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WO1998006424A1 - Inhibiteurs des metastases cancereuses administres par voie orale - Google Patents

Inhibiteurs des metastases cancereuses administres par voie orale Download PDF

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Publication number
WO1998006424A1
WO1998006424A1 PCT/JP1997/002685 JP9702685W WO9806424A1 WO 1998006424 A1 WO1998006424 A1 WO 1998006424A1 JP 9702685 W JP9702685 W JP 9702685W WO 9806424 A1 WO9806424 A1 WO 9806424A1
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Prior art keywords
peptide
amino acid
hydrolyzate
peptides
pharmaceutically acceptable
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PCT/JP1997/002685
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English (en)
Japanese (ja)
Inventor
Hiroyuki Tsuda
Masaaki Iigo
Mamoru Tomita
Seiichi Shimamura
Zenta Takatsu
Kazunori Sekine
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Morinaga Milk Industry Co., Ltd.
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Application filed by Morinaga Milk Industry Co., Ltd. filed Critical Morinaga Milk Industry Co., Ltd.
Publication of WO1998006424A1 publication Critical patent/WO1998006424A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a cancer metastasis inhibitor that can be administered orally. More specifically, the present invention relates to a non-ferrous saturated lactoferrin, a hydrolyzate of lactoferrin, a pharmaceutically acceptable derivative of the hydrolyzate, a pharmaceutically acceptable salt of the hydrolyzate, and a hydrolysis of lactoferrin. Containing, as an active ingredient, one or two substances selected from the group consisting of a peptide derived from a product, a pharmaceutically acceptable derivative of the peptide, and a pharmaceutically acceptable salt of the peptide. It relates to a cancer metastasis inhibitor. Background art
  • metastasis Cancer diagnosis and treatment techniques have advanced remarkably, and the cure rate of cancers detected earlier has been improving. However, cancers that once seem to have healed often grow again in other organs, and the problem of metastasis suppression in cancer clinical practice is increasing in importance.
  • the outline of metastasis is the release of cancer from the primary tumor, invasion into blood vessels or lymph nodes, migration in the bloodstream or lymph, adhesion to vascular endothelium, basement membrane or lymph nodes, and specific organs. It is known that it undergoes a number of processes, such as the propagation of germ (Experimental Medicine, Vol. 12, No. 8, pp. 906-911, 1994), and any of these processes, or By inhibiting all, metastasis of cancer cells can be suppressed.
  • Cancer swelling often occurs early from the primary tumor, such as breast cancer, but metastasis recurs even after 5 and 10 years, as the survival rate after 5 years can be interpreted as a cure. Shigeru (Toshima Shigeru, Cancer Recurrence and Metastasis, p. 64, Jiyokuminsha, September 10, 1979, and Internal Medicine, Vol. 49, No. 6, pp. 1061-1066, 1982 ). Therefore, cancer patients who have been discharged from hospital usually use cancer metastasis inhibitors continuously at home medical treatment for several years to more than 10 years, while injections are used after home medical treatment or reintegration.
  • DHA Docosahexaenoic acid
  • Hei 8-53351 and perilla leaf extract Japanese Unexamined Patent Publication No. Hei 8-73371
  • These oral cancer metastasis inhibitors derived from natural products generally have few side effects, but are often ineffective, and have unique flavors and properties, and are liable to be oxidized. It is a substance having properties. Therefore, foods that have high personal taste and can be mixed are limited. For many patients, it was difficult to use the drug for a long time and continuously without resistance to control cancer metastasis.
  • lactoferrin is present in bodily fluids of mammals including humans, such as milk and saliva, tears, and mucous secretions, and has an approximately 10% sugar chain content and an iron-binding molecular weight of around 80,000. ⁇
  • natural lactoferrin usually binds 10 to 20% of iron in a saturated state (hereinafter, non-iron-saturated lactoferrin may be referred to as Lf).
  • Lactoferrin is known to exhibit antibacterial activity against harmful microorganisms such as Escherichia coli, Candida and Clostridium [Journal of Pediatrics, Vol. 94, No. 1, 1979], also known to have antibacterial activity against staphylococci and enterococci [Journal of Dairy Science, 67, 606, 1984] ].
  • lactoferrin has studied the acidity of mammalian lactoferrin, apolactoferrin, and metal-saturated or partially-saturated lactoferrin (hereinafter, these may be collectively referred to as Lf).
  • Lf metal-saturated or partially-saturated lactoferrin
  • the present inventors isolated peptides having strong antibacterial activity from hydrolyzates of Lf compounds, synthesized peptides having the same amino acid sequence as those peptides and derivatives of those peptides, An antimicrobial peptide consisting of 20 amino acid residues (JP-A-5-92994); an antibacterial peptide consisting of 11 amino acid residues (JP-A-5-78392); An antimicrobial peptide consisting of amino acid residues (JP-A-5-148297), an antibacterial peptide consisting of five amino acid residues (JP-A-5-1498296), and 3 to 6 amino acid residues Antibacterial properties consisting of base Invented a peptide (Japanese Patent Application Laid-Open No.
  • lactoferrin As an example of using lactoferrin as a therapeutic agent for diseases, an antirheumatic agent (JP-A-5-186368) is known, and lactoferrin hydrolyzate includes tyrosinase activity inhibition (European Patent Publication No. 438750), Prevention of adhesion of pathogenic bacteria to cells (JP-A-3-220130), antiviral action (JP-A-12332326) and the like are known.
  • lactoferrin as an anticancer agent has also been studied.
  • iron-saturated lactof:!: Phosphorus is known to have an antitumor effect (Japanese Patent Publication No. 5-86932).
  • the present inventors have discovered that a peptide having the same amino acid sequence as a substance obtained by hydrolyzing lactoferrin with an acid or an enzyme or a derivative of these peptides has a parenteral antitumor effect, and filed a patent application (Japanese Patent Application Laid-Open No. 7-1995). No. 309771).
  • lactoferrin lactoferrin hydrolyzate, or a lactofer:!: Phosphorus-derived peptide with a specific amino acid sequence, etc.
  • lactoferrin hydrolyzate or a lactofer:!: Phosphorus-derived peptide with a specific amino acid sequence, etc.
  • lactoferrin hydrolyzate or a lactofer:!: Phosphorus-derived peptide with a specific amino acid sequence, etc.
  • lactoferrin hydrolyzate and peptides derived from lactofer:!: Phosphorus are more likely to be degraded by digestive enzymes than proteins before hydrolysis. It was not being considered.
  • the present invention has been made in view of the above prior art, and has as its object to provide a cancer metastasis inhibitor that can be administered for a long time with few side effects and that can be administered orally. Disclosure of the invention
  • the present inventors have searched for a cancer metastasis inhibitor that has few side effects, can be administered for a long period of time, and can be administered orally, but surprisingly, digestion by digestive enzymes is inevitable.
  • Lf has been found to have a cancer metastasis inhibitory effect by oral administration.
  • a more surprising phenomenon was the hydrolysis of lactoferrins, which are more susceptible to degradation by digestive enzymes than Lf.
  • the inventors have found that a peptide derived from lactoferrins has an effect of suppressing cancer metastasis by oral administration, and repeated tests for confirming the effectiveness thereof, thereby completing the present invention.
  • the present invention relates to non-iron-saturated lactofu:!: Phosphorus, a hydrolyzate of lactoferrin, a pharmaceutically acceptable derivative of the hydrolyzate, a pharmaceutically acceptable salt of the hydrolyzate, and a lactoferrin.
  • a hydrolyzate of lactoferrin a pharmaceutically acceptable derivative of the hydrolyzate
  • a pharmaceutically acceptable salt of the hydrolyzate a lactoferrin.
  • the oral cancer transfer inhibitor of the present invention includes non-iron-saturated lactofurin, a hydrolyzate of lactoferrins, a pharmaceutically acceptable derivative of the hydrolyzate, or a pharmaceutically acceptable salt of the hydrolyzate.
  • the compound is orally administered at a rate of 3 kg / kg of body weight.
  • the oral cancer transfer inhibitor of the present invention may be a peptide derived from a hydrolyzate of lactoferrin, a pharmaceutically acceptable derivative of the peptide, or a pharmaceutically acceptable salt of the peptide. It is a desirable embodiment that the compound is orally administered at a rate of 2 to 3 20 mg / kg body weight.
  • the peptides have the amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 31.
  • the present invention also provides a food composition and a feed composition containing the above-mentioned oral cancer transfer inhibitor as an essential component.
  • Lf which is one of the active ingredients of the oral cancer metastasis inhibitor of the present invention, is a commercially available product or is isolated from mammalian milk by a conventional method, and is isolated from milk because of its large production amount. Things are desirable.
  • An example of the separation and purification of Lf is as follows. CM-Sepharose FF (Pharmacia) was packed in a column, hydrochloric acid was passed through, washed with water, the ion exchanger was equilibrated, and skim milk with a pH of 6.9 cooled to 4 ° C was passed through the column. Then, the permeate is collected and passed through the column again. Next, distilled water is passed through the column, and saline is passed through to obtain an eluate of the basic protein adsorbed on the ion exchanger.
  • ammonium sulfate was added at a saturation of 80% to precipitate the protein, and the precipitate was collected by centrifugation, washed with an ammonium sulfate solution having a saturation of 80%, and deionized water was removed.
  • the resulting solution was ultrafiltered using an ultrafiltration membrane module (for example, SLP 005 3 manufactured by Asahi Kasei Corporation), water was added, and then filtration was performed using the same apparatus. , Desalting and freeze-drying to obtain powdered lactolactoferrin.
  • an ultrafiltration membrane module for example, SLP 005 3 manufactured by Asahi Kasei Corporation
  • the purity of Lf obtained by the above method was measured by electrophoresis, and as a result, it was found to have a purity of 95% or more (weight; hereinafter the same, except for the decomposition rate, unless otherwise specified). It is needless to say that the lactofurin-containing solution in each purification step before freeze-drying can be used in the present invention.
  • human Lf cannot be produced in large quantities, it is human Lf obtained from recombinant fungi or dairy cows (transgenic 'caws) obtained by recombinant DNA technology. Can also be used in the present invention.
  • the effective dose of Lf is in the range of 3 to 3200 mg / kg body weight per day based on the results of animal studies.
  • lactoferrin hydrolyzate or peptide which is another active ingredient of the oral cancer metastasis inhibitor of the present invention
  • lactoferrin used as a starting material is commercially available lactoferrin, mammals (for example, human, Colostrum, sheep, goats, goats, etc., colostrum, transitional milk, normal milk, end-stage milk, etc., or the processed products of these milks, such as skim milk, whey, etc., in a conventional manner (eg, ion exchange) Lf separated by chromatography, etc., and Apolactov which was deferred with hydrochloric acid, citric acid, etc .:!
  • Lin a It is a metal-saturated or partially-saturated lactoferrin obtained by chelating polactopherin with a metal such as iron, copper, zinc, and manganese, and a commercially available product or a preparation produced by a known method can also be used.
  • the decomposed product of Lf can be obtained by hydrolyzing Lf using an acid or an enzyme. Hydrolysis with an acid is performed by dissolving Lf in a concentration of 0.1 to 20%, preferably 5 to 15%; water or purified water; and adding an inorganic acid such as hydrochloric acid or phosphoric acid, or quinic acid to the resulting solution.
  • the pH of the solution is adjusted to 1 to 4, preferably 2 to 3, and the mixture is heated at an appropriate temperature for a predetermined time according to the adjusted pH to hydrolyze.
  • Enzymatic hydrolysis involves dissolving Lf in water or purified water at a concentration of 0.5 to 20%, preferably 5 to 15%, adjusting the pH of the solution to the optimal pH of the enzyme to be used, and ° C, preferably 30 to 50 ° C, and hold and hydrolyze for 30 to 600 minutes, preferably 60 to 300 minutes. Deactivates enzymes.
  • enzymes there are no particular restrictions on the enzymes used.
  • Commercially available enzymes for example, Morcine (trademark, manufactured by Morishin Pharmaceutical Co., Ltd., optimal pH 2.5-3.0), butapepsin (Wako Pure Chemical Industries, Ltd., optimal pH 2-3) , Sumiteam AP (trademark, manufactured by Shin Nippon Chemical Co., Ltd., optimal pH 3.0), Amano M (trademark, manufactured by Amano Corporation, optimal pH 7.0), tribcine (Novo Corp., optimal pH 8.0), etc. Used alone or optionally in combination.
  • the amount of enzyme used is in the range from 0.1 to 5.0%, particularly preferably from 0.5 to 3.0%, based on the substrate.
  • the rate of hydrolysis degradation is 4 to 50%, preferably 6 to 40%, as a percentage measured by the following method.
  • this decomposition rate is the formol state measured by formol titration with respect to the total amount of nitrogen measured by the Kjeldahl method.
  • Decomposition rate (%) (formol nitrogen content total nitrogen content) x 100
  • the effective dose of Lf hydrolyzate is in the range of 3 to 320 Omg / kg of body weight per day, based on the results of animal studies.
  • the peptide derived from Lf which is another active ingredient of the cancer metastasis inhibitor of the present invention, is the same as the peptide isolated from the hydrolyzate of the Lf by a known separation means.
  • a peptide having the same or homologous amino acid sequence, a pharmaceutically acceptable derivative of these peptides, a pharmaceutically acceptable salt of these peptides, an amino acid sequence identical or homologous to these peptides It is a chemically synthesized peptide, or an arbitrary mixture thereof (hereinafter, these may be referred to as peptides).
  • the filtrate of the hydrolyzate of Lf is neutralized with a sodium hydroxide solution, heated at 80 ° C for 10 minutes to inactivate the enzyme, cooled to room temperature, and centrifuged. Obtain a clear supernatant.
  • the supernatant was subjected to reversed-phase high-performance liquid chromatography and eluted with a gradient of 20 to 60% acetonitrile containing 0.05 WTFA (trifluoroacetic acid), and fractions having an acetonitrile content of 27 to 30% were separated. The fraction is dried under vacuum to obtain peptides derived from Lf.
  • Fmoc-amino acid whose amine function is protected by 9 fluorenylmethoxycarbonyl group [Hereinafter, sometimes referred to as Fmoc-amino acid or Fmoc-unique amino acid name (for example, Fmoc-asparagine)], N, N-dicyclohexylcarboximide is added to form a desired amino acid anhydride. This Fmoc-amino acid anhydride is used for the synthesis.
  • Fmoc-amino acid anhydride corresponding to the amino acid residue at the C-terminus is immobilized via its carboxyl group on Ultrocin A resin (Pharmacia LKB Biotechnology, Inc.) using dimethylaminopyridine as a catalyst. I do.
  • the resin is then washed with dimethylformamide containing piperidine to remove the protecting group of the amine function of the C-terminal amino acid.
  • the Fmoc-amino acid anhydride corresponding to the second from the C-terminal of the amino acid sequence is coupled to the deprotected amine functional group of the amino acid fixed to the resin via the C-terminal amino acid residue.
  • amino acids are sequentially fixed in the same manner. After coupling of all amino acids is completed and a peptide chain of the desired amino acid sequence is formed, removal of protecting groups and removal of the peptide with a solvent consisting of 94% TFA, 5% phenol, and 1% ethanediol. The peptide is purified by high performance liquid chromatography, and the solution is compressed and dried to obtain peptides derived from Lf by synthesis.
  • peptides having the same amino acid sequence or homologous amino acid sequence as these peptides, derivatives of these peptides, pharmaceutically acceptable salts of these peptides, or any mixture thereof are, for example, The methods described in the inventions of JP-A-5-92994, JP-A-5-78392, JP-A-5-148297, JP-A-5-1498296 and JP-A-5-148295 are disclosed. Can be obtained by
  • the effective dose of peptides derived from Lf is in the range of 0.2 to 320 mgZ / kg of body weight per day when integrated from the results of animal tests.
  • peptides having the following amino acid sequence, derivatives or salts thereof can be exemplified as desirable embodiments.
  • Examples of the pharmaceutically acceptable salts of the peptides include acid addition salts such as hydrochloride, phosphate, sulfate, citrate, lactate and tartrate. Amidated or acylated derivatives can be exemplified.
  • Lf, Lf hydrolysates, and Lf-derived peptides obtained as described above are formulated into oral dosage forms such as sugar-coated tablets, tablets, capsules, and nutrients by conventional methods, and formulated as enteral dosage forms. can do. Furthermore, it can be provided as a food composition by being blended with food such as a beverage or jelly, or a feed composition by being blended with feed.
  • Test example 1 is a diagrammatic representation of Test example 1
  • mice Ninety-six 6-week-old CDF1 mice (purchased from Nippon Charles Riva Co., Ltd.) were randomly used in 9 groups (10 mice per group).
  • Co26Lu cells were implanted subcutaneously on the back of all 90 CDF1 mice in 9 groups (day 0). Mice in each group were orally administered on day 5-9, 12-16 and 19-21 up to 300-1000 mg Lf of kg body weight or 30-100 mg Lf-derived peptide of kg body weight 1 time However, nothing was administered to the control group.
  • the lungs were excised, fixed with acetone, and the number of lung metastases was visually counted to test the effect of suppressing metastasis to the lungs.
  • the size of the transplanted tumor was reduced due to its toxicity with general metastasis inhibitors, in this test the size of the transplanted tumor was different between the control group and the Lf and Lf-derived peptide-administered groups. Therefore, their toxicity was estimated to be low. Furthermore, no metastasis to other organs such as the liver was observed by microscopic observation of each organ.
  • Lf powder manufactured by Morinaga Milk Products Co., Ltd. administered to Group 1
  • an Lf hydrolyzate prepared from this Lf powder by the same method as in Reference Example 1 administered to Group 2
  • Lf-derived peptide prepared from this hydrolyzate by the method administered to Group 3
  • Lf-derived peptide chemically synthesized by the same method as in Reference Example 3 organic synthetic peptide; administered to Group 4
  • serum serum albumin fraction V, manufactured by Sigma
  • CDF1 mice Twenty 6-week-old CDF1 mice (purchased from Nippon Charls Riva Co., Ltd.) were randomly used in 4 groups (5 mice per group).
  • the highly metastatic lung cell line Co26Lu prepared in Test Example 1 was used.
  • each group was treated in the same manner as in Test Example 1 except that administration was performed once daily from No. 5 to Day 27 at the dose shown in Table 2, and lungs were removed on Day 28. Tested by the same method.
  • the Lf hydrolyzate produced by the same method as in Reference Example 1 was dissolved in water for injection (Otsuka Pharmaceutical Co., Ltd.), and a single gavage was administered at a rate of 4 ml Zl00 g body weight using a metal ball-pointed needle. Toxicity was tested. Dosage 1000, 2000 and 4000
  • SD rats purchased from Japan SLC
  • 35 amphoteric sex 35 amphoteric sex were used, and male and female were randomly divided into seven groups (five in each group).
  • the hydrolyzate was prepared by using the following method using Lf.
  • the above peptide was hydrolyzed with 6N hydrochloric acid, and the amino acid composition was analyzed by an ordinary method using an amino acid analyzer. The same sample was subjected to Edman degradation 25 times using a gas-phase seek sensor (Applied Biosystems) to determine the sequence of 25 amino acid residues.
  • a disulfide bond analysis method using DTNB [5,5-dicyclohexyl bis (2-dibenzobenzene) '] [Analytical Biochemistry], Vol. 67, No. 493 P. 1975] confirmed the presence of disulfide bonds.
  • this peptide consists of 25 amino acid residues, the 3rd and 20th cysteine residues form a disulfide bond, and 2 amino acid residues N-terminal from the 3rd cis-in residue. Group is located at the C-terminal side from the 20th cysteine residue It was confirmed that each of the five amino acids had the amino acid sequence of SEQ ID NO: 26 linked thereto.
  • Reference Example 3 Organic synthesis of peptides
  • N, N-Dicyclohexylcarbodiimide is added to an amino acid having its amine functional group protected with a 9-full-year-old enylmethoxycarbonyl group to form an anhydride of the desired amino acid, and this Fmoc-amino acid anhydride is synthesized.
  • Fmoc-asparagine anhydride corresponding to the C-terminal asparagine residue is converted to pertrosin A resin (Pharmacia LKB Biotechnology Co., Ltd.) via its carboxyl group using dimethylamino pyridine as a catalyst. Made).
  • the resin is then washed with dimethylformamide containing piperidine to remove the protecting group for the amine function of the C-terminal amino acid.
  • the Fmoc-arginine (Pmc: 2,2,5,7,8-pentamethy chromato-6-sulphonyl group) anhydride corresponding to the second from the C-terminal of the amino acid sequence is then replaced with the C-terminal amino acid residue Via the above, was coupled to the deprotected amine functional group of asparagine fixed to the resin.
  • Glutamine, tributofan, glutamine, and phenylalanine were sequentially fixed in the same manner as described below.
  • the peptide was analyzed for amino acid composition by a conventional method using an amino acid analyzer, and the sequence was determined using the same sequencer as in Reference Example 2.As a result, the peptide had the amino acid sequence of SEQ ID NO: 10. It was confirmed.
  • Reference Example 4 Preparation of Apolactoferrin
  • the peptide was hydrolyzed in the same manner as in Reference Example 2, the amino acid composition was determined, the amino acid sequence was determined, and the presence of disulfide bonds was confirmed by disulfide bond analysis using DTNB.
  • this peptide consists of 32 amino acid residues, the 10th and 27th cysteine residues form a disulfide bond, and the 9th amino acid residue N-terminal from the 10th cyspine residue. It was confirmed that the group had the amino acid sequence of SEQ ID NO: 29 in which 5 amino acids were bonded to the C-terminal from the cysteine residue at position 27, respectively.
  • Example 1 Preparation of powdered animal feed containing Lf
  • skim milk powder (Morinaga Milk Industry Co., Ltd.) is dissolved in 800 ml of hot water at 50 ° C. (Nissin Seiko Co., Ltd.) 30 g, instant coffee powder (Nestlé Co., Ltd.) 14 g, caramel (Showa Kako Co., Ltd.) 2 g and coffee flavor (San-Ei Kagaku Co., Ltd.) 0.01 g were sequentially added with stirring and dissolved. After cooling to 10 ° C., a solution prepared by dissolving 1 g of Lf (Morinaga Dairy) in 75 ml of water was added to prepare a milk drink containing 1% of LfO.
  • Example 4 Preparation of Lf powder
  • Gelatin liquid (3), milk (4) and 1/2 lemon juice were added to cream cheese (5), mixed, and cooled.
  • the obtained wet mass is sieved with stainless steel 20 mesh, placed on (Washamori) and extruded by hand onto two stainless steel plates for drying to form condyles, quickly and evenly distributed, and dried.
  • the mixture was placed in a press and dried at 25 ° C for 2 days to obtain fine granules.
  • the dried granules are separated with a 20-mesh sieve made of polyethylene, and the granules that have passed through the sieve are spread on a wide sheet of paper, and 2 g of magnesium stearate (manufactured by Kanto Chemical Co., Ltd.) pre-sorted with 48 mesh is added. Mix to homogenize.
  • a tableting machine Karl Seisakusho, KT-1 type 2
  • the number of tablets is 10
  • the tablet weight is 0.62 g
  • the Monsanto hardness is 3.5 to 5.
  • Tableting was performed with the compression pressure set to obtain a 50% Lf-containing agent.
  • the tablet was stored in a light-shielded desiccator (NRT-90B, manufactured by Nippon Rikagaku Kikai).
  • Example 7 Preparation of encapsulated Lf hydrolyzate
  • Lactose (manufactured by Wako Pure Chemical Industries) 60 g, corn starch (manufactured by Nisshin Seifun Co., Ltd.) 40 g, crystalline cellulose (manufactured by Wako Pure Chemical Industries) 40 g, and Lg hydrolyzate 60 g prepared by the same method as in Reference Example 1 was separated by a 50-mesh sieve (manufactured by Yamato Scientific Co., Ltd.), placed in a 0.5 mm-thick polyethylene bag, mixed by inversion, and the above powder was mixed using a fully automatic capsule filling machine (manufactured by Cesere Pedini; press type). Capsules (made by Elanco Japan, No. 1 gelatin capsule, Op.
  • Example 12 Capsule containing organic synthetic peptide
  • Example 14 Tablet Containing Peptide Derived from Apolactoferin Hydrolyzate
  • the cancer metastasis inhibitor of the present invention can be easily orally ingested as foods, pharmaceuticals and the like to suppress cancer metastasis.
  • the cancer metastasis inhibitor of the present invention contains Lf, a protein derived from milk as a food, a hydrolyzate of Lf or a peptide derived from Lf as an active ingredient. It is safe with no side effects. iH column table
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Cys.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Cys.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Gys.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Cys.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Gys Show.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Cys.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Cys.
  • Sequence characteristics the present peptide, and a peptide comprising the present peptide as a fragment.
  • R01 represents any amino acid residue except Cys.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • R01 represents any amino acid residue except Cys.
  • Sequence characteristics the present peptide and a peptide containing the present peptide as a fragment ( sequence:
  • Sequence characteristics the present peptide, and a peptide containing the present peptide as a fragment.
  • Sequence characteristics the present peptide and a peptide containing the present peptide as a fragment ( sequence:
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • Cys 2 and Cys 19 are disulfide bonded.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • Cys * indicates a cysteine in which the thiol group has been chemically modified to prevent the formation of disulfide bonds.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • Cys No. 2 and Cys No. 19 are disulphide yarns o ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • C * indicates a cysteine in which the thiol group has been chemically modified to prevent the formation of disulfide bonds.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • Gys 3 and Cys 20 are disulfide bonded.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • Cys # 16 and Cys # 33 are disulfide bonded.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • Cys No. 10 and Cys No. 27 are disulfide bonded.
  • Sequence features the present peptide and peptides containing the present peptide as fragments.
  • the peptide having the sequence length of 36 and having Cys at positions 9, 26, and 35 has a disulfide bond between Gys 9 and Cys 26, and the length of the sequence 36 No. 35 of the peptide has a Cys force of ⁇ , the sequence length is "M”, and the peptide having Cys at No. 10 has a disulfide bond with Cys at No. 10.
  • Sequence characteristics the present peptide, and a peptide comprising the present peptide as a fragment.
  • R01 represents any amino acid residue except Cys.

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Abstract

Inhibiteurs des métastases cancéreuses administrés par voie orale, qui contiennent comme principe actif une ou plusieurs substances choisies dans le groupe comprenant la lactoferrine saturée dépourvue de fer, les hydrolysats des lactoferrines, les dérivés et les sels pharmaceutiquement acceptables desdits hydrolysats, les peptides issus des hydrolysats de lactoferrines, ainsi que les dérivés et les sels pharmaceutiquement acceptables de ces peptides. Ces inhibiteurs des métastases cancéreuses, qui ont peu d'effets secondaires et peuvent être administrés par voie orale sur de longues durées, ont des effets inhibiteurs sur les métastases.
PCT/JP1997/002685 1996-08-15 1997-08-01 Inhibiteurs des metastases cancereuses administres par voie orale WO1998006424A1 (fr)

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JP8233652A JPH1059864A (ja) 1996-08-15 1996-08-15 経口がん転移抑制剤

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JP (1) JPH1059864A (fr)
WO (1) WO1998006424A1 (fr)

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WO2000001730A1 (fr) * 1998-07-06 2000-01-13 A+ Science Invest Ab Peptides reposant sur la sequence de la lactoferrine humaine et leur utilisation
WO2003082921A1 (fr) * 2002-04-03 2003-10-09 Fonterra Research Centre Limited Lactoferrine
WO2005089788A1 (fr) 2004-03-19 2005-09-29 Morinaga Milk Industry Co., Ltd. Médicament pour la thérapie de cancers
EP2421894A1 (fr) * 2009-04-24 2012-02-29 Westland Co-operative Dairy Company Limited Procédé de préparation d'une lactoferrine à faible teneur en fer

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EP1635766A4 (fr) 2003-06-06 2009-09-30 Agennix Inc Lactoferrine en tant qu'adjuvant de vaccins contre le cancer
US9115211B2 (en) * 2009-01-28 2015-08-25 Jean-Paul Perraudin Method for production of lactoferrin
JP2015067560A (ja) * 2013-09-27 2015-04-13 国立大学法人広島大学 ラクトフェリンを含有する癌転移抑制剤

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JPH07309771A (ja) * 1994-05-17 1995-11-28 Morinaga Milk Ind Co Ltd 非経口用抗腫瘍剤
JPH0873499A (ja) * 1994-09-01 1996-03-19 Snow Brand Milk Prod Co Ltd 新規ペプチドおよび免疫賦活剤
JPH08143468A (ja) * 1994-11-17 1996-06-04 Morinaga Milk Ind Co Ltd 抗潰瘍剤
JPH08151331A (ja) * 1994-09-30 1996-06-11 Snow Brand Milk Prod Co Ltd 骨強化剤

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JPH07309771A (ja) * 1994-05-17 1995-11-28 Morinaga Milk Ind Co Ltd 非経口用抗腫瘍剤
JPH0873499A (ja) * 1994-09-01 1996-03-19 Snow Brand Milk Prod Co Ltd 新規ペプチドおよび免疫賦活剤
JPH08151331A (ja) * 1994-09-30 1996-06-11 Snow Brand Milk Prod Co Ltd 骨強化剤
JPH08143468A (ja) * 1994-11-17 1996-06-04 Morinaga Milk Ind Co Ltd 抗潰瘍剤

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JPN. J. CANCER RES., Vol. 88, No. 2, (1997), pages 184-190. *
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010090162A (ja) * 1998-07-06 2010-04-22 Pharmasurgics In Sweden Ab 人ラクトフェリンの配列に基づくペプチドおよびその使用
WO2000001730A1 (fr) * 1998-07-06 2000-01-13 A+ Science Invest Ab Peptides reposant sur la sequence de la lactoferrine humaine et leur utilisation
US7253143B1 (en) 1998-07-06 2007-08-07 Pharmasurgics In Sweden Ab Peptides based on the sequence of human lactoferrin and their use
US7803757B2 (en) 1998-07-06 2010-09-28 Pharmasurgics In Sweden Ab Peptides based on the sequence of human lactoferrin and their use
WO2003082921A1 (fr) * 2002-04-03 2003-10-09 Fonterra Research Centre Limited Lactoferrine
US8703699B2 (en) 2002-04-03 2014-04-22 Auckland Uniservices Limited Lactoferrin
EP1726310A1 (fr) * 2004-03-19 2006-11-29 Morinaga Milk Industry Co., Ltd. Medicament pour la therapie de cancers
EP1726310A4 (fr) * 2004-03-19 2009-06-24 Morinaga Milk Industry Co Ltd Medicament pour la therapie de cancers
WO2005089788A1 (fr) 2004-03-19 2005-09-29 Morinaga Milk Industry Co., Ltd. Médicament pour la thérapie de cancers
EP2421894A1 (fr) * 2009-04-24 2012-02-29 Westland Co-operative Dairy Company Limited Procédé de préparation d'une lactoferrine à faible teneur en fer
EP2421894A4 (fr) * 2009-04-24 2013-07-24 Westland Co Operative Dairy Company Ltd Procédé de préparation d'une lactoferrine à faible teneur en fer
AU2010239795B2 (en) * 2009-04-24 2014-07-10 Westland Co-Operative Dairy Company Limited Method of preparing low-iron lactoferrin
US9359426B2 (en) 2009-04-24 2016-06-07 Westland Co-Operative Diary Company Limited Method of preparing low-iron lactoferrin

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