the effect of gum arabic treatment on hematocrit
  • Fig. 5 shows the effect of gum arabic treatment on body weight embodiments
  • the animals were kept under controlled environmental conditions (22-24 ° C, 50-70% humidity on a 12 hour day / night cycle).
  • the mice had free access to standard pelleted feeds (C1310, Altromin, Heidenau, Germany) and tap water or gum arabic nutrient solution, respectively. All animal experiments were carried out in accordance with the guidelines of the American Physiological Society and the German animal welfare laws and were approved by the local authorities.
  • Colon carcinoma was generated as described in Wang et al. ; A novel mouse model for colitis-associated colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sulfate sodium. World J. Gastroenterol. 2004; 10: 2958-2962.
  • BALB / c were divided into four groups of 12 mice (both male and female) per group.
  • the animals of two groups (C, D) were treated with 10% (w / w) gum arabic dissolved in tap water (100 g / l, made fresh every three days).
  • the gum arabic solution was administered via drinking water for two weeks before and during the study period. There was a comparison with animals from two other groups (A, B), which received distilled water.
  • mice in Groups C and D received alternating administration of distilled water containing 30 g / l synthetic dextran sodium sulfate (DSS, molecular mass 5,000, Wako Pure Chemical Industries, Led, Japan) for seven days for three cycles followed by distilled water for subsequent 14 days after intraperitoneal pretreatment with 20 mg / kg 1,2-dimethylhydrazine (DMH; Sigma-Aldrich Corp., St. Louis, MO, USA).
  • DSH 1,2-dimethylhydrazine
  • the animals were lightly anesthetized with diethyl ether (Roth, Düsseldorf, Germany) and approximately 130 ⁇ l of blood was drawn into heparinized capillaries by puncturing the retro-orbital plexus.
  • the blood loss was compensated with 400 ⁇ l subcutaneously administered 0.9% NaCl solution.
  • the erythrocyte count, hematocrit and blood hemoglobin concentration were determined using an electronic hematology particle counter (Type MDM909 from Medical Diagnostics Marx, Butzbach, Germany) equipped with a photometric unit for hemoglobin determination. The gating was adjusted for use on mouse erythrocytes. All measurements were made according to the manufacturer's instructions.
  • the Quiagen RNeasy Fibrous Tissue Midi Kit was used according to the manufacturer's instructions (Quiagen, Hilden, Germany).
  • Syntheses of the second strand were performed using a commercially available kit (Invitrogen Life Technologies, Rockville, MD, USA and oligo d (T) 2 T7 primers cRNA was synthesized using biotin-labeled cytidine 5'-triphosphate (CTP ) and uridine 5'-triphosphate (UTP) are prepared by in vitro transcription using a T7 promoter-coupled double-stranded cDNA as a template and the T7 RNA transcript labeling kit (ENZO Diagnostics, Farmingdale, NY, USA) CRNA was fragmented and hybridized to the mouse genome MOE430A oligonucleotide array chip (Affymetrix, Santa Clara, Calif.) The arraychips were then cloned using phycoerythrin-conjugated streptavidin (Molecular Probes, Invitrogen Life Technologies) and fluorescence intensities were determined using a confocal laser scanner (Affymetrix).
  • CTP biotin
  • the intensity of the scanned images was analyzed using Microarray Suite Version 5 (Affymetrix). All arrays were scaled globally, so the average intensity of each array was equivalent. For global scaling, the raw signal value of each sample cell was multiplied by a scaling factor. Genes whose expression varied significantly with a signal-to-log ratio of 0.5 were identified using the Data Mining Tool (Affymetrix).
  • mice drank about 5 ml of fluid per day due to free access to the nutrient solution, which corresponded to an intake of about 0.5 g of gum arabic per day and per mouse.
  • the treatment with gum arabic inhibits massively the expression of angiogenic factors.
  • the decrease in the red blood cell count can be significantly reduced by treatment with gum arabic; see. Bars on the far right with bars arranged to the left.
  • gum arabic and exudates derived from Acacia Senegal, Acacia seyal, Acacia karroo, Acacia laeta-related plants are substances which act as angioinhbines and / or those which are used for prevention and treatment / or treatment of a tumor disease, inflammation, anemia or obesity are suitable.

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Abstract

L'invention concerne une nouvelle angioinhibine.
PCT/EP2007/010963 2006-12-18 2007-12-13 Angioinhibine WO2008074437A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07856706A EP2109453A2 (fr) 2006-12-18 2007-12-13 Angioinhibine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006061517A DE102006061517A1 (de) 2006-12-18 2006-12-18 Angioinhibin
DE102006061517.4 2006-12-18

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WO2008074437A2 true WO2008074437A2 (fr) 2008-06-26
WO2008074437A3 WO2008074437A3 (fr) 2009-01-22

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EP (1) EP2109453A2 (fr)
DE (1) DE102006061517A1 (fr)
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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5268467A (en) * 1988-05-23 1993-12-07 Verbiscar Anthony J Immunomodulatory polysaccharide fractions from Astragalus plants
CN1307473A (zh) * 1998-05-19 2001-08-08 研究发展基金会 三萜组合物和它们的使用方法
JP2008521791A (ja) * 2004-11-30 2008-06-26 ベリトロン・リミテッド アラビアガムを含む副腎皮質ホルモン剤の作用増強剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BAUER ET AL.: "Lehrbuch der Pharmazeutischen Technologie, 6. Auflage", 1999, WISSENSCHAFTLICHE VERLAGSGESELLSCHAFT STUTTGART MBH
OLIVIERA ET AL.: "Antitumor Activity of Condensed Flavanols", AN. ACAD. BRASIL. CINC.44, 1972
ROW ET AL.: "Handbook of Pharmaceutical Excipients, 5th Edition", 2006, PHARMACEUTICAL PRESS

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WO2008074437A3 (fr) 2009-01-22
DE102006061517A1 (de) 2008-06-19
EP2109453A2 (fr) 2009-10-21

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